angiotensin and angiotensin-converting enzyme inhibitors

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7 Angiotensin and angiotensin-converting enzyme inhibitors BEREND METS EDWARD D. MILLER A greater knowledge of the physiology of the renin-angiotensin system (RAS) is becoming increasingly important as the role of this system in cardiovascular and body fluid homoeostasis, as well as its role in the pathogenesis of various disease states, is better appreciated. The intense interest in modulating this system using angiotensin-converting enzyme (ACE) inhibitors to control hypertension and cardiac failure has spawned the synthesis of many new agents, which are at various stages of clinical development (Salvetti, 1990). Anaesthetists will be increasingly called upon to care for patients using these drugs and need to appreciate the interaction of anaesthesia with the RAS as well as the effects of ACE inhibitor therapy on perioperative patient management. PHYSIOLOGY OF ANGIOTENSIN AND THE RAS The angiotensins Angiotensin, an oL2-globulin formed in the liver, is converted by renin into angiotensin I. Angiotensin I is a ten amino peptide (decapeptide), which although once thought to be inactive is now known to stimulate the CNS, to modulate peripheral sympathetic nervous activity and to stimulate the release of adrenal catecholamines in vitro (Peach, 1971; Buckley, 1972; Johnson et al, 1974). It seems likely, however, that these effects are immediately overshadowed by the conversion of angiotensin I to angio- tensin II by pulmonary ACE. This is because 95% of angiotensin I presented to the lung is converted in one circulation time (Oparil et al, 1971). The angiotensin II so formed has a short half-life (approximately 30 s) in the blood, but despite the longer half-life of renin (13 rain) (Christlieb et al, 1968) a constant stimulus for renin release is necessary to keep angiotensin concentrations in the blood elevated (Oates et al, 1974). Angiotensin II is converted to angiotensin III, a nonapeptide, by aminopeptidase A. Angiotensin III is a relatively weak pressor agent compared with angio- tensin II, retaining only 30% of its activity in humans (Khosla et al, 1974). BailliOre's Clinical Anaesthesiology-- 151 Vol. 8, No. 1, March 1994 Copyright 1994,byBailli6reTindall ISBN0-7020-1824-4 All rights ofreproductionin anyformreserved

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Page 1: Angiotensin and angiotensin-converting enzyme inhibitors

7

Angiotensin and angiotensin-converting enzyme inhibitors

BEREND METS EDWARD D. MILLER

A greater knowledge of the physiology of the renin-angiotensin system (RAS) is becoming increasingly important as the role of this system in cardiovascular and body fluid homoeostasis, as well as its role in the pathogenesis of various disease states, is better appreciated. The intense interest in modulating this system using angiotensin-converting enzyme (ACE) inhibitors to control hypertension and cardiac failure has spawned the synthesis of many new agents, which are at various stages of clinical development (Salvetti, 1990). Anaesthetists will be increasingly called upon to care for patients using these drugs and need to appreciate the interaction of anaesthesia with the RAS as well as the effects of ACE inhibitor therapy on perioperative patient management.

PHYSIOLOGY OF ANGIOTENSIN AND THE RAS

The angiotensins

Angiotensin, an oL2-globulin formed in the liver, is converted by renin into angiotensin I. Angiotensin I is a ten amino peptide (decapeptide), which although once thought to be inactive is now known to stimulate the CNS, to modulate peripheral sympathetic nervous activity and to stimulate the release of adrenal catecholamines in vitro (Peach, 1971; Buckley, 1972; Johnson et al, 1974). It seems likely, however, that these effects are immediately overshadowed by the conversion of angiotensin I to angio- tensin II by pulmonary ACE. This is because 95% of angiotensin I presented to the lung is converted in one circulation time (Oparil et al, 1971). The angiotensin II so formed has a short half-life (approximately 30 s) in the blood, but despite the longer half-life of renin (13 rain) (Christlieb et al, 1968) a constant stimulus for renin release is necessary to keep angiotensin concentrations in the blood elevated (Oates et al, 1974). Angiotensin II is converted to angiotensin III, a nonapeptide, by aminopeptidase A. Angiotensin III is a relatively weak pressor agent compared with angio- tensin II, retaining only 30% of its activity in humans (Khosla et al, 1974).

BailliOre's Clinical Anaesthesiology-- 151 Vol. 8, No. 1, March 1994 Copyright �9 1994, by Bailli6re Tindall ISBN 0-7020-1824-4 All rights of reproduction in any form reserved

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Angiotensin III, like angiotensin II, has steroidogenic potency; earlier studies suggested that it was equivalent to angiotensin II in its ability to stimulate aldosterone release; however, subsequent studies have indicated that it is less potent (Morton, 1993). Thus, in humans the importance of angiotensin III as a circulating hormone is minor (Morton, 1993).

At the current level of knowledge, angiotensin I! is the major mediator of the RAS and the active hormone most affected by the inhibition of ACE, thus its effects will be discussed in more detail.

Angiotensin II has multiple extrarenal actions, but considerable evidence indicates that the direct intrarenal actions play a dominant role in the long-term regulation of volume homeostasis and blood pressure. Two of its most important actions in this regard are constriction of efferent arterioles and probably a direct stimulatory effect on tubular sodium transport in the kidney (Hall and Hall, 1992). The exact mechanism by which angiotensin II directly controls sodium balance remains unclear (Hall and Brands, 1993); however, that it has an important role to play in this regard has been ascertained (Hall et al, 1980). Constriction of the efferent arterioles by angiotensin II tends to maintain the glomerular filtration rate (GFR) when renal blood flow becomes precarious, but blocking this effect with ACE inhibitors impairs GFR autoregulation (Kastner et al, 1984). Further, con- striction of these efferent arterioles provides a means for increasing tubular reabsorption by altering peritubular capillary forces, and by maintaining GFR allows excretion of metabolic waste especially when renal perfusion is impaired, as is found in severe renal artery stenosis and congestive cardiac failure (Hall and Brands, 1993).

Angiotensin II also has vasoconstrictor effects on preglomerular vessels. This vasoconstriction is offset by renal prostaglandins but may be unmasked by the administration of the prostaglandin synthesis inhibitor meclofenemate (Olsen et al, 1986).

It is now clear that angiotensin II has a direct effect on aldosterone secretion and that the non-diurnal variations in aldosterone secretion can be attributed primarily to fluctuations in angiotensin lI plasma levels (Brown et al, 1979). Angiotensin II (as well as angiotensin III) acts in the zona glomerulosa of the adrenal cortex, stimulating the conversion of stored cholesterol to pregnenolone as well as the conversion of corticosterone to aldosterone (Espiner and Nicholls, 1993). While angiotensin II remains the primary factor determining blood levels of aldosterone, other factors too may result in increased aldosterone secretion; adrenocorticotropic hormone, acting globally in stimulating all cortical adrenal hormones, also stimulates aldosterone release and probably accounts for the diurnal variation in its level (Richards et al, 1986). Plasma potassium concentration may also effect aldosterone synthesis: an increase provokes enhanced aldosterone formation while a reduction decreases this (Gill, 1985). By stimulating aldosterone production angiotensin II maintains plasma volume and plasma sodium and potassium levels within the physiological range. Aldosterone causes an exchange transport of sodium for potassium (and to a lesser extent hydrogen) in the tubular epithelium of both the collecting ducts and distal tubule of the kidney. (A similar mechanism is also operative in

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A N G I O T E N S I N A N D ACE INHIBITORS 153

sweat, salivary and gastrointestinal glands.) In this way aldosterone effects sodium conservation and potassium excretion.

The systemic physiological effects of angiotensin II are directed at increasing blood pressure, primarily through direct vasoconstriction. In this regard its immediate (fast) effects are well known; of increasing interest, however, is the slowly developing pressor effect of angiotensin II (Bean et al, 1979). The mechanisms for this are at present unclear. Angiotensin II also has the ability to inhibit the cardiac vagus (Kostis, 1988a) and to increase cardiac contractility and efferent sympathetic nervous system activity, as well as increase the release of noradrenaline and adrenaline (Peach et al, 1966; Scroop et al, 1971; Blumberg et al, 1975).

Angiotensin II has remarkable dipsogenic effects when injected directly into the cerebral ventricles (Severs and Daniel-Severs, 1973) and in addition stimulates specific sodium intake (Bryant et al, 1980), which is enhanced synergistically by systemically administered mineralocorticoids (Fluharty and Epstein, 1983).

Angiotensin II stimulates erythropoiesis (Fischer and Crook, 1962), which may explain the mild anaemia that has been described with the use of enalapril in humans (Griffing and Melby, 1982).

Angiotensin II also has trophic effects on vascular smooth muscle (Itoh et al, 1990) as well as cardiac muscle. The evidence suggests that endocrine as well as mechanical factors contribute to cardiac hypertrophy (Morgan and Baker, 1991). There is evidence that this cardiac hypertrophy can be inhibited or may regress upon treatment with ACE inhibition, while this may not occur with the use of pure vasodilators (Pfeffer et al, 1982). It is also clear that experimental infusion of high doses of either renin or angiotensin II can cause arterial fibrinoid necrosis, as well as myocardial necrosis and acute renal failure. This occurs, however, only when there is a concurrent rise in arterial pressure and workload (Garvas and Garvas, 1993). It is possible that this may also occur clinically with high endogenous levels of angiotensin II.

Vasopressin release by the posterior pituitary is dependent on changes in plasma osmolality sensed by the organum vasculosum of the lamina terminalis in the brain (Thrasher and Keil, 1987). However, vasopressin (arginine-vasopressin, formerly antidiuretic hormone) may also be under the control of the RAS through a direct action of angiotensin II. To demonstrate this, Brooks and colleagues (1986) infused angiotensin II into conscious dogs and noted a rise in the plasma vasopressin concentration accompanied by a rise in arterial pressure. As an increase in arterial pressure inhibits vasopressin release per se, they infused sodium nitroprusside to normalize this and demonstrated a further rise in the level of vasopressin.

Renin release and elimination

Renin, a proteolytic enzyme and the prime activator of the RAS, is secreted by cells associated with the juxtaglomerular apparatus of the kidney. Renin release from these cells is increased by: (a) stimulation of the sympathetic nervous system, probably via direct renal nerve stimulation (Vander, 1965)

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154 B. METS A N D E. D. MILLER

and circulating catecholamines, mediated through the [31-receptor (Churchill et al, 1983). Recent evidence suggests that o~-adrenergic stimu- lation also increases plasma renin activity (Blair et al, 1986); (b) a decrease in baroreceptor stimulation of juxtaglomerular cells in the walls of the afferent arterioles caused by a decrease in renal perfusion pressure (Blaine et al, 1971); (c) a decrease in right atrial pressure (Broshnihan and Bravo, 1978), probably mediated through inhibition of vagal afferents to the kidney (Mancia et al, 1975); and (d) a decrease in filtered tubular sodium delivery to the macula densa (Vander, 1967).

The release of renin may be decreased by: (a) atrial natriuretic factor; (b) angiotensin II; or (c) vasopressin (Davis and Freeman, 1976). The juxta- glomerular cells in the kidney thus receive a barrage of information which is integrated into a single renin release response elevating renin and so angiotensin II which in turn feeds back to inhibit further renin release.

Tissue RAS

Traditionally the RAS was viewed as a humoral endocrine system. Recently, however, it has been proposed that in addition the RAS is present in many local tissues (Campbell, 1987; Williams, 1988) and that the major site of angiotensin I and II production is in fact the peripheral tissues (Campbell, 1987). These systems may thus exert autocrine and paracrine influences on local tissue functions. This theory is supported by the demon- stration of renin-like enzymatic activity, renin substrate, ACE as well as angiotensins and angiotensin receptors in multiple tissues including the heart, kidney, blood vessels, placenta and brain (Dzau, 1988). Of particular importance is the notion that the effects of ACE inhibition may not only be the result of pertubation of the systemic RAS but are very likely to be due to local tissue effects as well (Dzau, 1987). This new line of exploration suggests that the RAS is more complex than previously thought and that further research into its production and metabolism is required (Campbell, 1987).

Integration of the RAS

Under ordinary circumstances the rate-limiting component of the RAS is renin (Kostis, 1988a), which is thus the principal regulator of the system (Gill, 1985). The system is integrated primarily to maintain intravascular and extracellular fluid volume as well as electrolyte (sodium and potassium) status. Feedback mechanisms thus exist to diminish renin release when homoeostasis is achieved. Hence, renin release is stimulated by factors indicating a decrease in intravascular volume such as decreased right atrial pressure or renal baroreceptor stimulation, or by activation of the sympa- thetic system, in response to the threat to homoeostasis. In addition, a decrease in renally filtered sodium will enhance renin release. In turn, renin release is inhibited directly by angiotensin II, as well as by the effects of angiotensin II in increasing intravascular volume and renal perfusion pressure (through renal afferent and systemic vasoconstriction, augmen-

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tation of the sympathetic system, vasopressin and erythropoietin secretion and by further enhancing vascular volume through the effect of angiotensin II on stimulating drinking as well as specific sodium intake). These angio- tensin II induced effects dampen sympathetic and baroreceptor stimulation. Renin secretion is also inhibited directly by atrial natriuretic factor and vasopressin. Aldosterone is released primarily by angiotensin II but also independently of renin in response to plasma potassium increases, while its diurnal variation depends on secretion of adrenocorticotrophic hormone.

ANTAGONISM OF THE RAS

The RAS can be blocked at various levels. The release of renin can be inhibited using [3-blockers or central oL-antagonists. Renin can be inhibited by using specific antibodies or inhibitory peptides, while the effect of angiotensin II can be competitively inhibited by saralasin. The effects of aldosterone can be antagonized by the use of spirinolactone, and its synthesis resulting from the effect of angiotensin II can be inhibited by decreasing angiotensin II formation by the action of ACE inhibitors (Kostis, 1988a).

ACE INHIBITORS

Physiology of ACE and its inhibition

ACE is a peptidase that is activated by chloride ions (Skidgel and Gerdos, 1993). ACE is present in both a tissue-bound and a soluble form throughout the body of humans, and in all mamalian species tested so far. It is a zinc metalloenzyme with a molecular weight of 140-170000Da. Chelating agents and sulphhydryl compounds inhibit ACE by complexing the active zinc site. ACE does not simply convert angiotensin I to angiotensin II, but affects numerous other hormonal systems (Williams, 1988; Skidgel and Gerdos, 1993). One of these systems, the formation and inactivation of bradykinin, is now realized to be of importance in understanding the mechanism of action of therapeutic ACE inhibitors (Skidgel and Gerdos, 1993). Prekallikrein is converted to kallikrein, which in turn converts the substrate, kininogen, to the physiologically active bradykinin (Figure 1). Bradykinin causes vasodilatation, bronchoconstriction, afferent vagal fibre stimulation (Skidgel and Gerdos, 1993) and histamine release, as well as increased vascular permeability (Kostis, 1988a), and is inactivated by at least two kininases, I and II. Kininase II is identical to ACE. Bradykinin can also increase the rate of conversion of arachidonic acid to prostaglandins with vasodilator action. Thus, theoretically, the administration of an ACE inhibitor should result in a decrease in angiotensin II (vasoconstriction) and an increase in vasodilatory bradykinin and prostaglandin concentrations (Skidgel and Gerdos, 1993). However, although the decrease in plasma levels of angiotensin II (and increase in renin and angiotensin I levels) after

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156 B. METS AND E. D. MILLER

Activated Factor Xll Kininogen

Prekallikroin_ I ,. Kallikrein ~ t

Arachidonic Acid Bradykinin

Angiotensinogen

Angiotensin I

~ f Kininase~ll~E~EnnVemrteing Y

+ E C F

+Sodium

/ Aldosterone

Figure 1. Relationship of the renin-angiotensin-aldosterone system to bradykinin and prosta- glandin production. These interactions may occur in the circulation but are more likely in tissue, except for the effect of angiotensin II on aldosterone secretion. ECF, extracellular fluid. From Williams (1988), with permission.

ACE inhibitor administration has been documented, the effect of ACE inhibition on bradykinin degradation and prostaglandin formation has been controversial, probably because this effect is more likely to occur at the tissue than the systemic level (Dzau, 1987; Skidgel and Gerdos, 1993). Plasma levels of both bradykinin (Heel et al, 1980) and prostaglandins (Swartz et al, 1980) have been found to be elevated following administration of the ACE inhibitor, captopril. Nevertheless, it appears that the long-term effects of ACE inhibition on blood pressure are a result of tissue enzyme inhibition. This is supported by the fact that there is a poor correlation between pretreatment plasma renin levels and the antihypertensive efficacy of these agents (Dzau, 1987), as well as a poor correlation between inhibition of plasma ACE activity and the hypotensive response (Dzau, 1987; Williams, 1988). Further support for this hypothesis is that ACE inhibitors reduce the activity of ACE and angiotensin II concentration in the vascular wall of arteries and veins, and also in the heart, lung, kidney and brain (Kostis, 1988a).

Vascular effects of ACE inhibition

ACE inhibition in normal subjects or in hypertensive individuals who do not have left ventricular failure results in a decrease in blood pressure through a decrease in systemic vascular resistance without resulting in a significant change in cardiac output. However, in patients with cardiac failure, an increase in cardiac output may be seen with an improvement in left ventricular function. Despite inducing a decrease in blood pressure, ACE

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ANGIOTENSIN AND ACE INHIBITORS

Table 1. Predominant haemodynamic and hormonal effects of converting enzyme inhibition.

157

Haemodynamic parameter

Patients with

Hypertension Heart failure

Blood pressure (systolic, diastolic) $ --* ~, Systemic vascular resistance $ ,L Heart rate --. ~ Stroke volume ~ 1' Cardiac output ~ 1' Ejection fraction ~ 1' Pulmonary capillary wedge pressure ~ Right atrial pressure ~ Renal blood flow ~ 1' --~ 1' Renal vascular resistance --~ $ --~ Glomerular filtration rate ~ ~ 1' $ Forearm blood flow 1' 1' Capacitance and distensibility of large vessels 1' 1' Cerebral blood flow ~ 1' * --~ 1' Coronary blood flow ~ $ ~ $ Exercise capacity I' Angiotensin II ~ Angiotensin I 1' 1" Renin 1' '~ Aldosterone 1" ~ Converting enzyme activity $ Kinin levels ~' ~ I' Plasma noradrenaline ~ ~ Prostaglandins (urinary) ~ 1' ~ I'

1", Increase; $, decrease; ~ , unchanged. * Autoregulation due to decreased double products. Modified from Kostis (1988a), with permission.

inhibitors increase renal p lasma flow and decrease renal vascular resistance wi thout marked changes in the G F R (Kostis, 1988a) (Table 1). In patients with bilateral renal arterial stenosis, acute renal failure has, however , been repor ted (Hricik et al, 1983). This may be because the R A S plays a critical role in mediat ing efferent (postglomerular) capillary vasoconstr ict ion, and g lomerular capillary pressure is de te rmined by the balance be tween afferent (preglomerular) and efferent vascular tone. U n d e r circumstances where renal perfus ion is substantially diminished, efferent arteriolar constr ict ion serves to maintain an effective filtration pressure and G F R which might be conte rac ted by A C E inhibition (Hricik et al, 1983).

The vasodi la tory propert ies of A C E inhibitors do not affect all vascular beds equally. Thus renal, splenic and hepatic b lood flow is m o r e affected than skeletal muscle or brain vascular beds (Kostis, 1988a). The A C E inhibi tor- induced decrease in systemic vascular resistance as a result of this vasodi latat ion is not accompanied by a reflex increase in hear t rate. This is p robab ly due to modificat ion of parasympathe t ic activity th rough angio- tensin I I wi thdrawal (Ajayi et al, 1985) and an effect of these drugs in resett ing the ba ro recep to r sensitivity downwards (Guidicelli et al, 1985).

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1 5 8 B. METS AND E. D. MILLER

Cardiac effects of ACE inhibition

ACE inhibitors are increasingly used in the long-term treatment of cardiac failure (Consensus Trial Study Group, 1987; SOLVD investigators, 1991). The rational for this is based, first, on the fact that they are vasoditators and so break the vicious circle that occurs in this condition. In this circle of cardiac failure, depressed cardiac output triggers compensatory responses that increase systemic vascular resistance and in so doing further depresses cardiac performance. The decreased renal peffusion associated with cardiac failure also results in activation of the RAS and angiotensin II secretion, which further worsens the situation because of vasoconstriction, thus increasing cardiac work, and aldosterone secretion, resulting in further sodium and fluid retention. Thus, the second rationale for the use of ACE inhibitors in chronic cardiac failure is their propensity to block the effects of RAS activation (Kostis, 1988b). In this regard the addition of enalapril to conventional therapy for severe congestive cardiac failure has been found to reduce mortality and improve symptoms (Consensus Trial Study Group, 1987). The SOLVD investigators (1991) confirmed the effectiveness of enalapril in reducing the mortality rate in a large group of patients with reduced left ventricular ejection fractions and congestive heart failure. In addition, they showed that this therapy decreased the need for hospital- ization of patients.

ACE inhibitors may have 'cardioprotective' effects and may be of use in managing patients with myocardial infarction. Experimentally, ACE inhibitors have been used to reduce infarct size in the dog after coronary occlusion (Ertl et al, 1982), while captopril may be useful in attenuating ventricular enlargement associated with anterior myocardial infarction (Pfeffer et al, 1988).

It is clear that angiotensin II has both direct and indirect actions on cardiac tissue (Morgan and Baker, 1991). Angiotensin II may directly accelerate protein synthesis, resulting in cardiac hypertrophy (Lindpaintner and Ganten, 1991). There is now experimental evidence that the administration of an ACE inhibitor may not only prevent this but may also cause regression of established left ventricular hypertrophy (Pfeffer et al, 1982; Lindpaintner and Ganten, 1991).

Additional effects of ACE inhibition

While experimental models indicate that ACE inhibition may influence diabetic nephropathy favourably, in diabetic humans it has been established that there is a reduction in renal albumin-protein secretion which cannot be adequately explained by a decrease in the ACE inhibitor-induced GFR or blood pressure (Kalil et al, 1993).

Experimentally, it has been shown that rapid recovery following moderate haemorrhage is due to a complex response in which the renin- angiotensin, vasopressin and sympathetic nervous systems are all essential components (Zerbe et al, 1981). In anaesthetized rats, it was shown that spontaneous recovery of blood pressure was almost completely blocked by

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captopril following haemorrhage (Zerbe et al, 1981). This effect of ACE inhibition has also been confirmed in dogs (Yamashita et al, 1977) and would have important implications in patients subjected to surgery where signifi- cant blood loss is anticipated.

A recent study indicated that exercising patients treated with captopril had higher plasma [3-endorphin levels than those receiving placebo. This is probably because this ACE inhibitor decreases the metabolism of [3- endorphins by inhibiting peptidyl dipeptidase. The investigators postulated that this may explain the improved physiological state, determined using quality-of-life questionnaires, in the captopril-treated group (Handa et al, 1991).

While there are many evolving indications, both diagnostic (for primary aldosteronism, renovascular hypertension) and therapeutic (pulmonary hypertension, aortic insufficiency, subarachnoid haemorrhage, idiopathic oedema) for the use of ACE inhibitors (Kostis, 1988b) beyond the treatment of hypertension and cardiac failure (for which the agents are currently approved), most remain experimental and are beyond the scope of this chapter.

Adverse effects of ACE inhibition

Although side-effects occur with ACE inhibition, one of the reasons for their increasing popularity, especially in hypertension, is their efficacy and scant profile of common side-effects when compared to conventional anti- hypertensive agents (Mirenda and Grissom, 1991). Furthermore, the rebound hypertension after discontinuation of clonidine has not been described with ACE inhibition (Mirenda and Grissom, 1991).

The longer the duration of action of converting enzyme inhibitors, the more frequent and severe their side-effects (Williams, 1988). There are four important side-effects: hypotension, renal haemodynamic dysfunction, coughing and angio-oedema. In addition, hyperkalaemia, taste disturb- ances, neutropenia, skin rash and the nephrotic syndrome have been reported (Williams, 1988). These adverse effects can be divided into two categories--those assumed to be related to the sulphhydryl moiety (skin rashes, taste disturbance, neutropenia and proteinuria) and those associated with ACE inhibition (hypotension, renal insufficiency, hyperkalaemia, cough and angio-oedema) (Editorial, 1988).

Hypotension is more likely in sodium-depleted patients with elevated plasma renin activity, in whom large initial doses are used, as well as in patients who are intravascularly depleted following diuretic therapy for cardiac failure (DiBianco, 1986; Kostis, 1988b). In addition to this, high pretreatment arterial blood pressure may also be a risk factor (Hodsman et al, 1983).

Renal dysfunction is of concern in bilateral renal artery stenosis or renal artery stenosis in a patient with a solitary kidney (Hricik et al, 1983) as renal insufficiency may be induced by elimination of the vasoconstrictive effect of angiotensin II in maintaining efferent arterial tone with a resultant fall in the GFR (Kostis, 1988a). Proteinuria in association with ACE inhibition rarely

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160 B. METS A N D E. D. MILLER

occurs in patients with severe hypertension, and in general the treatment of essential hypertension using these agents does not promote renal insuffi- ciency but rather improvement (DiBianco, 1986). However, monitoring of renal function in patients receiving ACE inhibitors is mandatory (Brecken- bridge, 1988). (The debate as to the advisability or otherwise of the use of ACE inhibitors in renovascular hypertension is beyond the scope of this chapter, but see Menard et al (1993) and Hollenberg (1993).) Angio- oedema is the most serious cutaneous response to ACE inhibitors. Fortu- nately, this complication is rare (0.1%) but if angioneurotic oedema of the larynx occurs,.it could be fatal (Slater et al, 1988).

ACE inhibition is accompanied by a small increase in the plasma concen- tration of potassium (0.1-0.2mmol/1), probably due to inhibition of angiotensin II-mediated aldosterone secretion (DiBianco, 1986). However, hyperkalaemia may occur with potassium supplementation or with potassium-sparing diuretics, as well as when ACE inhibitors are used in the setting of diabetes mellitus, heart failure or when non-steroidal anti- inflammatory agents are administered (Williams, 1988).

These drugs are not known to have adverse metabolic, hepatic, CNS or gastrointestinal effects. They are, however, contraindicated in pregnancy as their use is associated with neonatal limb defects and renal failure (Lubbe, 1990).

Drug interactions

The concomitant use of ACE inhibitors with prostaglandin synthetase inhibitors may counteract the antihypertensive and peripheral vasodilating effects of ACE inhibitors (DiBianco, 1986) and may result in hyperkalaemia (Williams, 1988) as well as nephrotoxicity (Seelig et al, 1990).

Decreased renal clearance of digoxin with an increase in the serum digoxin level has been demonstrated in patients receiving captopril (Cleland et al, 1986) but not in those receiving enalapril (Douze-Blazy et al, 1986). However, while serum digoxin and potassium levels should be monitored when captopril therapy is initiated in patients with heart failure, a routine reduction in digoxin dose seems not to be necessary (Cleland et al, 1986).

When hypertension is treated with diuretics, the RAS is activated. This tends to decrease the therapeutic efficiency of diuretic therapy and thus it may be appropriate to add an ACE inhibitor. The combination of a potassium- sparing diuretic (amiloride, triamterene or spirinolactone) with an ACE inhibitor is, however, not appropriate for fear of inducing hyperkalaemia, which may be severe if there is renal impairment or occult renal artery disease (Hansson et al, 1993). In the setting of renal arterial stenosis the detrimental renal effects of ACE inhibition may be exacerbated by combined therapy with a diuretic agent (Watson et al, 1983). Captopril has been shown to have short-lasting analgesic effects and to potentiate metenkephalin-induced analgesia in mice, probably by inhibiting an enzyme, or enzymes, responsible for the metabolism of intracerebroventricularly administered metenkephalin (Stine et al, 1980).

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ACE Inhibitors

Since the in t roduc t ion of captopri l into clinical practice in 1980 a n u m b e r of A C E inhibi tors are now available and m a n y more are at var ious stages of deve lopmen t (Salvetti , 1990). This review will, however , be l imited to the three drugs in this group in c o m m o n clinical usage, namely captopri l , enalapr i l and l isinopril (Table 2).

A few impor t an t dist inct ions can be made be tween these agents with respect to chemical s t ructure, potency, disposi t ion, side-effects and drug in terac t ions (Kostis, 1988b); however , as they all work at the same enzyme wi thout k n o w n subtypes, there are no repor ted differences in their mech- an ism of act ion (Will iams, 1988). Of impor t ance is the presence or absence of a sulphhydryl group. As a strong zinc l igand, this group may enhance the po tency of A C E inhibi tors but has been impl icated in some side-effects (see above) . Fur ther , this group may enhance the oxidat ion of captopri l (50%), which may explain the shorter dura t ion of its act ion when compared with

Table 2. Properties of marketed angiotensin-converting enzyme (ACE) inhibitors.

ACE inhibitor Captopril Enalapril Lisinopril

Zinc ligand Sulphhydryl (SH) Carboxyl (COOH) Carboxyl (COOH) Pro-drug No Yes No Oral absorption (%) 75 60 30 Cmax (ng/ml) 800 (x D = 100 mg) 120 (D = 10 mg) 100 (D = 10 mg) Tm.x (h) 0.8 1.4" 7 Bioavailability (%) 70 40* 25 AUC (ng x h/ml) 1150 1400" 1500 Terminal half-life (h) 2 > 30*? > 30? Accumulation half-life (h) 2 11" 12.6 Onset of action (h) 0.5-1 1-2" 2-4 Duration of action (h) 3-4 12-24" 24 Elimination Renal Renal Renal Renal clearance 388 (ngkg-lh -1) 300 (150 ml/min) 100 (ml/min) Po tency (Ki) 1.7 X 10 -7 2 x 10 -1~ 1 x 10 -1~ Potency ICs0 2.6 x 10 a 2.4 x 10 7. 1.7 x 10 .9

(22M x 109) (4.5 M X 109) * (4.5 M X 109) Metabolism Oxidation (50%) n.s. (<6%) n.s. (>3%) Protein binding (%) 30 50 n.s.:~ Dosage for hypertension 25-50 b.i.d, or 10-40 mg (1 or 2 20-40 mg daily

t.i.d, doses daily) (one dose) Usual starting dose when 6.25 mg t.i.d. 2.5 mg 5 mg

patient on diuretics Formulation 12.5, 25, 50, 5, 10, 20mg 5, 10, 20mg

100 mg tablets tablets tablets

D, dosage; AUC, area under the plasma concentration time curve; ICs0, inhibitory concentra- tion 50%; n.s., not significant. * Enalaprilat is the diacid active compound. ? Concentration versus time relationship is polyphasic, with a prolonged terminal phase that may be due to binding of the inhibitor on ACE. ~+ Binds only to ACE. Cmax = maximum concentration; Tm~, = time to maximum concentration. From Kostis (1988a), with permission.

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162 B. METS A N D E. D. MILLER

that of enalaprilat and lisinopril, which have carboxy zinc ligands and undergo little or no metabolism (< 6%) (Kostis, 1988a).

Captopril is well absorbed after oral administration (75%), and is 30% protein bound in plasma (Romankiewicz et al, 1983). Its terminal half-life is 2 h. Following metabolism, unchanged captopril (35%) and its metabolites are eliminated in the urine (Romankiewicz et al, 1983).

Enalapril is administered orally as a pro-drug to enhance absorption (60%) (Todd and Heel, 1986). It is metabolized in the liver to the active (diacid) compound, enalaprilat, which is 50% bound in plasma. Its terminal half-life is > 30 h (Kostis, 1988a). (As for lisinopril, the concentration versus time relationship of enalaprilat is polyphasic, with a prolonged terminal phase (Ulm et al, 1982) that may be due to the binding of the ACE inhibitor to ACE (Todd and Heel, 1986).) Enalapril is also available as the diacid enalaprilat for direct intravenous administration (DiPette et al, 1985). Enalaprilat is eliminated unchanged by the kidney.

Lisinopril is less well absorbed (25-50%) (Todd and Heel, 1986) after oral administration and is not significantly bound to proteins, binding only to ACE (Kostis, 1988a). Its terminal half-life is approximately 30 h (Ulm et al, 1982) and 30% is eliminated unchanged in urine and 70% in faeces (Williams, 1988). As elimination of these three ACE inhibitors is closely related to renal function there is an increased potential for adverse effects in patients with renal impairment, including elderly individuals and those with heart failure (Editorial, 1988).

In general, new drug development of ACE inhibitors has focused on changes in the zinc-binding ligand, and increased bioavailability and prolongation of action (Salvetti, 1990); however, not all are agreed that the plethora of ACE inhibitors waiting in the wings are likely to have any major advantages (Editorial, 1988). The important question that remains is whether there is any real advantage of the use of one ACE inhibitor over another, justifying it a niche in the therapeutic armementarium. A recent paper comparing treatment of hypertension in men with captopril or enalapril found that they were indistinguishable according to clinical assess- ment of efficacy and safety but had different effects on quality of life (Testa et al, 1993). This is an intriguing finding and has been postulated to be due to differences in distribution of the two drugs with respect to access to the CNS (Oparil, 1993).

ANAESTHESIA

Anaesthesia, surgery and the RAS

Perioperative challenges to the patient, through surgical stimulation, dehydration and blood loss, will activate the RAS (Miller, 1980). However, what is the role of the administration of anaesthesia per se? The first study to examine this question used rats anaesthetized with halothane, fluroxene or ketamine, administered at equipotent anaesthetic doses (Miller et al, 1978). No surgery was performed and control measurements were made in the

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ANGIOTENSIN AND ACE INttlBITORS 163

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Figure 2. (a) Decrease in mean arterial pressure after i h of stable anaesthesia with ketamine, halothane or fluroxene as compared to the awake state in rats. (b) Plasma renin activity in rats when awake or during stable anaesthesia. No significant increase occurred despite significant decreases in blood pressure. (c) Blood pressure response to the angiotensin II receptor antagonist , saralasin. A significant decrease in pressure was seen in animals anaesthet ized with halothane. This response was not predicted by the measu remen t of plasma renin activity. Resul ts are mean + SEM. From Miller (1993), with permission.

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164 B. METS A N D E. D. MILLER

awake state prior to anaesthesia. The important finding was that, despite a significant decrease in mean arterial pressure during anaesthesia, there was no significant rise in plasma renin activity. However, when saralasin, a competitive angiotensin II receptor antagonist, was infused, a 20 mm Hg decrease in blood pressure occurred in animals anaesthetized with halothane but not in those given ketamine or fluroxene (agents both known to support arterial blood pressure) (Figure 2). Thus, it was concluded that the anaes- thetic agents studied did not activate the RAS p e r se. Further, this study indicated that the RAS was important in maintaining blood pressure under anaesthesia, as angiotensin II inhibition unmasked the hypotensive effect of halothane. The importance in this respect of the RAS has been confirmed in patients for isoflurane and halothane anaesthesia (Kataja et al, 1988). In addition, it has been shown that, in humans, ketamine administration while increasing arterial blood pressure does not increase plasma renin activity (Miller et al, 1975). Thus, it appears that anaesthesia p e r se (with the agents mentioned) does not activate the RAS.

What, then, of the effects of anaesthetic agents on ACE activity. Miller and co-workers examined the influence of anaesthetic agents on ACE activity and found that this enzyme did not appear to be inhibited by halothane both in vitro and in vivo (Miller et al, 1979a).

Involvement of the RAS in perioperative hypertension remains contro- versial. It is, however, likely that perioperative hypertension is multi- factorial in origin, with additional factors such as volume status, depth of anaesthesia and degree of sympathetic stimulation being of importance (Miller et al, 1979a,b). There is increasing evidence that RAS activation may contribute to hypertension associated with surgery involving cardio- pulmonary bypass (Roberts et al, 1977).

During deliberate hypotension using sodium nitroprusside, activation of the RAS occurs (Miller et al, 1977). One of the sequelae of deliberate hypotension is rebound hypertension, which can be prevented by inhibition of the RAS (Delaney and Miller, 1980). Monitoring of the blood pressure alone, however, does not adequately describe the importance of the RAS with respect to distributional changes of blood flow during deliberate hypotension. To evaluate this further, arterial blood pressure was reduced to a similar degree in rats using either sodium nitroprusside or saralasin (Miller and Delaney, 1981). Using microspheres, blood flow to various organ beds was then determined, indicating that at similar levels of arterial pressure renal blood flow was markedly reduced by sodium nitroprusside but not by saralasin. The decrease in renal blood flow induced by sodium nitroprusside was reversed by the addition of saralasin, indicating that distribution of renal blood flow under these circumstances was under the control of the RAS.

In vascular surgery, cross-clamping of the aorta is associated with characteristic haemodynamic changes. Renal blood flow, and more specific- ally cortical renal blood flow, is decreased and may remain low for some time after release of the cross-clamp (Clark and Stanley, 1990). It has been proposed that these haemodynamic responses may relate to activation of the RAS. Experimental data indicate that, when the thoracic aorta is clamped in

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dogs, plasma renin activity is elevated both during and after the clamp is released. After 60 min of aortic cross-clamping, renal cortical blood flow had returned to base-line values in animals treated with enalaprilat but not in control dogs or in those receiving saralasin (Joob et al, 1986). It appears from this study that the level of blood pressure is not as important as is the distribution of the blood flow with a particular arterial pressure. In patients undergoing infrarenal cross-clamping, a single oral dose of 25 mg captopril was given prior to induction of anaesthesia (Kataja et al, 1989). When compared with values in control patients, the urine output was almost twice as high in the captopril-treated group and remained almost twice as high for the first 24 h after operation. Whether the improved urine output was due to a renoprotective effect of captopril, or to the additional volume replacement that was required to maintain cardiovascular stability in the captopril- treated patients, is unclear from this trial.

ACE inhibitors and anaesthesia

Therapy with ACE inhibitors may either have been established before operation, or might be considered by the anaesthetist for the management of hypertension occurring during or after surgery.

Preoperative ACE inhibition

Given the interest in, and use of, ACE inhibitors for the management of both hypertension as well as cardiac failure, anaesthetists will increasingly be called on to anaesthetize patients using these drugs before surgery. There are a number of reports associating preoperative therapy with these agents and severe intractable intraoperative hypotension after induction of anaesthesia (McConachie and Healy, 1989; Selby et al, 1989). The fact that the RAS appears to play a role in maintaining arterial blood pressure under anaesthesia may explain this (Miller et al, 1978). Jensen et al (1989) demonstrated that acute preoperative treatment with oral captopril (lmg/kg), when compared with metroprolol (0.07mg/kg) given intra- venously at induction, resulted in lower cerebral blood flow (corrected for carbon dioxide concentration) in the captopril group but did not show adverse outcome associated with this. This finding prompted these authors to suggest that ACE inhibition therapy should be stopped prior to anaes- thesia. Colson et al (1992) studied the haemodynamic effects of induction of anaesthesia in a more representative population of hypertensive patients treated chronically with ACE inhibitors compared with patients on alterna- tive antihypertensive therapy. They noted that the incidence of hypotension may be high during induction of anaesthesia in patients treated with ACE inhibitors, but that this was easily treated with the administration of intra- venous crystalloids and moderate doses of phenylephrine.

The role of the RAS in defence against blood loss would also appear to merit consideration when deciding whether ACE inhibitor therapy should be stopped before operation, as it appears that hypotension due to severe blood loss during surgery may be more difficult to combat when patients

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1 6 6 B. METS AND E. D. MILLER

have received preoperative ACE inhibitors (Yamashita et al, 1977; Zerbe et al, 1981).

The recommendation of withholding ACE inhibitor therapy prior to anaesthesia would depart from the usual recommendation to maintain all antihypertensive therapy in order to minimize haemodynamic instability associated with surgical anaesthesia in hypertensive patients. It has been shown, however, that in the short term cardiac performance and electrolyte balance are not affected adversely by the withdrawal of captopril used in the therapy of cardiac failure (Maslowski et al, 1981), and that discontinuation of ACE inhibition does not result in rebound hypertension, as found with clonidine withdrawal (Mirenda and Grissom, 1991). No clear guidelines regarding the cessation of preoperative ACE inhibitor therapy can be given with the present level of knowledge; however, this may well be considered acceptable therapy, especially where major blood loss is likely (Mirenda and Grissom, 1991).

Intraoperative ACE inhibition

ACE inhibitor therapy has been used in an attempt to control the haemo- dynamic response to intubation and might be considered for hypertension associated with surgical anaesthesia.

Yates and Hunter (1988) found that preoperative oral administration of enalapril (5 mg), 4h before induction of anaesthesia blunted the hyper- tensive response to intubation but had no detrimental effects on haemo- dynamic parameters, when compared with placebo, for the duration of the operative anaesthesia. McCarthy et al (1990) studied the effect of sublingual captopril (12.5 mg and 25 mg) on haemodynamics 25 min before tracheal intubation. They found that both doses of captopril resulted in a significant reduction in the pressor response to intubation but did not affect heart rate changes when compared with placebo. They observed that untoward hypotension occurred in the treatment groups. Murphy et al (1989) found that the intravenous administration of enalaprilat 17 rain before induction acted as an hypotensive agent and could not have been regarded as reducing the pressor response to intubation. They noted one patient who received l mg enalaprilat intravenously and whose preinduction mean arterial pressure of 90 mm Hg fell to 40 mm Hg after induction of anaesthesia. Many agents have been advocated to obtund the hypertensive response to intubation (Heffman et al, 1991). It would appear that ACE inhibitors do not have any specific advantages in this regard and may be associated with unpredictable severe haemodynamic decompensation.

The advent of intravenous enalaprilat offers the opportunity to use this drug to combat perioperative hypertension. However, potential drawbacks of the use of this agent in the perioperative setting must be considered. During surgical anaesthesia, the ideal agent for control of raised blood pressure would have a rapid predictable onset, allow titration to effect and have a rapid offset of action or reversibility should the need arise. Intra- venous enalaprilat has been used in the therapy of hypertensive crisis, not associated with anaesthesia, in a study employing a regimen of enalaprilat

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ANGIOTENSIN AND ACE INHIBITORS 167

1 mg intravenously, followed by 10 mg intravenously 30 min later and then 40 mg intravenously 30 min later if required (DiPette et al, 1985). In the seven patients studied, the maximum effect on arterial pressure was observed 15 min after the 1-mg dose and 30 min after the 10-mg dose. Five patients received the 40-mg dose without further effect. The heart rate did not change as a result of this therapy. Three of the seven patients did not respond with a significant decrease in blood pressure to this dosage regimen. One patient returned to normotensive levels within minutes of receiving the 1-mg dose. The terminal half-life of enalapril is estimated to be 35 h (Ulm et al, 1982). Thus, enalaprilat, administered intravenously, does not meet any of the criteria for an ideal antihypertensive to use during anaesthesia. Further, as it is clear that the use of ACE inhibitors in association with anaesthesia and blood loss may on occasion lead to severe haemodynamic instability (Murphy et al, 1989; McCarthy et al, 1990), further studies may need to be performed to elucidate the place of intravenous ACE inhibitors in the treatment of intraoperative hypertension. Until such time, these agents should probably be held in reserve for this purpose.

However, the increased use of deliberate hypotension during surgery to

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168 B. METS A N D E. D. MILLER

decrease blood loss can be greatly facilitated by the use of ACE inhibitors. Woodside and colleagues (1984) studied 12 patients undergoing spinal fusion. Six patients received captopril (3 mg/kg), orally 1 h before surgery. After the induction of anaesthesia, arterial blood pressure was decreased to 60mmHg with sodium nitroprusside in both groups. Significantly less sodium nitroprusside was needed to achieve similar target arterial blood pressures in the captopril-treated group compared with the control group, and so the whole-blood cyanide concentration was significantly lower in patients receiving captopril (Figure 3). Similar effects should be able to be achieved using intravenous ACE inhibitors.

Postoperative ACE inhibition

There appear to be no reports on the postoperative use of ACE inhibitors. One study, however, compared the efficacy of oral and sublingual captopril (25 rag) with sublingual nifedipine in patients with essential hypertension. This study established the efficacy of captopril in this regard, the effect lasting for approximately 6h, with fewer side-effects than found with nifedipine (Hauger-Klevene, 1986).

SUMMARY

The advent of the increasing use of different angiotensin-converting enzyme (ACE) inhibitors for the treatment of hypertension and cardiac failure has resulted in intense interest in the renin-angiotensin system (RAS) and its manipulation for therapeutic gain, and thus more patients will present for surgical anaesthesia while on maintenance therapy with these agents.

The RAS is increasingly described in terms of systemic and tissue components. The systemic component is important in maintaining cardio- vascular and body fluid homoeostasis, and is activated through renin release by the juxtaglomerular cells of the kidney in response to signs of dis- equilibrium. Angiotensin I is formed from renin substrate and is converted by ACE to angiotensin II, the major mediator of this system, which in turn stimulates aldosterone release from the adrenal cortex. In addition, aldosterone can be released independently in response to changes in plasma potassium concentration. The release of these hormones is regulated through various feedback mechanisms. The role of the tissue RAS is not clear but has been found to be present in many organ systems and is increasingly seen as the major site of action of ACE inhibitor drugs. The first oral ACE inhibitor, captopril, introduced in 1977, was followed by enalapril (which can also be administered intravenously) and lisinopril. These agents inhibit the conversion of angiotensin I to angiotensin II. ACE inhibitors also inhibit the inactivation of bradykinin, a vasodilator, which in turn enhances vasodilatory prostaglandin formation.

ACE inhibitors have been found increasingly useful in the therapy of hypertension and cardiac failure, and new indications for their use are under investigation.

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The effect of anaes thes ia on the R A S has u n d e r g o n e l imi ted study. Indica t ions are that ne i the r the R A S nor A C E are direct ly af fec ted by anaesthet ics . P reope ra t i ve the rapy with A C E inhibi tors has been associated with severe hypo tens ion af ter induct ion of and during anaesthes ia . In addi t ion , the critical role of the R A S in the defence of b lood loss is becoming appa ren t in pat ients rece iv ing A C E inhibi tors . In aor t ic surgery , howeve r , A C E inhibi t ion may be r enopro tec t ive , and exper imen ta l ly these drugs have b e e n shown to reduce myocard ia l infarct size after co ronary occlusion in dogs. Thus , fur ther studies are r equ i r ed to d e t e r m i n e the exact role of A C E inhibi tors in the pe r iope ra t i ve per iod .

REFERENCES

Ajayi AA, Campbell BC, Meredith PA et al (1985) The effect of captopril on the reflex control of heart rate: possible mechanisms. British Journal of Clinical Pharmacology 20: 17-25.

Bean BL, Brown J J, Caslas-Stenzel J et al (1979) The relation of arterial pressure and plasma angiotensin II concentration. A change produced by prolonged infusion of angiotensin II in the conscious dog. Circulation Research 44: 452-458.

Blaine EH, Davis JO & Prewitt RL (1971) Evidence for a renal vascular receptor in the control of renin secretion. American Journal of Physiology 220: 1593-1597.

Blair ML, Chen YH & Hisa H (1986) Elevation of plasma renin activity by alpha-adreno- receptor agonists in the conscious dogs. American Journal of Physiology 251: E695-702.

Blumberg AL, Ackerly JA & Peach MJ (1975) Differentiation of neurogenic and myocardial angiotensin II receptors in isolated rabbit atria. Circulation Research 36" 719-726.

Breckenbridge A (1988) Angiotensin converting enzyme inhibitors. British Medical Journal 296: 618-620.

Brooks VL, Keil LC & Reid IA (1986) Role of the renin-angiotensin system in the control of vasopressin secretion in conscious dogs. Circulation Research 58: 82%838.

Broshnihan K & Bravo EL (1978) Grade reductions of atrial presuare and renin release. American Journal of Physiology 235: H175-181.

Brown JJ, Casals-Stenzel J, Cumming AMM et al (1979) Angiotensin II, aldosterone and arterial pressure: a quantitative approach. Hypertension 1: 159-179.

Bryant RW, Epstein AN, Fitzsimons JT et al (1980) Arousal of a specific and persitent sodium appetite in the rat with continuous intracerebroventricular infusion of angiotensin II. Journal of Physiology 301: 365-382.

Buckley JP (1972) Actions of angiotensin on the central nervous sytem. Federation Proceedings 31: 1332-1337.

Campbell DJ (1987) Circulating and tissue angiotensin systems. Journal of Clincial Investi- gation 79: 1.

Christlieb AR, Couch NP, Amsterdam EA et al (1968) Renin extraction by the human liver. Proceedings of the Society for Experimental Biology and Medicine 128: 821-823.

Churchill MC, Churchill PC & Donald FDM (1983) Evidence that [3~-adrenoreceptor acti- vation mediates isoproterenol stimulated renin secretion in the rat. Endocrinology 113: 687-692.

Clark NJ & Stanley RH (1990) Anesthesia for vascular surgery. In Miller RD (eds) Anesthesia, pp 1693-1736. New York: Churchill Livingstone.

Cleland JFG, Dargie H J, Pettigrew A et al (1986) The effects of captopril on derum digoxin and urinary urea and digoxin clearances in patients with congestive heart failure. American Heart Journal 112: 130-135.

Colson P, Saussine M, Seguin JR et al (1992) Hemodynamic effects of anesthesia in patients chronically treated with angiotensin-converting enzyme inhibitors. Anesthesia and Analgesia 74: 805-808.

Consensus Trial Group (1987) Effects of enalapril on mortality in severe congestive heart failure. New England Journal of Medicine 316: 1429-1435.

Page 20: Angiotensin and angiotensin-converting enzyme inhibitors

170 B. METS AND E. D. MILLER

Davis JO & Freeman RH (1976) Mechanisms regulating renin release. Physiological Reviews 56: 1-56.

Delaney TJ & Miller ED (1980) Rebound hypertension after sodium nitroprusside prevented by saralasin. Anesthesiology 52: 154-156.

DiBianco RD (1986) Adverse reactions with angiotensin converting enzyme inhibitors. Medical Toxicology 1: 122-141.

DiPette D J, Ferraro JC, Evans RR et al (1985) Enalaprilat, an intravenous angiotensin- converting enzyme inhibitor, in hypertensive crises. Clinical Pharmacology and Thera- peutics 38: 199-204.

Douze-Blazy P, Blanc M, Monastruc JL et al (1986) Is there an interaction between digoxin and enalapril? British Journal of Clinical Pharmacology 22: 752-753.

Dzau VJ (1987) Implications of local angiotensin production in cardiovascular physiology and pharmacology. American Journal of Cardiology 59: 59A-65A.

Dzau VJ (1988) Circulating versus local renin-angiotensin system in cardiovascular homeo- stasis. Circulation 77: I4-13.

Editorial (1988) ACE inhibitors--thc trickle becomes a flood. Lancet ii: 885-886. Ertl G, Kloner RA, Alexander RW & Braunwald E (1982) Limitation of experimental infarct

size by an angiotensin-converting enzyme inhibitor. Circulation 65: 40-48. Espiner EA & Nicholls MG (1993) Renin and the control of aldostione. In Robertson JIS &

Nicholls MG (eds) The Renin-Angiotensin System, pp 33.1-33.2. London: Gower Medical.

Fischer JW & Crook JJ (1962) Influence of several hormones on erythropoesis and oxygen consumption in the rat. Blood 19: 5557-5565.

Fluharty SJ & Epstein AN (1983) Sodium appetite elicited by intracerebroventricular infusion of angiotensin II in the rat: II. Synergistic interaction with systemic mineralocorticoids. Behavioural Neuroscience 97: 746-758.

Garvas I & Garvas H (1993). Angiotensin II--possible adverse effects on arteries, heart, brain, and kidney: experimental, clinical, and epidemiological evidence. In Robertson JIS & Nicholls MG (eds) The Renin-Angiotensin System, pp 40.1-40.11. London: Gower Medical.

Gill GN (1985) The adrenal gland. In West JB (ed.) Physiological Basis of Medical Practice, pp 881-901. Baltimore: Williams and Wilkens.

Griffing GT & Melby JC (1982) Enalapril and white cell count and haematocrit. Lancet i: 1361. Guidicelli JF, Berdeaux A, Edouard A et al (1985) The effect of enalapril on baroreceptor

mediated reflex function in normotensive subjects. BritishJo urnal of Clinical Pharmacology 20: 211-218.

Hall JE & Brands MW (1993) Intrarenal and circulating angiotensin II and renal function. In Robertson JIS & Nicholls MG (eds) The Renin-Angiotensin System, pp 26.1-26.43. London: Gower Medical.

Hall JE & Hall MW (1992) The renin-angiotensin-aldosterone systems: renal mechanisms and circulatory homeostasis. In Seldin DW & Giebish G (eds) The Kidney, Physiology and Pathophysiology, 2nd edn, pp 1455-1504. New York: Raven Press.

Hall JE, Guyton AC, Smith MJ & Coleman TG (1980) Long-term regulation of arterial pressure, glomerular filtration and renal sodium reabsorption by angiontensin II in dogs. Clinical Science 59: 87-90.

Handa K, Sasaki J, Tanaka H et al (1991) Effects of captopril on opioid peptides during excercise and quality of life in normal subjects. American Heart Journal 122: 1389-1394.

Hansson L, Dahlof B, Himmelman A e t al (1993) Angiotensin-converting enzyme inhibitors in the treatment of essential hypertension. In Robertson JIS & Nicholls MG (eds) The Renin-Angiotensin System, pp 91.1-91.24. London: Gower Medical.

Hauger-Klevene JH (1986) Comparison of sublingual captopril and nifedipine. Lancet i: 219. Heel RC, Brogden RN, Speight TM & Avery GS (1980) Captopril: a preliminary review of its

pharmacological prperties and therapeutic efficacy. Drugs 20: 409-452. Heffman SM, Gold MI, DeLisser EA et al (1991) Which drug prevents tachycardia and

hypertension associated with tracheal intubation: lidocaine, fentanyl, or esmolol. Anes- thesia and Analgesia 72: 482-486.

Hodsman GP, Isles CG, Murray GD et al (1983) Factors related to first dose hypotensive effect of captopril: prediction and treatment. British Medical Journal 286: 832-834.

Hollenberg NK (1993) A bouyant view of the value of angiotensin-converting enzyme

Page 21: Angiotensin and angiotensin-converting enzyme inhibitors

ANGIOTENSIN AND ACE INHIBITORS 171

inhibition in renovascular disease. In Robertson JIS & Nicholls MG (eds) The Renin- Angiontensin System, pp 90.1-90.8. London: Gower Medical.

Hricik DE, Browning PJ, Kopelman R et al (1983) Captopril induced functional renal insufficiency in patients with bilateral renal artery stenosis or renal artery stenosis in a solitary kidney. New England Journal of Medicine 308: 373-376.

Itoh H, Pratt RE & Dzau VJ (1990) Antisense oligonucleotides complementary to PGDF mRNA attenuate angiotensin II-induced vascular hypertrophy. Hypertension 16: 325-326.

Jensen K, Buneman L, Riisager Set al (1989) Cerebral blood flow during anaesthesia: influence of pretreatment with metropolol or captopril. British Journal of Anaesthesia 62: 321-323.

Johnson EM, Marshall GR & Needleman P (1974) Modification of responses to sympathetic nerve stimulation by the renin-angiotensin system in rats. British Journal of Pharmacology 51: 541-547.

Joob AW, Human PK, Kaiser DL et al (1986) The effect of renin-angiotensin system blockade on visceral blood flow during and after thoracic aortic cross-clamping. Journal of Thoracic and Cardiovascular Surgery 91: 411-418.

Kalil RSN, Katz SA & Keane WF (1993). Angiotensin-converting enzyme inhibitors in diabetes mellitus. In Robertson JIS & Nicholls MG (eds) The Renin-Angiotensin System, pp 92.1-92.20. London: Gower Medical.

Kastner PR, Hall JE & Guyton AC (1984) Control of glomerular filtration rate: role of intrarenally formed angiotensin II. American Journal of Physiology 246: F897-906.

Kataja J, Viinamaki O, Punnonen R et al (1988) Renin-angiotensin-aldosterone system and plasma vasopressin in surgical patients anesthetized with halothane or isoflurane. European Journal of Anaesthesia 5: 121-129.

Kataja JH, Kaukenin S, Viinamaki OV et al (1989) Hemodynamic and hormonal changes in patients pretreated with captopril for surgery of the abdominal aorta?Journal of Cardio- thoracic Anesthesia 3: 425-432.

Khosla MC, Smeby RR & Bumpus FM (1974) Structure-activity Relationship in Angiotensin H Analogues. Berlin: Springer.

Kostis JB (1988a) Angiotensin converting enzyme inhibitors. Pharmacology. American Heart Journal 116: 1580-1591.

Kostis JB (1988b) Angiotensin converting enzyme inhibitors. II. Clinical use. American Heart Journal 116: 1591-1605.

Lindpaintner K & Ganten D (1991) The cardiac renin-angiotensin system. Circulation 68: 905-921.

Lubbe WF (1990) Treatment of hypertension. Journal of Cardiovascular Pharmacology 16: $110-$113.

McCarthy G J, Hainsworth M, Lindsay K et al (1990) Pressor responses to tracheal intubation after sublingual captopril. A pilot study. Anaesthesia 45: 243-245.

McConachie I & Healy TEJ (1989) ACE inhibitors and anaesthesia. Postgraduate Medical Journal 65: 273-274.

Mancia G, Romero JC & Shepherd JT (1975) Continuous inhibition of renin release in dogs by vagally innervated receptors in the cardiopulmonary region. Circulation Research 36: 529-535.

Maslowski AH, Nicholls MG, Ikram H et al (1981) Haemodynamic, hormonal, and electrolyte responses to withdrawal of long-term captopril treatment for heart failure. Lancet ii: 959-961.

Menard J, Michel JB & Plouin P-F (1993) A cautious view of the value of angiotensin- converting enzyme inhibition in renovascular disease. In Robertson JIS & Nicholls MG (eds) The Renin-Angiotensin System, pp 89.1-89.9. London: Gower Medical.

Miller ED (1980) The renin-angiotensin system in anesthesia. In Brown BR (ed.) Anesthesia and the Patient with Endocrine Disease, pp 19-28. Philadelphia: Davis.

Miller ED (1993) Renin with anesthesia and surgery. In Robertson JIS & Nicholls MG (eds) The Renin-Angiotensin System, vol. 2, pp 81.1-81.2. London: Gower Medical.

Miller ED & Delaney TJ (1981) Blood flow alteration induced by saralasin or sodium nitroprusside in rats. Anesthesiology 54: 199-203.

Miller ED, Bailey DR, Kaplan JA et al (1975) The effect of ketamine on the renin-angiotensin system. Anesthesiology 42: 503-505.

Miller ED, Ackerly JA, Vaughn ED et al (1977) The renin-angiotensin system during controlled hypotension with sodium nitroprusside. Anesthesiology 47: 257-262.

Page 22: Angiotensin and angiotensin-converting enzyme inhibitors

172 B. METS AND E. D. MILLER

Miller ED, Longnecker DE & Peach MJ (1978) The regulatory function of the renin- angiotensin system during general anesthesia. Anesthesiology 48: 399-403.

Miller ED, Gianfagna W, Ackerly JA et al (1979a) Converting enzyme activity and pressor responses to angiotensin I and II in the rat awake and during anesthesia. Anesthesiology 50: 88-92.

Miller ED, Longnecker DE, Peach MJ (1979b) Renin response to hemorrhage in awake and anesthetized rats. Shock 6: 271-276.

Mirenda JV & Grissom TE (1991) Anesthetic implications of the renin-angiotensin system and angiotensin-converting enzyme inhibitors. Anesthesia and Analgesia 72: 667-683.

Morgan HE & Baker KM (1991) Cardiac hypertrophy: mechanical, neural and endocrine dependence. Circulation 83: 13-25.

Morton JJ (1993) Biochemical aspects of the angiotensins. In Robertson JIS & Nicholls MG (eds) The Renin-Angiotensin-System, pp 9.1-9.12. London: Gower Medical.

Murphy JD, Vaughan RS & Rosen M (1989) Intravenous enalaprilat and autonomic reflexes. Anaesthesia 44: 816-821.

Oates HF, Fretten JA & Stokes GS (1974) Disappearance rate of circulatory renin after bilateral nephrectomy in the rat. Clinical and Experimental Pharmacology and Physiology 1: 547-549.

Olsen ME, Hall JE, Montani JP & Cornell JC (1986) Interaction with renal prostaglandins and angiotensin II in controlling glomerular filtration rate in the dog. Clinical Science 72: 429-436.

Oparil S (1993) Antihypertensive therapy---efficacy and quality of life. New England Journal of Medicine 328: 959-961.

Oparil S, Tregear GW, Koerner T et al (1971) Mechanism of conversion of angiotensin I to angiotensin II in the dog. Circulation Research 29: 682-690.

Peach MJ (1971) Adrenal medullary stimulation induced by angiotensin II and analogues. Circulation Research 28-29: II107-Iil17.

Peach MJ, Cline WH & Watts DT (1966) Release of adrenal catecholamines by angiotensin II. Circulation Research 19: 571-575.

Pfeffer JM, Pfeffer MA, Mirsky I & Braunwald E (1982) Regression of left ventricular hypertrophy and prevention of left ventricular dysfunction by captopril in the spon- taneously hypertensive rat. Proceedings of the National Academy of Sciences of the USA 79: 3310-3314.

Pfeffer MA, Lamas GA, Vaughan DE et al (1988) Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. New England Journal of Medicine 319: 80-86.

Richards AM, Nicholls MG, Espiner EA et al (1986) Diurnal patterns of blood pressure, heart rate and vasoactive hormones in normal man. Clinical and Experimental Hypertension A8: 153-166.

Roberts A J, Niarchos AP, Subramanian VA et al (1977) Systemic hypertension associated with coronary artery bypass surgery. Journal of Thoracic and Cardiovascular Surgery 74: 846-857.

Romankiewicz JA, Brogden RN, Heel RC et al (1983) Captopril: An update review of its pharmacological properties and therapeutic efficacy in congestive heart failure. Drugs 25: 6-40.

Salvetti A (1990) Newer ACE inhibitors. A look at the future. Drugs 40: 800-828. Scroop G, Katic F, Joy Me t al (1971) Importance of central vasomotor effects in angiotensin-

induced hypertension. British Medical Journal 1: 324-326. Seelig CB, Maloley PA & Campbell JR (1990) Nephrotoxicity associated with concomitant

ACE inhibitor and NSAID therapy. Southern Medical Journal 83: 1144-1148. Selby DG, Richards JD & Marshman JM (1989) ACE inhibitors. Anaesthesia and Intensive

Care 17: 110-111. Severs WB & Daniel-Severs AE (1973) Effects of angiotensin on the central nervous system.

Pharmacology Reviews 25: 415-449. Skidgel RA & Gerdos E (1993). Biochemistry of angiotensin I-converting enzyme. In

Robertson JIS & Nicholls MG (eds) The Renin-Angiotensin System, pp 10.1-10.10. London: Gower Medical.

Slater EE, Merril DD, Guess HA et al (1988) Clinical profile of angioedema associated with angiotensin converting enzyme inhibition. Journal of the American Medical Association 260: 967-970.

Page 23: Angiotensin and angiotensin-converting enzyme inhibitors

ANGIOTENSIN AND ACE INHIBITORS 173

SOLVD investigators (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive cardiac failure. New England Journal of Medicine 325: 239-302.

Stine SM, Yang HYT & Costa E (1980) Inhibition of in situ metabolism of [3H](metS)- enkephalin and potentiation of (metS)-enkephalin analgesia by captopril. Brain Research 188: 295-299.

Swartz SL, Williams GH, Hollenberg NK et al (1980) Captopril induced changes in prosta- glandin production: relationship to vascular responses in normal man. Journal of Clincial Investigation 65: 1257-1264.

Testa MA, Anderson RB, Nackley JF et al (1993) Quality of life and antihypertensive therapy in men. A comparison of captopril with enalapril. New England Journal of Medicine 328: 907-913.

Thrasher TN, Keil LC (1987) Regulation of drinking and vasopressin secretion: role of the organum vasculosum laminae terminalis. American Journal of Physiology 253: R108-120.

Todd PA & Heel RC (1986) Enalapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive cardiac failure. Drugs 31: 199-248.

Ulm EH, Hichens M, Gomez HJ et al (1982) Enalapril maleate and a lysine analogue (MK-521): disposition in man. British Journal of Clinical Pharmacology 14: 357-362.

Vander AJ (1965) Effect of catechotamines and the renal nerves on renin secretion. American Journal of Physiology 209: 659-662.

Vander AJ (1967) Control of renin release. Physiological Reviews 47: 359-382. Watson MI, Bell GM, Muir AL et al (1983) Captopril/diuretic combination in severe

renovascular disease: a cautionary note. Lancet ii: 404. Williams GH (1988) Converting enzyme inhibitors in the treatment of hypertension. New

England Journal of Medicine 319: 1517-1525. Woodside J, Garner L, Bedford RF et al (1984) Captopril reduces the dose requirement for

sodium uitroprusside induced hypotension. Anesthesiology 60: 413-417. Yamashita M, Oyama T & Kudo T (1977) Effect of the inhibitor of angiotensin I converting

enzyme on endocrine function and renal perfusion in haemorrhagic shock. Canadian Anaesthesia Society Journal 24: 695-701.

Yates AP & Hunter DN (1988) Anaesthesia and angiotensin-converting enzyme inhibitors. Anaesthesia 43: 935-938.

Zerbe RL, Feurstein G & Kopin IJ (1981) Effects of captopril on cardiovascular, sympathetic and vasopressin response to hemorrhage. European Journal of Pharmacology 72: 391-395.