148-1.pdf

#{176}Director,Department ofClinical Pharmacology, Hoffmann-La Roche, Inc., Nutley, New Jersey.

148 WILLIAM B. ABRAMS

DIS. CHEST, VOL. 55, NO. 2, FEBRUARY 1969

Rauwolfia group again prescribed unless severeside effects prevented its use. Rauwolfia decreasesthe dosage of hydralazine required and thus mini-mizes the side effects.

Hydralazine (Apresoline) is more potent thanthe Rauwolfia group and should be the next agentprescribed. The initial dose is 10 mg four times a

day, increased after the first week to 25 mg fourtimes a day. At weekly intervals increase the dailydose 25 mg until a total of 100 mg four times a dayis being given, or an adequate blood pressure de-crease has resulted. The maximum daily dose is400 mg.

Hydralazine administration may lead to a clinicalpicture simulating acute systemic lupus erythema-tosis or an arthritis-like syndrome. Although thisusually occurs only with doses greater than 400 mga day, infrequent instances have been reportedwith a dose of 100 mg a day. Coronary artery dis-ease and congestive heart failure are contraindica-tions to the use of hydralazine.

If an insufficient blood pressure decrease occurs,guanethidine ( Ismelin) may be added to the regi-men of a diuretic, the Rauwolfia group and hydra-

The Mechanisms of Action ofAntihypertensive DrugsWilliam B. Abrarn, M.D., F.C.C.P.*

T he current treatment of essential hypertensionis based on the following concepts: ( 1 ) a single

cause has not been identified. Indeed, essential hy-pertension appears to be a multifactorial disorder.Specific therapy, therefore, is not possible;1 (2) thehomeostatic mechanisms that regulate blood pres-sure are intact in hypertensive subjects and re-sponsive to physiologic and chemical interventions.This applies to baroreceptor activity,2 sympatheticnerve activity35 and reriin-aldosterone secretion.69It is evident, however, that the baroreceptor setis abnormal in this disease because the high bloodpressure is tolerated without invoking the hypoten-sive reflexes which are available.1011 It is also evi-dent that despite normal sympathetic nerve traffic,arteriolar tone is increased; the characteristic find-ings in essential hypertension are increased periph-eral vascular resistance and a normal cardiacoutput;351213 (3) it is the elevated blood pressure

lazine. It should be given as a single morning doseof 10 mg, increased at weekly intervals by 10 mguntil the desired blood pressure results in the stand-ing position.

Side effects are diarrhea and failure of ejacula-tion. Frequent stools may be controlled with anti-cholinergic drugs (e.g. atropine).

The ganglioplegic drugs comprise the most po-tent group of antihypertensive agents, but are veryrarely required today. Several agents are available,but mecamylamine ( Inversine ) is the one of choicedue to its complete absorption from the gastro-intestinal tract and more uniform effect. The doseis 2.5 mg twice daily increased by 2.5 mg at weeklyintervals until the desired blood pressure is ob-tained with the patient in the standing position.

Side effects consist of constipation and dryness ofthe mouth and are parasympatholytic. This drugshould be avoided if the blood urea nitrogen ex-ceeds 50 mg per ml. The presence of coronary orcerebrovascular insufficiency merits caution inmecamylamine administration.

Reprint requests: Dr. Grenfell, 514-H East Woodrow WilsonDrive, Jackson, Mississippi 39216

per se which is responsible for the clinical mani-festations of hypertensive cardiovascular disease.Any consistent elevation of blood pressure, slightor marked, systolic or diastolic, is associated withincreased morbidity and mortality.4 It is now clearthat treatment can alter this picture. Deaths due tohypertension in the United States fell by over 50percent between the before period of 1950 to1953 and the drug therapy period of 1960 toJ9fi3#{149}5 Successful drug treatment may even lead topermanent remission.16 In a recent U. S. VeteransAdministration cooperative study involving 143 hy-pertensive men, those treated with placebo suffered27 severe complications and four deaths while anequal-sized and matched drug-treated group ex-perienced only two severe complications and nodeaths;17 ( 4 ) treatment, therefore, is required, andit is logical to attempt to lower blood pressure inhypertensive subjects by affecting regulatory mech-anisms which may or may not be etiologicallyinvolved.

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CAROTID

I BETA ADRENERGIC4 RECEPTOR

ADRENAL MEDULLA

MECHANISMS OF ACTION OF ANTIHYPERTENSIVE DRUGS 149


FIGURE 1. Diagramatic representa-tion of blood pressure regulatingmechanisms.

These regulatory mechanisms are the sympa-thetic nervous system which controls myocardialcontractility and arteriolar tone, the renal excretoryfunctions and the renal and adrenal hormonal in-teractions which control blood volume ( Fig 1).

The only class of antihypertensive agents whichact on the afferent side of the sympathetic nervoussystem are the veratrum alkaloids (Fig 2). Theseagents sensitize the afferent receptors, particularlyin the heart and the carotid sinus so that a givenlevel of pressure results in a larger amount ofafferent nerve traffic.89 This is interpreted by thevasomotor centers in the brain stem as a higherthan actual pressure, and sympathetic tone is de-creased and vagal tone is increased. The result islowering of blood pressure and bradycardia. This isa rather ideal mechanism of action, but unfortu-nately, the afferent receptors for nausea and vomit-ing are about equally sensitized2#{176} and these sideeffects have greatly limited the clinical use of theseagents. The veratrum alkaloids still enjoy some usein hypertensive crises and toxemia of pregnancy.

The role of the emotions in arousing sympatheticresponses including hypertension is well known and

barbiturates and tranquillizers are logical agents touse in anxious hypertensive subjects. Many drugshave more specific central nervous system actionsrelative to blood pressure lowering in pharmaco-logic studies, but the relationship of these actionsto their clinical effects is in doubt.

Reserpine has potent CNS effects, clinically evi-denced by sedation and depression, but consider-able data exist to indicate that the locus ofhypotensive action is the peripheral sympatheticneurone.22 Hydralazine was also once thought toact centrally,24 but it, too, has a peripheral site of

action in lowering blood pressure.25Mebutamate (Capla) is closely related to mepro-

bamate. Animal experiments employing cross circu-lation techniques and direct electrical stimulation ofthe hypothalamic and medullary vasomotor centerssuggest mebutamate lowers blood pressure by in-hibiting tonic stimuli from these centers and bysuppressing sympathetic flow at the spinal level aswell.22625 A direct vasodilator action has also been

identified.28 Clinically, mebutamate is at best weakand drowsiness is a common side effect.

Guanoxan ( Fig 3 ) chemically resembles guan-


(ARATIfl siaic -

M EB U TAM ATE

tctr , irn

AORTIC ARCHVERATRUM RECEPTORSL. VENTRICLRECEPTORS

FIGURE 2. Diagramatic representation of the sites of action of antthypertensive drugs affectingthe afferent sympathetic nervous system, the central nervous system or sympathetic ganglia.

ethidine and other neurone blocking agents and likethese drugs, can inhibit sympathetic transmissionat the postganglionic neurone. It differs, however,in having alpha adrenergic blocking effects and inbeing a potent depleter of catecholamines fromsympathetic nerves, adrenal medulla and the

brain,29 an action similar to reserpine. It is an effec-tive hypotensive agent in man,3#{176}but clinical trialshave been terminated because of a high incidenceof liver function abnormalities.31

Catapres, ST 155 (Fig 4) is a derivative of im-idazole, a class of drugs which includes tolazoline(Priscoline), an alpha adrenergic blocking agentwith predominantly hypotensive effects and tetra-hydrolazine ( Tyzine ), a vasoconstrictor. Catapreswas, in fact, designed to be a vasoconstrictor fornasal decongestion, but when tried by this routein man it produced lowering of blood pressure,sedation, bradycardia and dry mouth. This isanother example of a drug effect being identifiedfirst in man. Extensive pharmacologic studies have

NHCH2-NH -C

NH2

GUANOXANFIGURE 3. Structural formula of guanoxan.

:1

failed to define clearly its mechanism of action.Studies involving injection of the drug into the ver-tebral artery32 and into the fourth ventricle33 sug-

gest suppression of the brain stem vasomotorcenters. This concept is supported by the demon-stration that Catapres reduces efferent sympathetic

nerve activity after afferent stimulation.34 Thepharmacologists responsible for its developmenthave demonstrated that it is not a ganglionic orpostganglionic sympathetic blocking agent and itdoes not deplete catecholamines from the heart.3335

CATA PR ES

N-.CH2____I,

NH NH-CH2

C 2

NH-CH2

FIGURE 4. Structural formulas of Catapres and tolazoline.

TOLAZOLINE



PHENOBARBITALCHLORDIAZEPOXIDEMEPROBAMATE

MEBUTAMATE

DIAZEPAMCATAPRESRESERPINE ?

GUANOXANHYDRALAZINE

HEXAMETHONIUMPENTOLIN hUM

CHLORISON DAM INE

MECAMYLAMINETRIM ETHAPHANTRIMETHIDINIUM

MAO INHIBITORS ?


POSTGANGLIONICSYMPATHETIC

NEURONENOREPINEPHRINE

BIOSYNTHESIS #{149}TYROSINE

MITOCHONDR ION

TERMINAL NETWORK

ACETYL CHOLINE ?

CELL MEMBRANEPUMP

cx RECEPTOR / RECEPTOR

FIGURE 5. Diagramatic representation of the principal features of the physiology and bio-chemistry of the postganglionic sympathetic neurone. For details see text. Acetyl cholineis included with a question mark because the presence and/or significance of this substancein sympathetic neurones has not been established with certainty.



However, like other imidazole derivatives, it doeshave transient sympathomimetic effects followedby alpha adrenergic blockade.5 The observation

that propranalol can block its hypotensive effectsmay indicate a beta adrenergic agonist effect aswell.6 Clinically, Catapres appears to be an effec-tive antihypertensive agent of moderate potency,perhaps comparable to alpha methyldopa.37 It fea-tures a mini dose, in the range of 75-500 p.g/day389 and can be given parenterally as well asorally.9 Side effects include sedation, dry mouth,and salt and water retention,38 the last of whichcan be overcome by the concurrent administrationof a diuretic.38 This effect is consistent with renalhemodynamic studies showing a reduction in renal

plasma flow and glomerular filtration rate4#{176}and arise in serum sodium and chloride concentrationsin clinical studies.41 Catapres continues to be ex-tensively studied and may some day be availablefor general use.

Descending the efferent sympathetic nervous

system we come to the autonomic ganglia. As is

well known, sympathetic and parasympathetic im-pulses cannot be separately blocked at this level,

so ganglionic blocking agents have given way to

drugs acting more distally. Some ganglionic block-ing agents are occasionally used in hypertensiveemergencies.

The distal end of the postganglionic neurone,however, is another story (Fig 5). The sympa-thetic neuroeffector junction has become an almostpermanent home for many pharmacologists andclinical pharmacologists. As the postganglionic neu-rone approaches the effector organ, it subdividesinto a terminal network.42 Special staining tech-niques have demonstrated that the terminalnetwork contains great numbers of norepinephrine-rich granules from which the norepinephrine is

released in response to nerve stimuli.4 Norepineph-rine gains access to the granules by means of bio-

symthesis and uptake from the circulation.43 Theuptake mechanism has special importance because

it is the major means of inactivating released nor-epinephrine, and it can involve certain drugs aswell, leading to interactions which will be discussedsubsequently. Norepinephrine is metabolized intra-

neuronally by monoamine oxidase in the mitochon-dna and extxaneuronally by catechol-0-methyl trans-ferase, with both enzymes acting to produce van-illylmandelic acid.44


I IPOSTGANGLIONIC

SYMPATHETIC

HYDRALAZINEDIAZOX IDE

THIAZIDE DIURETICSMEBUTAMATE



A multitude of drug actions exist21 (Fig 6). Tyra-mine, amphetamine, ephedrine, mephentermineand other indirect acting pressor amines releasenorepinephrine but do not block nerve transmission.Debrisoquin, bretylium and bethanidine are capa-ble of releasing some of the peripheral stores ofnorepinephrine when given intravenously but then

go on to nerve impulse blockade. Guanethidine andguanoxan initially release norepinephrine, thenblock nerve transmission, and then go on to depletemuch of the granular and extragranular norepineph-nine. The hypotensive effects result from the nerveblockade.

Reserpine and the other Rauwolfia alkaloids havelittle or no initial releasing effect, but they gradu-ally deplete practically all of the neurotransmittorsubstance, norepinephrine, from sympathetic nervetissue and this is their major mechanism of lower-ing blood pressure.2145 They accomplish this deple-tion by inhibiting the uptake of norepinephrine bythe nerve granules.46

Methyldopa interferes with norepinephrine bio-synthesis. Originally, it was believed it did thisby inhibiting the enzyme DOPA decarboxylase. Itnow appears that methyldopa acts by replacingnorepinephrine in sympathetic tissues (and in the

brain) with a false transmitter substance-alpha-methylnorepinephrine.47 The false transmitter hy-pothesis holds that norepinephrine is stoichiometric-ally replaced by alpha-methylnorepinephrine at the

sympathetic nerve endings;47 the latter substanceis released by sympathetic nerve activity,48 but hasonly one-half to one-ninth the pressor effect ofnorepinephrine.49 The amine-releasing effect ofmethyldopa is not unlike that of reserpine. Anadditional pharmacologic activity that may relateto the antihypertensive action is competition ofalpha-methyldopamine, formed from alpha methyl-dopa, with endogenous dopamine for the beta hy-droxylating enzyme necessary to produce norepi-nephrine.5#{176} Methyldopa is a moderately potentantihypertensive agent which lowers blood pres-sure by reducing peripheral vascular resistance withlittle or no effect on cardiac output.51 A feature ofits activity, at least by the oral route, is a decreasein renal vascular resistance greater than in the gen-eral circulation, and thus renal blood is increased.52This makes methyldopa particularly useful in sub-jects with impaired renal function. The most com-mon side effect is sedation which usually diminisheswith continued therapy. Other side effects includedrug fever, skin rashes, headache and fluid reten-

FIGURE 6. Diagramatic representation of the mechanisms of action of dnigs affecting thepostganglionic sympathetic neurone, adrenergic receptors, vascular smooth muscle andblood volume. For details see text.


R(S(NPINE

[I:3Jc:I::1sNH 1N_CH I

DESRISOQUIN SULFATE

H_N_CH_CCH

CH3

PARAYLINE



tion. A side effect of current interest is the devel-opment of a Coombs positive state by many sub-jects. This immunologic phenomenon, however, isnot usually associated with anemia.53

Pargyline is a non-hydrazine monoamine oxidase

( MAO) inhibitor. The ability of the MAO inhib-itors to lower blood pressure, considered an unde-sirable side effect when these drugs were originallyused to relieve depression, has been advanced as adesirable property to this compound. Like otherMAO inhibitors, pargyline causes an accumulationof norepinephrine in the heart, brain and otheradrenergic tissues.54 The relationship of MAO in-hibition to blood pressure lowering is not clear.One hypothesis is that the blood pressure is loweredby the accumulation and release of a false trans-

mitter substance, octopamine,55 which, like alpha-methylnorepinephrine is a less effective pressoragent than norepinephrine. Another suggestion isthat norepinephrine accumulation produces a neg-ative feedback mechanism with inhibition of theproduction of norepinephrine.56

Pargyline lowers blood pressure predominantlyin the upright position and decreases peripheralvascular resistance.57 A decrease in the blood pres-

sure and cardiac output response to exercise alsooccurs.58

Monoamine oxidase inhibitor activity, while pro-ducing the desired lowering of blood pressure, hasinherent hazards. The general inhibition of mono-amine oxidase in liver and gut produces a markedsensitivity to tyramine-rich foods and beverages andto sympathomimetic drugs. As a result, paradoxichypertension crises may occur.59 Psychic stimula-tion varying from insomnia to the unmasking oflatent schizophrenia may also occur.

The structures of the sympathetic neurone block-ing agents are shown in Figure 7.

In a previous paragraph, drug interactions involv-ing the membrane pump were mentioned. Cocaine,imipramine, desmethyl imipramine, protriptyline,amphetamine and numerous similar agents canblock the uptake of norepinephrine by the neuro-nal membrane. Since this is the principal mechan-ism of norepinephrine inactivation, the responsesto endogenous or administered norepinephrine areexaggerated and this action is important in theclinical activities and side effects of these agents.However, these substances also prevent the uptakeof the neurone blocking drugs, and thus negate

POSTGANGLIONIC SYMPATHETIC BLOCKING AGENTS

I1LCN2 _NtCN5#{149} CN3J1Sr CN3

SRETYLIUM

NH

-CH2-CH-NH-C #{149} l2H2SO4NH2

#{149}UANETHIDINE

?sHOCH_C_N

HO OH

ALPHA METHYL DORA

OCH

0OC

FIGu 7. Structures of postgangli-onic sympathetic neurone blockingagents.


0.6 1.0LOS DOSE TYRAMINE (*q)



their antihypertensive effects. Mitchell6#{176} and Pet-tinger and associates1 have demonstrated reversalof the antihypertensive effects of guanethidine,l)ethanidrne and debrisoquine by desipramine andprotriptyline. Similar effects can be shown foramphetamine. These observations suggest that inrefractory cases, one should inquire about the con-comitant use of interfering drugs such as anti-

depressants, anorectics, nose drops or certain coldremedies. These comments should not be inter-preted to suggest that drug combinations shouldnever l)e used in the management of hypertension.On the contrary, hypertension is one of the fewindications of internal medicine where effectivetreatment usually requires more than one medica-tion. It is important to know the pharmacology andpossible interactions of the agents involved.

In addition to the production of potentiation,interference or side effects, drug combinations may

also provide information on mechanisms of action.Such an interaction is demonstrated by the effects

of debrisoquin on reserpine. When animals orhumans are given reserpine, the pressor responsesto tyramine are reduced.626 This is to be expectedbecause tyramine acts only by releasing nor-epinephrine and reserpine depletes norepinephrine.However when debrisoquin is added to the reser-pine treatment, this effect is reversed. In Figure 8,it can he seen that reserpine moves the pressor

x

4)

U

0I-(1,4,

z

zIU

I

4I

FIGURE 8. Dose response curves of the pressor responses tointravenous tyramine in untreated patients, patients treatedwith debrisoquin or reserpine or combinations of theseagents. It can be seen that reserpine treatment moves theresponse curve slighfly to the right (reduced response), de-brisoquin moves the curve markedly to the left (increasedresponse) and the addition of either drug to the other resultsin an intermediate curve.

dose-response curve to tyramine to the right, de-brisoquin moves it to the left and when eitherdrug was added to the other, the dose-responsecurves take an intermediate position.64 In otherwords, each drug reverses the effect of the other.Debrisoquin alone neither depletes nor accumu-lates norepinephrine in sympathetic tissues.62 How-ever, debrisoquin, and also bretylium and bethan-idine, inhibit the depleting action of reserpine andin some instances guanethidine.65

Intensive studies in humans have demonstratedthat in addition to increasing the pressor responsesto intravenously administered tyramine, debri-soquinc treatment is associated with a decreasedurinary excretion of VMA, an increased excretionof normetanephrine and no changes in the excre-tion of tryptamine and tyramine.6466 These changesare best explained by monoamine oxidase inhibitioninvolving peripheral sympathetic neurons but not

the kidney or gastrointestinal tract. Indeed, Gia-

chetti and Shore7 have demonstrated that debriso-quine, bretylium and other adrenergic neuronalblocking agents are selectively accumulated bysympathetic tissues achieving concentrations whichare capable of MAO inhibition. Further confirma-tion is provided by the observations in our lahora-tories that human platelet MAO is inhibited whenthe platelets are exposed to appropriate concentra-tions of debrisoquin.#{176}8 Debrisoquin bretylium,bethanidine and certain other neurone blockingagents reverse the reserpine-induced reduction inthe pressor responses to tyramine by protecting nor-epinephrine released from the granules by reserp-ine from MAO in the mitochondrial membrane.Thus, these agents lower blood pressure not onlyby neuronal blockage,60 but perhaps also by themechanisms attributed to the MAO inhibitors. Thisselective MAO inhibition creates the possibility ofpressor reactions in treated patients from indirectacting pressor amines, such as tyramine, admin-istered parenterally but not orally or in foods, sincegastrointestinal MAO is intact. Guariethidine is alsoselectively accumulated by sympathetic nerves,70but differs in not being an MAO inhibitor;7 thus,when guanethidine releases norepinephrine fromthe storage granules, catecholamine depletion en-sues. The precise mechanism by which all the neu-

iao ronal blocking agents interfere with impulse trans-mission at the neuroeffector junction appears to bea local anesthetic effect involving the preterminalsympathetic fibers.72 This action is related to theaccumulation of high concentrations of these agents

in this area.

Finally, we come to drugs acting directly on ar-




terioles to produce vasodilation. The importantagents here are hydralazine, diazoxide and the oraldiuretics (Fig 6).

The pharmacologic properties of hydralazine(Apresoline) were first reported in 1950 and clini-cal trials followed promptly. In 1953, hydralazinebecame commercially available in the United Statesand dthydralazine was introduced in Europe. Theseagents remain useful to this day despite the adventof several new classes of antthypertensive drugs.Extensive pharmacologic studies over many yearshave shown hydralazine to be a nonspecific inhibi-tor of a variety of vasoconstrictor stimuli such ashistamine, barium chloride, vasopressin, pressoramines and sympathetic tone.74 This evidence, plusthe clinical behavior of producing hypotension andreflex tachycardia, indicates these drugs produce di-rect vasodilatation. The precise mechanism of thevasodilatation is not clear, but may involve chela-tion of metal ions,75 monoamine oxidase inhibi-tion,7#{176}DOPA decarboxylase inhibition76 and/or cat-echolamine depletion.77 Pharmacodynamic studiesin man confirm that blood pressure is lowered by adecrease in peripheral vascular resistance due toarteriolar vasodilatation.78 There is evidence thatrenal arterioles are especially affected; thus, renalblood flow is preserved unless the blood pressurefall is marked. For this reason the hydralazines areoften recommended for hypertensive individualswith renal vascular damage. Despite their favorablepharmacodynamic properties, the clinical use of thehydralazines is limited by side effects. These in-dude headache, palpitations, nausea and vomiting,diarrhea, nasal congestion, conjunctivitis, drugfever, skiii rash, peripheral neuropathy and bonemarrow suppression. The cardiac stimulation re-sponsible for the palpitations is attributed to sym-pathetic reflexes, but may involve direct stimulationas well. This effect may precipitate angina pectorisand ECG changes in atherosclerotic subjects. Themost notorious side effect is a disseminated lupuserythematosis-like syndrome indistinguishable fromthis disease. The incidence of major side effects canbe minimized by limiting the daily dosage to 200mg.

Oral diuretic therapy is the cornerstone of thetreatment of hypertension. Wide acceptance ofthese agents followed by the synthesis of chloro-thiazide by Novello and Sprague in 1957 and theinitial reports of clinical utility.8081 The applica-tion of the oral diuretics to the treatment of hyper-tension was based on the clinical observation thatdietary restriction of sodium is beneficial in thisdisorder.82 Despite the truth of this observation,

and the naturetic activity (by definition) of the oraldiuretics, salt and water depletion contributes to the

antihypertensive activity of these agents only in theinitial phases of treatment. At this stage the fallin blood pressure is associated with reductions inthe plasma and extracellular fluid volumes and totalexchangeable sodium and potassium.8386 Cardiacoutput is decreased and peripheral vascular resis-tance is moderately increased.838587 These effectscan he at least partially reversed by salt or volumereplacement.838486 After weeks or months of treat-ment, however, plasma volume and cardiac outputreturn to normal levels,848588 but peripheral vascu-lar resistance is reduced8587 and the blood pres-sure remains lowered. At this stage the antihyper-tensive effects are not reversible by volume orsodium replacement.88 The significance of salt andwater depletion in the chronic antihypertensivemechanism of these agents is also diminished by theobservations that chlorothiazide lowers blood pres-sure despite the maintenance of sodium balance byfluorohydrocortisone89 and that the degree of bloodpressure lowering appears unrelated to weight lossor diuresis.#{176}#{176}It has been demonstrated that chioro-thiazide directly diminishes vascular resistance inthe forearm.#{176}#{176}The exact mechanism of this directeffect is not clear. It has been suggested thatthiazides diminish the pressor responses to norepi-

nephrine9 and angiotensin,92 but such were notconfirmed subsequently.93 On the other hand it istrue that mercurial diuretics and oral diuretic sub-stances with diverse chemical structures possessantihypertensive activity. This may be related tothe mechanisms operating during the initial phasesof treatment or to a role of electrolytes and/orvolume in the control of vasomotor tone.9194

The advent of diazoxide has provided importantevidence for a direct vascular effect of this classof drugs and has provided a focus for researchon this subject. This benzothiadiazine analogue pro-duces salt and water retention by renal mechanismsyet is a very potent hypotensive agent.#{176}5 The oraluse of diazoxide leads to fluid retention and hyper-

glycemia,9697 but when administered intravenouslyfor short periods of time in subjects with severehypertension, it is very effective, and the effects

may persist long after treatment.98 Hemodynam-ically, diazoxide reduces arteriolar tone in animals99and in man.97 Pharmacologically, like hydralazine,it nonspecifically suppresses the vascular responses

to a variety of vasoconstrictor agents.95 This sug-gests an inhibition of a basic contractile mechanism,

and WohI and co-workers10#{176} have demonstratedthat diazoxide inhibits the vasoconstrictive actions




of barium, used to represent calcium in their ex-periments because of greater potency. Althoughthe central role of calcium in the contractile processis well known, and it is true that the disorder ofcalcium metabolism has been implicated in thegenesis of hypertension,101 further evidence will beneeded to establish this mechanism as the locusof action of diazoxide and the oral diuretics.

As mentioned previously, all oral diuretic agents,including benzothiadiazines, phthalimidines, car-bonic anhydrase inhibitors, aldosterone antagonistsand the recent additions, ethacrynic acid and furo-semide, are antihypertensive.#{176}2103 Except fordiazoxide, they are about equipotent for this in-dication and are capable of only mild reductionsin blood pressure levels in therapeutic doses. Thedose-response curve for blood pressure lowering ismaximum at approximately 1.0 gm of chiorothiazideor its equivalent per day. In clinical use, normaliza-tion of blood pressure can be accomplished withoral diuretics alone only in some mildly hyperten-sive subjects. It is well established, however, thatthese agents potentiate the effects of more potentdrugs and permit the latter to be used at lowerdoses and with fewer side effects. The oral di-uretics (benzothiadiazines and phthalimidines ) areextremely well tolerated in the usual hypertensivesituation. Mild hypokalemia, hyperuricemia andhyperglycemia are observed regularly, but arerarely of clinical signfficance. Pre-existing renal in-

sufficiency may be aggravated and the blood urea

nitrogen levels increased. Hypersensitivity reactionsare rare.

Clinically, the diuretics and reserpine are usedalone or together for mild or moderately severehypertension. One must always be cautious of theinsidious depression which may occur with reser-pine. In cases failing to respond, methyldopa orhydralazine may he given with a diuretic or re-serpine. In more severe situations, an adrenergicneurone blocking agent may be added to the regi-men. The concomitant use of reserpine, guan-ethidine and/or methyldopa should be employedwith caution since all are catecholamine depleters.

Pargyline is useful in depressed hypertensives be-

cause of its mood-elevating properties. It shouldnot be used with methyldopa, parenteral reserpine,sympathomimetic agents or tricycline antidepres-sants. Reserpine, methyldopa and hydralazine areavailable in parenteral formulations for hyperten-sive emergencies.

In conclusion, the immediate and long-termcourse of essential hypertension can be favorablyaltered by a variety of drugs. The proper use of

these drugs requires a knowledge of their pharma-cology, toxicology and interactions with other drugs.In this paper some of these aspects are reviewedwith special emphasis on the mechanisms of actionin man.

ACKNOWLEDGMENT: The author is grateful to his as-sociates Drs. William A. Pettinger, Robert Pocelinko andHarvey M. Solomon for the use of their work in this paper.He is also grateful for the assistance of Mrs. Lillian Hemand Miss Maureen Cufone in the preparation of the manu-script.

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3 PETERSON, L. H. : Hemodynamic alterations in essen-tial hypertension, in: Brest, A. N. and Moyer, J. H.(Ed.) Hypertension: Recent Advances, Lea & Febiger,Philadelphia, 1961.

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from the heart and lungs, Physiol. Rev., 34: 167, 1954.19 BORISON, H. L., FAImsAr.ncs, V. F., AND WHITE, C. A.:

Afferent reflex factors in veriloid-induced hypotension,Arch. mt. Pharmacodyn., 101:189, 1955.




20 BomsoN, H. L., AND FAIRBANKS, V. F. : Mechanism ofveratrum induced emesis in the cat, I. Pharmacol. Exp.Ther., 105:317, 1952.

21 Amtss, W. B., PocEuNxo, R., MOE, R. A., BATES,H., HANAUER, L., AND CAMACHO, S. : The clinicalpharmacology of postganglionic sympathetic blockingagents, Dis. Chest, 48:178, 1965.

22 HEYMANS, C., DE SCHAEPDRYVER, A. F., DE VLEE5cH-HOUWER, C. H., TAQUINI, A. C., JR., AND VAN DEllSCHOOT, J. B. : Effects of reserpine on the cardio-inhibitory and vasomotor centers, Arch. mt. Pharma-codyn., 134:482, 1961.

23 KLETZKIN, M. : Neuropharmacological studies of themechanism of action of the centrally acting anti-hy-pertensive mebutamate, Arch. mt. Pharmacodyn., 164:71, 1966.

24 MOYER, J. H.: Hydralazine (Apresoline) hydrochlor-ide; pharmacological observations and clinical resultsin the therapy of hypertension, A.M.A. Arch. Intern.Med., 91:419, 1953.

25 DRUEY, J., AND TRIPOD, J.: In ref. 1, p. 223.26 BERGEn, F. M., DoUGzs, J. F., KLETZIUN, M., LuDwIG,

B. J., AND MARGOLIN, S. : The pharmacological prop-erties of 2-methyl-2-sec-butyl-1,3-propanediol dicarba-mate (mebutamate, W-583), a new centrally actingblood pressure lowering agent, J. Pharmacol. Exp.Ther., 134:356, 1961.

27 MARGOLIN, S., PLEKSS, 0. J., AND FEDOR, E. J. : Selec-tive inhibition of dog spinal vasoconstrictor tracts bymebutamate, J. Pharmacol. Exp. Ther., 140: 170, 1963.

28 WANG, H. H., MARKEE, S., KAHN, N., MILLS, E., ANDWANG, S. C.: Mechanism of hypotensive action ofmebutamate, J. Pharmacol. Exp. Ther., 151:285, 1966.

29 DAVEY, M. J., AND REINERT, H.: Pharmacology of theantihypertensive guanoxan, Brit. 1. Pharmacol., 24:29,1965.

30 Rusny, J., AND DAvirs, R. 0.: A comparative trial ofguanoxan and guanethidmne in essential hypertension,Clin. Pharmacol. Ther., 8:38, 1967.

31 FROHLICH, E. D., DUSTAN, H. P., AND PAGE, I. H.:Some dinical effects of guanoxan, Clin. Pharmacol.Ther., 7:599, 1966.

32 SATTLER, R. W., AND VAN ZWIETEN, P. A.: Acutehypotensive action of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (St 155) after infusion intothe cats vertebral artery, Europ. J. Pharmacol., 2:9,1967.

33 KOBINGER, W. : Uber den Wirkungsmechanismus einerneuen antihypertensiven Substanz mit Imidazolin-struktur, Arch. Pharmakol, Exptl. Pathol., 258:48,1967.

34 SCHMITT, H., Scrnrrrr, MME H., BoIssIER, J. R., ANDGITJDICELLI, J. F. : Centrally mediated decrease insympathetic tone induced by 2(2,6-dichlorophenyl-amino)-2 imidazoline (S.T. 155, Catapresan), Europ.J. Pharmacol., 2:147, 1967.

35 HOEFKE, W., AND KOBINGER, W.: PharmakologischeWirkungen des 2-(2,6-dichlorphenylammno)-2-imidazo-lin-hydrochlorids, einer neuen, antihypertensiven Sub-stanz, Arzneimittel-Forsch., 16:1038,1966.

36 NAYLER, W. C., ROSENBAUM, M., McINNE5, I., ANDLOWE, T. E.: Effect of a new hypotensive dnig, ST155, on the systemic circulation, Amer. Heart J., 72:764, 1966.

37 Bocx, K. D., HEnssoni, V., MERGUET, P., AND ScH#{246}N-ERMARK, J. : Klinische und klinisch-experimentelle Un-

tersuchungen mit einer neuen blutdrucksenkendenSubstanz: Dichlorphenylammnoimidazolin, Deut. Med.Wochschr., 91:1761, 1966.

38 DAVIDOV, M., KAKAVIATOS, N., AND FINNERTY, F. A.,JR. : The antihypertensive effects of an imidazolinecompound, Clin. Pharmacol. Ther., 8:810, 1967.

39 IlsALo, E., AND LAURILA, S.: A clinical trial with anew antihypertensive drug, ST-155 (Catapresan),Curr. Ther. Res., 9:358, 1967.

40 BAUM, P. : Experimentelle Untersuchungen zur Nie-ren-Hamodynamik und zum Verhalten der Elektrolytenach einmaliger Verabreichung von 2-(2,6-Dichlor-phenylammno)-2-imidazolmn-hydrochlorid, Arzneimittel-Forsch., 16:1162, 1966.

41 K0cH5IEK, K., AND FRITSCHE, H.: Die Wirkung einesImidazolin-Derivates auf den arteriellen Blutdnick, dieHamodynamik und die Ventilation, Arzneimittel-For-sch., 16:1154, 1966.

42 HILLARP, N-A.: The construction and functional or-ganization of the autonomic innervation apparatus,Acta. Physiol. Scand., 46:Suppl. 157, 1959.

43 Porrmi, L. T.: Role of intraneuronal vesicles in thesynthesis, storage and release of noradrenaline, Circu-lat. Res., ll:supp. 3, 13, 1967.

44 KOPIN, I. J., AND CORDON, E. K.: Metabolism of ad-ministered and drug released norepmnephrine-7-H3 inthe rat, 1. Pharmacol. Exp. Ther., 140:207, 1963.

45 COSTA, E., BOULLIN, D., HAMMER, W., Voc, W.,AND BRODIE, B. B. : Interactions of drugs with adrener-gic neurons, Pharmacol. Rev., 18:577, 1966.

46 VON EULER, U. S., AND LISHAJRO, F. : Mechanism ofdrug-induced catecholamine release from adrenergicnerve granules, Circulat. Res., 21:Supp. III, 63, 1967.

47 DAY, M. D., AND RAND, M. J.: A hypothesis for themode of action of a methyldopa in relieving hyper-tension, I. Pharm. Pharmacol., 15:221, 1963.

48 MUSCHOLL, E., AND MAITRE, L. : Release by sympa-thetic stimulation of a methylnorepinephrmne storedin the heart after administration of a methyldopa,Experimentia, 19:658, 1963.

49 DAY, M. D., AND RAND, M. J. : Some observations onthe pharmacology of a methyldopa, Brit. J. Pharma-col., 22:72, 1964.

50 PHILIPPU, A., AND SCHUMANN, H. J.: Effect of a-methyldopa, a-methyldopamine and a-methylnor-epinephrine on the norepinephrine content of theisolated heart, Life Sci., 4:2039, 1965.

51 SANNERSTEDT, R., VARNAUSKA5, E., AND WERK#{246}, L.:Hemodynamic effects of methyldopa (Aldomet#{174}) at restand during exercise in patients with arterial hyper-tension, Acta. Med. Scand., 171:75, 1962.

52 MOHAMMED, S., HANESON, I. B., MAGENHEIM, H. C.,AND GAFFNEY, T. E.: The effects of alpha-methyldopaon renal function in hypertensive patients, Amer.Heart J.,76:21, 1968.

53 Cnovr, J. D., SWISHER, S. N., Ja., GILLILAND, B. C.,BAKEMEIER, R. F., LEDDY, J. P., AND WEED, R. I.:Coombs-test positivity induced by drugs. Mechanismsof immunologic reactions and red cell destruction,Ann. Intern. Med., 68:176, 1968.

54 SCHOEPKE, H. C., AND WIEGAND, R. C. : Relation be-tween norepinephrine accumulation or depletion andblood pressure responses in the cat and rat followingpargyline administration, Ann. N.Y. Acad. Sci., 107:924,1963.

55 KOPIN, I. J., FISCHER, J. E., MUSACCHIO, J. M., HORST,




W. D., AND WEISE, V. K. : False neurochemical trans-mitters and the mechanism of sympathetic blockadeby monoamine oxidase inhibitors, J. Pharmacol. Exp.Ther., 147:186, 1965.

56 SPECTOR, S., CORDON, R., SJOERDSMA, A., AND UDEN-FRIEND, S.: End product inhibition of tyrosine by-droxylase as a possible mechanism for regulation ofnorepmnephrmne synthesis, Molec. Pharmacol., 3:549,1967.

57 Osrr, C., HOVACK, P., RAifmr.z, 0., BREST, A. N.,AND MOYER, J. H. : Hemodynamic effects of pargylinein hypertensive patients, Circulation, 30:830, 1964.

58 GOLDBERG, L. I., Hollwrrz, D., AND SJOERDSMA, A.:Attenuation of cardiovascular responses to exercise as apossible basis for the effectiveness of monoamine oxi-dase inhibitors in angina pectoris, J. Pharmacol. Exp.Ther., 137:39, 1962.

59 Honwirz, D., LOVENBERG, W., ENGELMAN, K., ANDSJOERDSMA, A. : Monoamine oxidase inhibitors, tyra-mine and cheese, J.A.M.A., 188:1108, 1964.

60 MITCHELL, J. R., ARIAS, L., AND OATES, J. A. : An-tagonism of the antihypertensive action of guanethi-dine sulfate by desipramine hydrochloride, J.A.M.A.,202:149, 1967.

61 PETTINGER, W. A., MITCHELL, J. R., AND OATES, J.A. : Cardiovascular effects and toxicity of psychotropicagents in man, in Psychopharmacology. A Review ofProgress, Ed. Daniel H. Effron (in press).

62 MOE, R. A., BATES, H. M., PALKOSKI, Z. M., ANDBANZIGER, R. : Cardiovascular effects of 3, 4-dihydro-2 (1H) isoqumnoline carboxamidine, Cur. Ther. Res.,6:299, 1964.

63 ABRAMS, W. B., Pocm..ixo, R., KLAUSNER, M., HAN-AUER, L., AND WHITMAN, E. N. : Clinical pharmaco-logical studies with debrisoquin sulfate, a new anti-hypertensive agent, I. New Drugs, 4:268, 1964.

64 POCELINKO, R., ABRAMS, W. B., CAMACHO, S., ANDTAYIon, W. J. R.: Effect of debrisoquin sulfate oncatecholamine metabolism in hypertensive subjects,Abstract, American College of Clinical Pharmacology,Spring 1967.

65 BOURA, A. L. A., AND GREEN, A. F. : Adrenergic neuronblocking agents, Ann. Rev. Pharmacol., 5:183, 1965.

66 PETTINGER, W. A., KORN, A., PocaTNxo, R., MAYNARD,D., AND SoLoroN, H. M.: Selective inhibition of sym-pathetic neuronal monoamine oxidase (MAO) by de-brisoquin in man, Clin. Res., 16:244, April, 1968.

67 CIACHETTI, A., AND SHORE, P. A.: Monoamine oxidaseinhibition in the adrenergic neuron by bretylium, de-brisoquin and other adrenergic neuronal blockingagents, Biochem. Pharmacol., 16:237, 1967.

68 SoLoMoN, H. M., ASHLEY, C., SPIRIT, N., ANDABRAMS, W. B.: The human platelet. A workingmodel for the adrenergic neurone 1. In-vivo and in-vitro studies with debrisoqumn, Clin. Pharmacol. Ther.,(in press).

69 BOURA, A. L. A., Cops, F. C.. GREEN, A. F., HODSON,H. F., RUFFELL, C. K., Svi, M. F., WALTON, E., ANDGRIVSKY, E. M.: Adrenergic neurone-blocking agentsrelated to choline 2,6-Xylyl ether bromide (TM1O),bretylium and guanethidmne, Nature, 191:1312, 1961.

70 SCHANKER, L. S., AND MORRISON, A. S. : Physiological(lispOSitIOfl of guanethidmne in the rat and its uptakeby heart slices, Int. J. Neuropharmacol., 4:27, 1965.

71 KUNTZMAX, R., AND JACOBSON, M. M. : Monoamineoxidase inhibition by a series of compounds struc-

turally related to bretylium and guanethidine, I.Pharmacol. Exp. Ther., 141: 166, 1963.

72 Boua, A. L. A., AND GREEN, A. F.: The actions ofbretylium, adrenergic neurone blocking and othereffects, Brit. J. Pharmacol, 14:536, 1959.

73 FREIS, E. D., AND FINNERTY, F. A., Jn.: Suppressionof vasomotor reflexes in man following L-Hydra-zi.nophthalazine (C5968), Proc. Soc. Exp. Biol. Med.,75:23, 1950.

74 DRUEY, J., AND TRIPOD, J.: Hydralazines in antihyper-1tensive agents, Ed. E. Schlittler, Academic Press, NewYork and London, 1967.

75 PERRY, H. M., AND SCHROEDER, H. A.: Studies on thecontrol of hypertension by Hypex. III: Pharmacolog-ical and chemical observations on 1-hydrazmnophthal-azine, Amer. J. Med. Sci., 228:396, 1954.

76 SCHROEDER, H. A.: In Hypertension, First HahnemannSymposium on Hypertensive Disease, Ed. j. H. Moyer,Saunders, Philadelphia, 1959.

77 BYGDEMAN, M., AND STJARNE, L.: Animal physiology:Effects of 1,4-dihydrazmnophthalazmne on the catechol-amine, Nature, 186:82, 1960.

78 ROWE, C. C., HUSTON, j. H., MAXWELL, C. M., CROS-LEY, A. P., JR., AND CRUMPTON, C. W. : Hemodynamiceffects of 1-hydrazinophthala7ine in patients with ar-terial hypertension, I. Gun. Invest., 34: 1 15, 1955.

79 NOVELLO, F. C., AND SPRAGUE, J. M. : Benzothiadiazinedioxides as novel diuretics, J. Amer. Chem. Soc., 79:2028, 1957.

80 FREIS, E. D., AND WilsoN, I. M.: Potentiating effectof chlorothiazide (Diuril) in combination with anti-hypertensive agent, Med. Ann. D.C., 26:468, 1957.

81 HOLLANDER, W., AND WILKINS, R. W. : Chlorothiazide,a new type of drug for the treatment of hypertension,Boston U. Med. Quart., 8:69, 1957.

82 GROLLMAN, A., HARRISON, T. R., MASON, M. F., BAX-TER, J., CRAMPTON, J., AND REICHSMAN, F. : Sodiumrestriction in the diet for hypertension, J.A.M.A., 129:533, 1945.

83 DUSTAN, H. P., CUMMING, C. R., CORCORAN, A. C.,AND PAGE, I. H. : A mechanism of chlorothiazide-enhanced effectiveness of antihypertensive gangliopleg-ic drugs, Circulation, 19:360, 1959.

84 WILSON, I. M., AND FRETS, E. D.: Relationship be-tween plasma and extracellular fluid volume depletionand the antihypertensive effect of chlorothiazide, Cir-culation, 20:1028, 1959.

85 CONWAY, j., AND LAUWERS, P. : Hemodynamic andhypotensive effects of long term therapy with chloro-thiazide, Circulation, 21:21, 1960.

86 WINER, B. M.: The antihypertensive action of henzo-thiadiazines, Circulation, 23:21 1, 1961.

87 VILLARREAL, H., EXAIRE, J. E., REVOLLO, A., ANDSorn, J. : Effects of chlorothiazide on systemic hemo-dynamics in essential hypertension, Circulation, 26:405,1962.

88 HOLLANDER, W., CHOBANTAN, A. V., AND WILKINS,R. W. : The role of diuretics in the management ofhypertension, Ann. N.Y. Acad. Sci., 88:975, 1960.

89 HOLLANDER, W., CHOBANIAN, A. V., AND WILKINS,R. W.: Relationship between diuretic and antihyper-tensive effects of chlorothiazide and mercurial di-uretics, Circulation, 19:827, 1959.

90 CONWAY, J., AND PALERMO, H. : The vascular effectof the thiazide diuretics, Arch. mt. Med., 11:203,1963.


AMERICAN COLLEGE OF CHEST PHYSICIANS1969 ALFRED A. RICHMAN ESSAY CONTEST



91 ALEKSANDROW, D., WYSNACKA, W., AND CAJEWSKI,J. : Influence of chlorothiazide upon arterial respon-siveness to norepinephrine in hypertensive subjects,New Eng. 1. Med., 261:1052, 1959.

92 GILLENWATER, J. Y., Scorr, J. B., AND FROHLKH,E. D. : Effect of chlorothiazide on response of renalvascular bed to vasoactive substances, Circ. Res., 11:283, 1962.

93 SILAH, J. C., Jos, R. E., BASHOUR, F. A., ANDKAPLAN, N. M. : The effect of acute administration ofchlorothiazide upon the pressor responsiveness to an-giotensin and norepinephrine, Amer. Heart J., 69:301,1965.

94 CIFFORD, R. W., JR., MATTOX, V. R., Onvis, A. L.,S0NE5, D. A., AND RO5EVEAR, j. W. : Effect of thiazidediuretics on plasma volume, body electrolytes, andexcretion of aldosterone in hypertension, Circulation,24:1197, 1961.

95 RurnN, A. A., ROTH, F. E., TAYLOR, R. M., ANDROSENKILDE, H. : Pharmacology of diazoxide, an anti-hypertensive, nondiuretic benzothiadiazine, I. Pharm-acol. Exp. Ther., 136:344, 1962.

96 HUTCHEON, D. E., AND BARTHALMUS, K. S. : Anti-hypertensive action of diazoxide, Brit. Med. I., 2:159,1962.

97 Wa.soN, W. R., AND OKUN, R.: The acute hemody-

Each year the College offers undergraduate medicalstudents throughout the world the opportunity to sub-mit manuscripts on any phase of the diagnosis andtreatment of cardiovascular or pulmonary disease, inopen competition.

Medical students wishing to enter the 1969 Alfred A.Richman Essay Contest of the American College of

Chest Physicians should observe the following rules:

1) Complete application form in duplicate, haveoriginal copy signed by the dean of the medicalschool, and return original copy at once to theAmerican College of Chest Physicians, 1 12 EastChestnut Street, Chicago, Illinois 60611.

2) Five copies of the manuscript, typewritten inEnglish (double spaced) must be submitted tothe American College of Chest Physicians officesin Chicago not later than April 15, 1969.

3) The length of manuscripts is optional; 2500-4500words suggested.

4) The only means of identification of the authorshall be a motto or other device on the title page.

namic effects of diazoxide in man, Circulation, 28:89,1963.

98 FINNERTY, F. A., DAVJDOV, M., AND KAKAVIATOS, N.:Hypertensive vascular disease. The long term effect ofrapid repeated reductions of arterial pressure withdiazoxide, Amer. J. Cardiol., 19:377, 1967.

99 RurnN, A. A., ZlTowrrz, L., AND HAUSLETI, L. M.:Acute circulatory effects of diazoxide and sodium ni-trate, J. Pharmacol. Exp. Ther., 140:46, 1963.

100 WOHL, A. J., HAU5LER, L. M., AND ROTH, F. E. : Stud-ies on the mechanism of antihypertensive action ofdiazoxide: In vitro vascular pharmacodynamics, J.Pharmacol. Exp. Ther., 158:531, 1967.

101 HIrncE, J. A. M.: Effect of Ca+ + upon contractilityof small arteries from DOCA-hypertensive rats, Circ.Res., 18-19:suppl. 1, 23, 1966.

102 WOLD, R. L., MENDLOWIrZ, M., Ronoz, J., AND Crr-LOW, S.: Treatment of hypertension with antihyper-tensive diuretic drugs, Amer. Heart I., 72:692, 1966.

103 DE STEVENS, C. : Diuretics in the clinical treatment ofhypertension, in The pathogenesis of hypertension inmedicinal chemistry, (Vol. 7) Ed.: Emil Schlittler,Academic Press, New York, 1967.

Reprint requests: Dr. Abrams, Hoffmann-La Roche, Inc.,Nufley, New Jersey.

A sealed envelope bearing the same motto on theoutside and enclosing the name and address of

the author must accompany the essay. (Mottomax be a word or brief phrase which has a sig-nificant meaning to the author.)

The First Prize will be $500; Second Prize will be $300;Third Prize will be $200. Each winner will also receivea certificate of merit. A trophy, inscribed with the name

of the First Prize winner and the name of his schoolwill be awarded to the winners school.

The winning contributions will be selected by a corn-mittee of chest specialists at the 35th Annual Meeting

of the American College of Chest Physicians to be heldin Chicago, Illinois in October, 1969. All manuscriptsbecome the property of the American College of Chest

Physicians and may be considered for publication in theCollege journal.

It is suggested that applicants study the format of theCollege journal, DISEASES OF THE CHEST, to guidethem in preparing the essay. A copy will be sent onrequest.


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