temporal relationship between the decrease in arterial pressure and sodium retention in conscious...

Temporal Relationship between the Decrease in Arterial Pressure and Sodium Retention in Conscious

Spontaneously Hypertensive Rats with Carbon Tetrachloride-induced Cirrhosis

CLARA LOPEZ, WLADIMIRO JIMENEZ, VICENTE ARROYO, JOAN Clh IA, GIORGIO LA VILLA, MONICA &BERT,

Hormonal Laboratory and Liver Unit, Hospital Clinic i Provincial, Barcelona 08036, Spain. JOAN GAYA, FRANCISCA RIVERA AND JOAN RODES

It has been proposed that the initial event of sodium retention in cirrhosis is a peripheral arteriolar vasodilation causing underfilling of the arterial vascular compartment and stimulation of the renin-aldosterone and sympathetic nervous systems. To test this hypothesis, systolic blood pressure, sodium balance and urinary excretion of sodium and aldosterone were sequentially measured in 13 conscious spontaneously hypertensive rats submitted to a cirrhosis induction program with carbon tetrachloride and phenobarbital and in 14 control hypertensive animals. No significant differences were found between control and cirrhotic rats in any of the measured parameters during the first 7 wk of the study. The eighth week sodium retention developed in cirrhotic rats as indicated by a positive sodium balance and a marked decrease of sodium excretion. At the same time a significant reduction in systolic blood pressure and a great increase in urinary excretion of aldosterone were detected. These changes were more marked the ninth week of the study. In cirrhotic rats there was a highly significant direct correlation between systolic blood pressure and urinary sodium excretion. Postmortem examination showed a histological picture of cirrhosis in all animals given carbon tetrachloride and ascites in six of them. These results indicate that the onset of hyperaldosteronism and sodium retention in conscious spontaneously hypertensive rats with carbon tetrachloride- induced cirrhosis is chronologically related to a significant decrease in arterial pressure, thus supporting the “peripheral arterial vasodilation hypothesis” of ascites. (HEPAMLAXY 1991; 13:585-589.)

Received January 29, 1990; accepted October 31, 1990. Supported by grants from FISS (91/0015) and CAICYT (PA 86/0405). Joan Cliria and Monica Asbert had grants from Fundacio Catalana per

Giorgio La Villa is a visiting investigator from the Clinica Medica 11,

Address reprint requests to: Wladimiro Jimknez, Ph.D.. Hormonal Labo-

31/1/26999

1’Estudi de les Malaties del Fetge and CIRIT, respectively.

University of Florence School of Medicine, Italy.

ratory, Hospital Clinic i Provincial, Villanoel 170, Barcelona 08036, Spain.

Present evidence from human and experimental studies indicates that the renin-aldosterone and the sympathetic nervous systems and antidiuretic hormone play an important role in the pathogenesis of sodium and water retention and ascites formation in cirrhosis (1-8). Recently it has been proposed that the initial event leading to these abnormalities is a reduction in peripheral vascular resistance (9). According to this theory, portal hypertension, by inducing a generalized splanchnic arteriolar vasodilation (10-141, would lead to underfilling of the arterial vascular compartment, de- creased arterial pressure, high pressure-baroreceptor- mediated activation of the renin-aldosterone and sympathetic nervous systems and antidiuretic hormone hypersecretion, sodium and water retention and accu- mulation of the retained fluid within the abdominal cavity.

This study was made to investigate whether, as proposed by this peripheral arterial vasodilation hypothesis, the onset of hyperaldosteronism and sodium retention is chronologically related to a decrease in arterial pressure in an experimental model of CCL,- induced cirrhosis in rats. Despite the well-known dif- ference in the renal perfusion pressure-natriuresis relationship between normotensive rats and spontaneously hypertensive rats (SHRs) (15, 16), this latter strain was selected for investigation to obtain reliable sequential measurements of arterial pressure by a noninvasive method in conscious animals and to detect minor reductions of blood pressure.

MATERIAL AND METHODS The investigation was performed in SHRs (Wistar-Kyoto

strain, Charles River Espafia, Barcelona, Spain) and includes 27 male rats 12 wk of age (270 to 290 gm body weight). These animals were placed in individual metabolic cages and fed ad libitum with normal sodium chow (74 mEq Na/kg food) and distilled water as drinking fluid. After allowing 1 wk for adaptation, a group of 13 rats (CT-SHRs) was submitted to a cirrhosis-induction protocol with CCl, and phenobarbital, as described elsewhere (6). CC1, was given by inhalation twice

585

586 LOPEZ ET AL. HEPATOLOGY

weekly (Monday and Saturday) throughout the study and phenobarbital was added to drinking water. The remaining 14 rats only received phenobarbital and served as controls.

Measurements of the 24-hr sodium intake, urine volume, urinary sodium excretion (UNaV) and urinary excretion of creatinine were made on three consecutive days each week (Tuesday, Wednesday and Thursday) during all the study. Sodium balance was calculated by subtracting daily U,,V from daily sodium intake. An aliquot of each 24-hr urine collection was frozen a t - 30" C until analyzed to determine the urinary excretion of aldosterone-18-glucuronide CU,,,V). Systolic blood pressure (SBP) and heart rate (HR) were measured once weekly (Friday) by tail-cuff plethysmography using an elec- trosphygmomanometer (LE 5000, Letica Scientific Instru- ments, Hospitalet de Llobregat, Spain) standardized with a mercury manometer. Results given represent the mean of five consecutive measurements, which were performed with conscious animals restrained in plastic cages on a warmed (30" C) heating table. Rats were habituated to this procedure during several training sessions. SBP and HR were always measured after 10 min of acclimation. Body weight was recorded after SBP measurement and a blood sample (0.5 ml) was obtained with the rats under light ether anesthesia from the cavernous sinus to measure serum creatinine concentration.

Since sodium retention developed in all CT-SHRs between the seventh and the ninth week after starting the cirrhosis- induction program, the study was finished at the end of the ninth week. CT-SHRs and control SHRs were then killed, and the abdominal cavity was opened to assess the presence of ascites and to obtain a liver sample. Liver specimens were stained with hematoxylin and eosin, Masson's trichrome stain and reticulin stain for histological examination. The study was performed according to the Hospital Clinic i Provincial Committee's guidelines for the care and use of laboratory animals.

Sodium was measured by flame photometry and creatinine by the Jaffe reaction. Aldosterone- 18-glucuronide was eval- uated in urine samples (250 p1) incubated for 24 hr with HCl 3.2 N (25 pl). Aldosterone was then extracted with ethyl acetate and measured by RIA (Diagnostic Products Corpo- ration, Los Angeles, CAI.

Data are presented as means * S.E.M. Comparison between CT-SHRs and control SHRs was made with Student's t test for unpaired data. Comparison within the same group was performed using the paired t test. The two-variable regression analysis was used to correlate SBP, U,,V and U,,V.

RESULTS Table 1 shows U,,V, sodium balance, U,,V and

creatinine clearance during the last 4 wk of the study in CT-SHRs and control SHRs. These parameters remained steady in control animals throughout the study. No significant changes in sodium intake were observed during the entire protocol in CT-SHRs and control animals. The amount of sodium ingested by CT-SHRs did not differ significantly from that of control rats at any time of the study. Sodium retention developed in all CT-SHRs, as indicated by a clear reduction in U,,V and a positive sodium balance. This was observed at the seventh week in two animals, a t the eighth week in four animals and at the ninth week in the remaining seven animals. A close chronological relationship existed between the onset of sodium retention and the development of hyperaldosteronism in this group of rats. During the first 7 wk of the study, CT-SHRs showed

U,,V, sodium balance and U,,,V similar to control rats. At the eighth week, a significant reduction in U,,V, a clearly positive sodium balance and a marked increase in U,,V were observed in CT-SHRs. These changes were more pronounced at the ninth week. A significant inverse correlation existed between U,,V and U,,V in CT-SHRs (r = -0.68, p < 0.001). Sodium retention occurred in the absence of changes in creatinine clearance.

Systolic blood pressure in CT-SHRs and control SHRs is depicted in Figure 1. SBP remained steady in control rats throughout the study. During the first 7 wk of the study, CT-SHRs showed SBP similar to control animals. However, at the eighth week SBP in CT-SHRs was significantly reduced with respect to both values obtained on previous weeks in the same group and values obtained on the same week in control animals. The reduction in arterial pressure was even more marked at the ninth week. Figure 2 shows that a close temporal relationship existed between the decrease in systolic blood pressure and the onset of sodium retention in CT-SHRs. A direct linear correlation in these animals between SBP and U,,V also was found (Fig. 3). CT-SHRs showed HR similar to control rats throughout the study. HR during wk 6 to 9 in CT-SHRs were 345 2 9, 340 * 12, 336 & 18 and 345 & 12 beatstmin, and 354 * 9,353 2 10,349 -+ 9 and 353 5 7 beatstmin in control SHRs.

At postmortem examination, variable amounts of ascites were found in the six CT-SHRs showing sodium retention within the seventh to eighth weeks of the study. Histological findings from the liver specimens obtained from CT-SHRs showed the characteristic fea- tures of cirrhosis. Control rats had no appreciable alteration in liver histological findings or ascites.

DISCUSSION During the past few years numerous studies have

characterized the systemic and splanchnic hemodynamic and renal function abnormalities in rats with CC1,-induced cirrhosis (17). Within the fifth to the seventh week of the initiation of CC1, administration, a histological picture of cirrhosis develops in these animals, which leads to portal hypertension, generalized splanchnic arteriolar vasodilation and hyperdynamic circulation (hypervolemia, high cardiac output and low peripheral vascular resistance) (7, 18). Sodium retention, impaired free water excretion and ascites develop later in the animals (6,8, 19). Sodium retention usually starts between the seventh and tenth week of CC1, administration in close chronological relationship with an elevation of urinary aldosterone excretion and always precedes the formation of ascites by 1 to 2 wk (6,8). Impairment in free water clearance and dilutional hyponatremia and hypoosmolality are later events, usually appearing 2 to 4 wk after the formation of ascites simultaneously with a nonosmotic hypersecretion of antidiuretic hormone (8, 20). When the animals have ascites, arterial pressure is reduced (6, 21, 22).

This study was designed to investigate whether there is a chronological relationship between the impairment

Vol. 13, No. 3, 1991 ARTERIAL PRESSURE AND SODIUM RETENTION IN CIRRHOSIS 587

WEEKS FIG. 2. Temporal relationship between systolic blood pressure and urinarv sodium excretion in CT-SHR. Wk -6 to -1 reuresent the six

FIG. 1. Systolic blood pressure in CT-SHRs (upper figure) and conseckve weeks before the onset of sodium retention. Wk 0 control SIIRs (lower figure) during the 9 wk of the study. represents the week in which sodium retention was first detected. Wk (a) = p < 0.05 and (b) = p < 0.01 with respect to values obtained 1 represents the week after the onset of sodium retention. during the first 7 wk. (c) = p < 0.05 and (d) = p < 0.001 with respect (a) = p < 0.005 and (6) = p < 0.001 with respect to the values to the corresponding values in CT-SHRs. obtained in wk -6 to -1.

TABLE 1. U,,V, sodium balance, U,,V and creatinine clearance in SHRS treated with CCl, and control SHRs w k 6 wk7 w k 8 wk9

Cirrhotic SHRs U,,V (mEq/day) Sodium balance (mEq/day) U,,V (ng/day) Creatinine clearance (ml/min)

U,*V (mEq/day) Sodium balance (mEq/day) U,,V (@day) Creatinine clearance (mumin)

Control SHRs

1.11 ? 0.07 0.04 t 0.06 20.6 t 1.5 1.10 t 0.08

1.12 2 0.04 0.10 t 0.02 18.8 t 1.5 1.40 ? 0.12

1.00 -t 0.11 0.09 t 0.06 32.0 f 6.6 1.20 f 0.12

1.00 t 0.08 0.02 t 0.03 19.0 t 1.1 1.17 t 0.15

0.81 -t 0.09” 0.41 t 0.09” 54.2 ? 10.4‘ 1.21 2 0.10

1.04 f 0.05“ 0.07 t 0.OY 18.7 t 1.3& 1.21 0.08

0.46 2 0.12’ 0.79 ? 0.07’ 109.6 IC_ 21.1” 1.04 c 0.08

1.01 ? 0.04‘ 0.08 5 0.03’ 19.4 ? 1.Y 1.02 2 0.09

Results given in the table represent the arithmetic mean of all values obtained weekly in each group of rats. “p < 0.005, &p < 0.001 and ‘p < 0.01 vs. values a t wk 6. “p < 0.05, ‘p < 0.001 and fp < 0.025 vs. values in the same week in cirrhotic rats.

in systemic hemodynamics, as estimated by the SBP, the activation of the renin-aldosterone system, as assessed by the urinary excretion of aldosterone, and the onset of sodium retention in rats with CC1,-induced cirrhosis. Arguments for the use of urinary aldosterone excretion as an index for the degree of activation of the renin- aldosterone system have been discussed in detail in a previous study (6). Blood pressure was determined by the noninvasive method of tail-cuff plethysmography,

which provides reliable sequential measurements of SBP in conscious rats (23, 24). The study was initially designed to be performed in normotensive conscious Wistar rats submitted to a cirrhosis-induction program with CC1, and phenobarbital. However, accurate measurements of SBP could not be obtained in these animals from the seventh to eighth week after starting the program because of marked instability of the registered pulse waves. This problem, which was probably related

588 LOPEZ ET AL. HEPATOLOCI

1275t - .

-0.57, pco. 001 in

1001 " - ' - ' . ' 0.0 0.2 0.4 0.6 0.e 1.0 1.2 1.4 1.6 i .e

URINARY SWIW EXCRETION (nEq/day)

FIG. 3. Relationship between systolic blood pressure and urinary sodium excretion in CT-SHRs during the entire study.

to a reduction of arterial pressure after the development of cirrhosis, did not occur in CT-SHRs. Spontaneous hypertensive rats were included in the study at 12 wk of age when hypertension is fully established, arterial pressure is steady, day-to-day variations of SBP are lower than lo%, sodium balance is normal and no activation of the renin-aldosterone and sympathetic nervous systems exists (15, 25-29). As with normotensive Wistar rats given CCl, and phenobarbital (6), sodium retention developed in CT-SHRs in close chronological relationship with hyperaldosteronism, with both events occurring between the seventh and ninth week after starting the cirrhosis-induction program. Therefore, although normal rats and SHRs are very different with respect to the relationship between renal perfusion pressure and natriuresis (15, 16), this dif- ference did not apparently modify the time-course of the events leading to sodium retention and ascites formation in CC1,-induced cirrhosis.

A marked reduction in SBP developed in all CT-SHRs. In the whole group the absolute decrease in SBP was of 25 mm Hg at the eighth week and 50 mm Hg at the ninth week. This represents a 10% and 20% decrease in SBP, respectively, which is comparable to the reduction in mean blood pressure observed in other investigations in normotensive rats with CC1,-induced cirrhosis and sodium retention (6,21). The most interesting finding of this study was the close temporal relationship between the fall in SBP and the increase in urinary excretion of aldosterone observed in CT-SHRs, which is consistent with the view that arterial hypotension may be a major stimulus for the activation of the renin- aldosterone system in cirrhosis (9). The observation that angiotensin-I1 blockade in patients (30) and experimental animals (31) with cirrhosis and sodium retention is associated with a further decrease in arterial pressure is another argument supporting this contention. The fall in SBP in CT-SHRs was also chronologically and quantitatively related to sodium retention. Several mechanisms, including hyperaldosteronism and a probable activation of the renal sympathetic nervous activity, may account for this relationship. The reduction of renal perfusion pressure caused by the arterial hypotension could be another important factor

because it is well documented that SHRs require an elevated arterial pressure to excrete normal quantities of sodium (15, 16).

The results of the current study do not allow knowledge of the mechanism of arterial hypotension in CT-SHRs. The cardiac output and the peripheral vascular resistances were not measured before and during arterial hypotension because they involve invasive pro- cedures and cannot be performed sequentially in conscious animals. Therefore the relative contribution of cardiac output and peripheral vascular resistances to the arterial hypotension in CT-SHRs is unknown. It is also impossible to ascertain whether the circulatory distur- bances leading to the decrease in arterial pressure in CT-SHRs occurred before or simultaneously with the development of arterial hypotension and sodium retention.

Nevertheless, it seems unlikely that a decrease in the cardiac output accounted for the arterial hypotension in CT-SHRs. First, no appreciable changes in the HR were observed in these animals throughout the study. Second, the cardiac output has been reported as increased and the peripheral vascular resistance as reduced in hemodynamic investigations performed on nonhypertensive rats with CC1,-induced cirrhosis, sodium retention (32) and ascites (18). Finally, Polio et al. (33) have recently shown that portal hypertension in portal vein-ligated SHRs, a model that mimics the hemodynamic distur- bances of cirrhosis (34), is associated with a reduction in arterial pressure, an increase in cardiac output and a marked fall in peripheral vascular resistance. Therefore the most likely mechanism of the decrease in arterial pressure in SHRs was a reduction in peripheral vascular resistances.

Studies in patients (35) and experimental animals without ascites (7, 22, 32) supports the view that the circulatory abnormalities that lead to arterial hypotension in cirrhosis occur before the onset of sodium retention, because the cardiac output and plasma volume are increased and arterial pressure and peripheral vascular resistance are reduced in these condi- tions. I t has been proposed that transient periods of renal sodium and water retention, which are difficult to detect, normalize the hemodynamic status a t this early stage of cirrhosis (9). The fluid retained by the kidney would remain in the intravascular compartment, refill the dilated vascular bed, increase arterial pressure to normal or near normal levels, suppress the signals stimulating the antinatriuretic systems (renin- angiotensin-aldosterone system, sympathetic nervous systems, antidiuretic hormone) and restore sodium and water excretion to normal. In later phases of cirrhosis, however, this type of compensation would not be sufficient to maintain circulatory homeostasis. This could be due to a progression of the systemic circulatory disturbance, an increase in portal pressure, which would promote the extravasation of the retained fluid to the peritoneal cavity, or both mechanisms.

In conclusion, the results of this study showing that the activation of the renin-aldosterone system and the onset of sodium retention in SHRs with CC1,-induced

Vol. 13, No. 3, 1991 ARTERIAL PRESSURE AND SODIUM RETENTION IN CIRRHOSIS 589

cirrhosis occur in close chronological relationship with a fall in arterial pressure are not consistent with the “overflow” theory of ascites formation in cirrhosis (361, which considers renal sodium retention a primary event unrelated to changes in systemic hemodynamics. This study supports the “peripheral arterial vasodilation hypothesis” of ascites (91, which proposes that sodium retention in cirrhosis is a secondary phenomenon, with the initial event being a peripheral arteriolar vasodilation leading to underfilling of the arterial vascular compartment and high-pressure-mediated stimulation of the renin-aldosterone and sympathetic nervous systems and antidiuretic hormone.

Acknowledgment: We are indebted to Ms. Carmen Escofet for her technical assistance.

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