Effect of 1-week losartan administration on bile duct-ligated cirrhotic rats with portal hypertension

https://doi.org/10.1016/S0168-8278(02)00037-5Get rights and content

Abstract

Background/Aims: Nitric oxide and angiotensin play important roles in the pathogenesis of the hemodynamic derangement in cirrhosis and portal hypertension. The hemodynamic effects of losartan, an angiotensin II type 1 receptor antagonist, in cirrhotic patients with portal hypertension are conflicting. This study was undertaken to explore the possible mechanism of action of losartan on portal hypertension in cirrhotic rats produced by bile duct ligation (CBL).

Methods: Three weeks after surgery, CBL and sham-operated rats randomly received vehicle or losartan (3 mg/kg per 12 h by gavage) for 1 week. Hemodynamic values, hormone levels, and aortic eNOS protein expression were measured after drug administration.

Results: In CBL rats, 1-week losartan treatment decreased portal pressure and ameliorated hyperdynamic circulation associated with a blunted vascular response to Nω-nitro-l-arginine methyl ester infusion. The hematocrit increased and the plasma volume, aldosterone, plasma renin activity, norepinephrine, and nitrate and nitrite levels decreased. The eNOS protein expression was reduced in CBL rats receiving losartan compared with those receiving vehicle.

Conclusions: One-week losartan treatment in CBL rats decreased portal pressure and ameliorated hyperdynamic circulation. In addition to the suppression of renin-angiotensin axis, the reduced aortic eNOS protein expression may play a partial role for the mechanism of action of losartan in CBL rats.

Introduction

Portal hypertension is the main complication of cirrhosis that is characterized by the development of peripheral arterial vasodilatation and hyperdynamic circulation [1], [2], [3], [4]. It has been shown that overproduction of nitric oxide (NO) plays an important role in the pathogenesis of vasodilatation in portal hypertension [5], [6], [7], [8], [9]. Additionally, inhibition of NO corrected the characteristic vascular hyporesponsiveness to vasoconstrictors, which is an important factor that contributes to the vasodilatation [10], [11]. In portal hypertensive animals, peripheral vasodilatation was found to be an initial phenomenon of the hemodynamic derangement following the development of portal hypertension [3], [4]. In response to the occurrence of vasodilatation, an activation of the sympathetic nervous activity and renin–angiotensin–aldosterone systems occurs that results in sodium and water retention [12], [13], [14], [15]. These changes lead to plasma volume expansion, which is necessary for the full expression of the hyperdynamic circulation [3], [4], [11], [12].

Angiotensin II (ANGII) is an important end product of renin-angiotensin axis that can be activated in cirrhosis. Arroyo et al. [16] reported a reduction of wedged hepatic vein pressure following ANGII blockade by saralasin indicating that ANGII plays a role in the pathogenesis of portal hypertension. Previous studies demonstrated a reduction of portal pressure and a natriuretic effect by losartan, an ANGII type I (AT1) receptor antagonist, in cirrhotic patients with portal hypertension without a significant effect on arterial pressure [17], [18]. In contrast, recent studies showed an absent or a modest effect of AT1 receptor antagonist in the decrease of portal pressure in cirrhotic patients, but with a fall in arterial pressure [19], [20]. Nevertheless, the mechanism of action of losartan on hemodynamics in cirrhotic portal hypertension has not yet been established. Therefore, the current study was undertaken to evaluate a possible such mechanism in cirrhotic rats produced by common bile duct ligation.

Section snippets

Animals

Adult male Sprague–Dawley rats (250–350 g) were used in all experiments. Cirrhosis with portal hypertension was produced by common bile duct ligation (CBL), as previously described [21]. Sham-operated rats had their bile duct exposed but not ligated. All rats were caged at 24 °C, with a 12:12-h light/dark cycle, and allowed free access to food and water. Animal studies were approved by the Animal Experiment Committee of the University and conducted humanely.

Study protocol

Three weeks (23–25 days) after

Experiment I: Hemodynamic measurements before and after l-NAME infusion

Four weeks after bile duct ligation, CBL rats receiving vehicle showed a hyperdynamic circulation characterized by lower MAP, SVR, and RSMA associated with higher CI, PP, and QSMA than sham-operated rats receiving vehicle (Table 1). Compared with CBL rats receiving vehicle, CBL rats receiving losartan showed a significant improvement in systemic and splanchnic hemodynamics (Table 1). In contrast, the hemodynamic values in sham-operated rats were not affected by losartan.

Following l-NAME

Discussion

In the current study, we clearly show that 1-week losartan administration decreases portal pressure in cirrhotic rats with portal hypertension. Schneider et al. [17] also observed a reduction in hepatic venous pressure gradient without a significant effect on mean arterial pressure in cirrhotic patients with portal hypertension. However, the mechanism of action of losartan was not established in their study. In our study, we found that administration of losartan in cirrhotic rats resulted in a

Acknowledgements

This study was supported by Grant No. NSC89-2315-B-075-010 from the National Science Council and Grant No. VGH89-62 from the Taipei Veterans General Hospital, Taipei, Taiwan.

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    The authors of this study state that they have no relationship past or present with the pharmaceutical company involved with the drugs mentioned in the study, neither have they received funding from the companies.

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