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