ABSTRACT
Arterial vasodilatation and activation of several vasoactive and neurohumoral systems may play a key role in the pathogenesis of sodium and water retention and ascites formation in cirrhosis. Strong evidence supports a role for an increased vascular production of the potent vasodilator, nitric oxide [NO], in vascular hyporeactivity of cirrhosis. Also, evidence indicated that dihydropyridine-type calcium channel blockers [DHP-CCBs] modulate the release and /or bioavailability of endothelial NO. So, it is possible that DHP-CCBs have the potential to exaggerate the hemodynamic derangements in cirrhosis. The present study was motivated to test the effect of DHP-CCBs [nifidipine] on experimental liver cirrhosis, induced in animal model by using CCI[4], either alone or in the presence of NO synthase inhibitor, N-nitro-L-arginine methyl ester [L-NAME]. Sixty four adult male albino rats were assigned into two main groups, non-cirrhotic [GI], n=32 and cirrhotic [GIl], n=32. Further classification into four subgroups was carried out for each group. GI included: Gla [non treated control], GIb [L-NAME treated], GIc [nifedipine treated] and GId [nifedipine + L-NAME treated]. While GIl included: Glla [cirrhotic untreated], GlIb [cirrhotic, L-NAME treated], GIIc [cirrhotic, nifedipine treated] and GIld [cirrhotic, nifedipine + L-NAME treated]. L-NAME and /or nifedipine administration [according to the group] was orally administrated daily for a week at a dose = 0.5mg/Kg/day for L-NAME and /or = 0.1mg/Kg/day for nifedipine. Results revealed that L-NAME treatment of healthy rats [GIb] had no significant effect on all the tested parameters including B.Wt. and plasma Na, aldosterone and NO levels. Significant elevation in plasma aldosterone and NO mean values was noted by nifedipine administration to non cirrhotic animals [GIc] compared to Gla, however, no significant difference was obtanied between GIc and Gla for each of B.Wt and plasma Na. Results also demonstrated that CCI[4] administration to rats [Glla] resulted in the appearance of ascites with a significant elevation in plasma aldosterone and NO mean values compared to Gla. Treatment of cirrhotic rats with L-NAME had nearly normalized the later two parameters with no significant difference when compared to Gla, beside reduction in ascitic fluid volume and consequently B.Wt. compared to non-treated cirrhotic group [Glla]. Our results indicated that nifedipine administration to cirrhotic rats [GIIc] significantly intensified the abnormalities associated with CCI[4] administration and resisted the normalization by L-NAME treatment [GIld]. It could be concluded that normalization of plasma NO by NO synthase inhibition is associated with improvement in renal sodium and water excretion which in turn resulted in decreased ascitic fluid volume in cirrhotic rats, while DHP-CCBs [nifedipine] by increasing the plasma NO levels exaggerate ascites in cirrhotic rats. This finding may raise the possibility of using long term NO synthase inhibition in patients with ascites and avoidance of the use of calcium channel blockers in those patients