Chronic nitric oxide synthase inhibition exacerbates renal dysfunction in cirrhotic rats

Abstract

Graebe, Martin, Lone Brønd, Sten Christensen, Søren Nielsen, Niels V. Olsen, and Thomas E. N. Jonassen. Chronic nitric oxide synthase inhibition exacerbates renal dysfunction in cirrhotic rats. Am J Physiol Renal Physiol 286: F288-F297, 2004. First published October 28, 2003 10.1152/ajprenal.00089.2003.-The present study investigated sodium balance and renal tubular function in cirrhotic rats with chronic blockade of the nitric oxide (NO) system. Rats were treated with the nonselective NO synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME) starting on the day of common bile duct ligation (CBL). Three weeks of daily sodium balance studies showed that CBL rats developed sodium retention compared with shamoperated rats and that L-NAME treatment dose dependently deteriorated cumulative sodium balance by reducing urinary sodium excretion. Five weeks after CBL, renal clearance studies were performed, followed by Western blotting of the electroneutral type 3 sodium/ proton exchanger (NHE3) and the Na-K-ATPase present in proximal tubules. Untreated CBL rats showed a decreased proximal reabsorption with a concomitant reduction of NHE3 and Na-K-ATPase levels, indicating that tubular segments distal to the proximal tubules were responsible for the increased sodium reabsorption. L-NAME-treated CBL rats showed an increased proximal reabsorption measured by the lithium clearance method and showed a marked increase in NHE3 and Na-K-ATPase protein levels. Our results show that chronic L-NAME treatment exacerbates the sodium retention found in CBL rats by a significant increase in proximal tubular reabsorption. common bile duct ligation; type 3 sodium/proton exhanger; proximal tubular function; lithium clearance THE EARLY STATE OF COMPENSATED cirrhosis is associated with renal sodium and water retention combined with a hyperdynamic circulation, evident as systemic arterial vasodilation with decreased total peripheral resistance and increased cardiac output. In 1991, Vallance and Moncada (56) suggested that increased systemic nitric oxide (NO) formation induced by low-grade endotoxemia could be the mediator of the hyperdynamic circulation. Since then, several studies in both animals and humans have validated this hypothesis and increased NO synthesis is now believed to be one of the early pathophysiological mechanisms of cirrhosis, being essential for systemic arterial vasodilation (3,7,19,24,37,38).The peripheral arterial vasodilation theory stated by Schrier and co-workers (49) proposes that the vasodilation-mediated relative vascular underfilling in cirrhosis is the primary event responsible for the renal sodium and water retention via activation of baroreceptors and humoral antinatriuretic mechanisms. Normalization of the hyperdynamic circulation by blockade of NO synthase (NOS) would in this context be a straightforward approach to try to prevent the sodium retention in cirrhotic liver disease, and a few studies have shown that short-term NOS inhibition in cirrhotic rats actually ameliorates the impaired sodium e...

The effect of albumin administration on renal dysfunction after experimental surgical obstructive jaundice in male rats

“…The excessive generation of NO has been observed both in experimental cholestasis [34,35] and in primary biliary cirrhosis patients [36,37]. Renal impairment occurs in cirrhotic patients with a high concentration of NO in the plasma and ascitic fluid.…”

Sodium retention and ascites formation in a cholestatic mice model

“…Comparison with BDL rats shows that liver histological lesions were similar in the two models. 3 The renal response was more precocious in mice than rats since about 50% of BDL mice already displayed ascites 4.5 wk after surgery whereas no rat was ascitic at 5 weeks. 32 In both BDL rat and mouse models, the volume of ascites was highly variable.…”

“…40,41 Na ϩ ,K ϩ -ATPase activity was decreased in the proximal tubule of BDL mice, confirming previous findings in cirrhotic BDL rats showing decreased proximal sodium reabsorption and expression of Na ϩ ,K ϩ -ATPase and of the sodium proton exchanger, the main apical sodium transporter in proximal tubule. 3 The third aim was to evaluate the role of hyperaldosteronemia in sodium retention in cirrhosis. Although BDL mice displayed significant hyperaldosteronemia, attested to by increased excretion of aldosterone and induction of sgk1 in CCD, experiments in corticosteroid-clamped animals definitely demonstrate that hyperaldosteronemia is not required for sodium retention, ascites formation and induction of Na ϩ ,K ϩ -ATPase in CCD in cholestatic mice.…”

Nitration of cardiac proteins is associated with abnormal cardiac chronotropic responses in rats with biliary cirrhosis†

“…Three weeks after the operation, the animals (BDL and control) were divided into three experimental groups, which received 130 mg/kg/twice a day of N-acetylcysteine (NAC; infusible solution, Celltech, UK), 0.5 mg/kg/ twice per day of N G -L-nitro-arginine methyl ester (L-NAME) or an equivalent volume of saline subcutaneously for 1 week. 16,17 In week 4, the rats were anesthetized with isoflurane (1.5 %) and a lead II electrocardiogram (ECG) was recorded (15 minutes) for spectral analysis of heart rate variability (Powerlab, ADInstrument, Australia). The heart of each animal was then removed and the atria were dissected out from isolated hearts in cold oxygenated physiological solution.…”