Nitric oxide synthase (NOS) inhibition for one week improves renal sodium and water excretion in cirrhotic rats with ascites.

Abstract

Normalization of the increased vascular nitric oxide (NO) generation with low doses of NG-nitro-L-arginine methyl ester (L-NAME) corrects the hemodynamic abnormalities of cirrhotic rats with ascites. We have undertaken this study to investigate the effect of the normalization of vascular NO production, as estimated by aortic cyclic guanosine monophosphate (cGMP) concentration and endothelial nitric oxide synthase (eNOS) protein expression in the aorta and mesenteric artery, on sodium and water excretion. Rats with carbon tetrachloride-induced cirrhosis and ascites were investigated using balance studies. The cirrhotic rats were separated into two groups, one receiving 0.5 mg/kg per day of L-NAME (CIR-NAME) during 7 d, whereas the other group (CIR) was administrated the same volume of vehicle. Two other groups of rats were used as controls, one group treated with L-NAME and another group receiving the same volume of vehicle. Sodium and water excretion was measured on days 0 and 7. On day 8, blood samples were collected for electrolyte and hormone measurements, and aorta and mesenteric arteries were harvested for cGMP determination and nitric oxide synthase (NOS) immunoblotting. Aortic cGMP and eNOS protein expression in the aorta and mesenteric artery were increased in CIR as compared with CIR-NAME. Both cirrhotic groups had a similar decrease in sodium excretion on day 0 (0.7 versus 0.6 mmol per day, NS) and a positive sodium balance (+0.9 versus +1.2 mmol per day, NS). On day 7, CIR-NAME rats had an increase in sodium excretion as compared with the CIR rats (sodium excretion: 2.4 versus 0.7 mmol per day, P < 0.001) and a negative sodium balance (-0.5 versus +0.8 mmol per day, P < 0.001). The excretion of a water load was also increased after L-NAME administration (from 28+/-5% to 65+/-7, P < 0.05). Plasma renin activity, aldosterone and arginine vasopressin were also significantly decreased in the CIR-NAME, as compared with the CIR rats. The results thus indicate that normalization of aortic cGMP and eNOS protein expression in vascular tissue is associated with increased sodium and water excretion in cirrhotic rats with ascites.

Sodium retention and ascites formation in a cholestatic mice model: Role of aldosterone and mineralocorticoid receptor?

“…5,6 Later, the "revised underfill theory" proposed that peripheral arterial vasodilatation leading to decreased effective blood volume was the primary determinant of intravasal underfilling. [9][10][11] Although it is consistent with experimental findings in different models of portal hypertension, 12,13 several studies performed mostly in humans failed to support the concept of arterial …”

Body Water Homeostasis

“…Recent evidence, however, indicates a prominent role of endothelial and inducible nitric oxide synthesis (83). In this regard, 7 d of treatment with a nonspecific nitric oxide synthase inhibitor at a dose to reverse the arterial vasodilation and thus the hyperdynamic circulation of experimental cirrhosis was found to suppress plasma AVP, increase solute-free water diuresis, and correct the hyponatremia (84).…”

Hyponatremia in cirrhosis: From pathogenesis to treatment

“…Furthermore, urinary sodium excretion, sodium balance, and water excretion are markedly improved by chronic NO synthase inhibition. 115 Further studies on the effect of chronic NO inhibition on the renal ability to excrete water are needed, but it is conceivable that inhibition of the vasodilator substance likely involved in the arterial vasodilation may correct the nonosmotic stimulation of VP. Moreover, there is evidence that NO can stimulate central release of VP, 116 and NO could therefore act through an indirect effect (baroreceptor-mediated) or a direct effect to activate a nonosmotic release of VP.…”