Neuronal nitric oxide synthase and systemic vasodilation in rats with cirrhosis.
Cirrhosis is typically associated with a hyperdynamic circulation consisting of low blood pressure, low systemic vascular resistance (SVR), and high cardiac output. We have recently reported that nonspecific inhibition of nitric oxide synthase (NOS) with nitro-L-arginine methyl ester reverses the hyperdynamic circulation in rats with advanced liver cirrhosis induced by carbon tetrachloride (CCl(4)). Although an important role for endothelial NOS (eNOS) is documented in cirrhosis, the role of neuronal NOS (nNOS) has not been investigated. The present study was carried out to specifically investigate the role of nNOS during liver cirrhosis. Specifically, physiological, biochemical, and molecular approaches were employed to evaluate the contribution of nNOS to the cirrhosis-related hyperdynamic circulation in CCl(4)-induced cirrhotic rats with ascites. Cirrhotic animals had a significant increase in water and sodium retention. In the aorta from cirrhotic animals, both nNOS protein expression and cGMP concentration were significantly elevated compared with control. Treatment of cirrhotic rats for 7 days with the specific nNOS inhibitor 7-nitroindazole (7-NI) normalized the low SVR and mean arterial pressure, elevated cardiac index, and reversed the positive sodium balance. Increased plasma arginine vasopressin concentrations in the cirrhotic animals were also repressed with 7-NI in association with diminished water retention. The circulatory changes were associated with a reduction in aortic nNOS expression and cGMP. However, 7-NI treatment did not restore renal function in cirrhotic rats (creatinine clearance: 0.76 +/- 0.03 ml. min(-1). 100 g body wt(-1) in cirrhotic rats vs. 0.79 +/- 0.05 ml. min(-1). 100 g body wt(-1) in cirrhotic rats+7-NI; P NS. ). Taken together, these results indicate that nNOS-derived NO contributes to the development of the hyperdynamic circulation and fluid retention in cirrhosis.
Xu
L
L
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Carter
E P
EP
Ohara
M
M
Martin
P Y
PY
Rogachev
B
B
Morris
K
K
Cadnapaphornchai
M
M
Knotek
M
M
Schrier
R W
RW
D000818:Animals; D001127:Arginine Vasopressin / Q000097:blood; D001201:Ascites / Q000378:metabolism; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007191:Indazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007677:Kidney Function Tests; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D009994:Osmolar Concentration; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000652:urine; D014664:Vasodilation / Q000502:physiology*
D004791:Enzyme Inhibitors; D007191:Indazoles; D001127:Arginine Vasopressin; D012964:Sodium; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D006152:Cyclic GMP; C080122:7-nitroindazole