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1 Division of Renal Diseases and Hypertension and 2 Cardiovascular-Pulmonary Research Laboratory, Departments of 3 Medicine and 4 Physiology, University of Colorado Health Sciences Center, Denver, Colorado 80262
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 (CCl4). 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 CCl4-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 wt1
in cirrhotic rats vs. 0.79 ± 0.05 ml · min1 · 100 g body wt1
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.
nitric oxide; liver disease; systemic hemodynamics
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