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.
Indirect evidence suggests that the renal and vascular production of prostaglandins is increased in cirrhosis with ascites. However, the activity of the enzymes regulating the prostaglandin pathway has not been investigated in cirrhosis. The aim of the current study was to determine the activity of phospholipase A 2 (PLA 2 ), the key enzyme in the regulation of prostaglandin synthesis, in kidney and vascular tissue obtained from rats with carbon tetrachlorideinduced cirrhosis and ascites (n ؍ 9) and control rats (n ؍ 6). PLA 2 activity was assayed in vitro using [ 14 C]arachidonylphosphatidylcholine (PC) and [ 14 C]arachidonyl-phosphatidylethanolamine (PE) as substrates in the presence of Ca 2؉ . Kidneys from cirrhotic rats had significantly higher PLA 2 activity compared with control rats, with both PC and PE (35 ؎ 5 and 40 ؎ 6 vs. 21 ؎ 2 and 26 ؎ 3 pmol/mg/min, respectively; P F .05 for both). PLA 2 activity was increased in the renal cortex as well as in the renal medulla. Fractionation of the kidney extracts by Mono-Q anionexchange chromatography showed that the elution position of PLA 2 activity corresponded to the cytosolic PLA 2 isoform (cPLA 2 ). Increased amounts of cPLA 2 protein were found in kidney extracts immunoblotted with an anti-cPLA 2 antibody. However, reverse-transcriptase polymerase chain reaction (RT-PCR) analysis did not detect any difference in cPLA 2 mRNA. PLA 2 activity was also higher in aortic tissue from cirrhotic rats than in controls (PC 38 ؎ 5 vs. 26 ؎ 1 and PE 66 ؎ 8 vs. 41 ؎ 3 pmol/mg/min; P F .05 for both). Incubation of renal and aortic extracts from cirrhotic rats with anti-cPLA 2 antibody reduced PLA 2 activity by 64% and 88%, respectively. In conclusion, PLA 2 activity is increased in kidneys and vascular tissue from cirrhotic rats with ascites. This can be accounted for by an induction of cPLA 2 , which would mediate, at least in part, the increased renal and vascular production of prostaglandins in cirrhosis.(HEPA-TOLOGY 1998;27:42-47.)
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