Effects of nitric oxide synthase inhibitors on retrograde bile salt-induced pancreatitis rats.
BACKGROUND
The serum levels of proinflammatory cytokines have been reported to be significantly higher in severe acute pancreatitis compared with mild pancreatitis. Nitric oxide (NO) produced by cytokine-inducible NO synthase might be involved as the mechanisms for the progression of pancreatitis and the occurrence of systemic complications. The aim of the study was to evaluate the effects of a non-selective NO synthase inhibitor, nitro-L-arginine methyl ester (L-NAME), and an inducible NO synthase inhibitor, L-canavanine, on sodium taurodeoxycholate-induced acute necrotizing pancreatitis in rats.


METHODS
Twenty-eight rats were randomized into 3 groups to receive L-NAME 5 mg/kg/h, L-canavanine 20 mg/kg/h, and equivalent volume of saline, respectively, i.v. infusion after the induction of pancreatitis for 5 hours. The serum levels of amylase and lipase and mean arterial pressure and heart rate at baseline and 5 hours, and cardiac output, systemic vascular resistance, the amount of ascites and pancreatic histopathology at 5 hours were examined.


RESULTS
Five hours after induction of pancreatitis, all rats treated with L-canavanine and all but 1 treated with saline survived; however, all rats treated with L-NAME died. As compared with the control group, L-canavanine significantly reduced serum levels of amylase and lipase, the severity of pancreatic edema and necrosis, and the volume of ascites in 5 hours. In addition, L-canavanine significantly improved the reduction of mean arterial pressure and systemic vascular resistance at 5 hours.


CONCLUSIONS
L-NAME results in the mortality of acute necrotizing pancreatitis. L-canavanine reduces serum pancreatic enzymes and improves the changes of pancreatic histopathology and systemic hemodynamics at the early stage of acute pancreatitis. Inducible NO synthase inhibitor is beneficial for severe acute pancreatitis.
Chen
Chun-Chia
CC
Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. chencc@vghtpe.gov.tw
Wang
Sun-Sang
SS
Tsay
Shyh-Haw
SH
Lee
Fa-Yauh
FY
Lu
Rei-Hwa
RH
Chang
Full-Yang
FY
Lee
Shou-Dong
SD
D000818:Animals; D002172:Canavanine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology* / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013657:Taurodeoxycholic Acid
D004791:Enzyme Inhibitors; D002172:Canavanine; D013657:Taurodeoxycholic Acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019331:NG-Nitroarginine Methyl Ester