An endothelial nitric oxide synthase inhibitor aggravates CDL-induced acute pancreatitis in rats.
To clarify the role of nitric oxide (NO) in the development and progression of acute pancreatitis, we investigated the effect of different NO synthase inhibitors and NO donors on experimental pancreatitis in rats. Closed duodenal loop (CDL)-induced pancreatitis was produced in male Wistar rats, and the animals were treated with normal saline, the NO-synthase substrate L-arginine, the NO donor S-nitroso-N-acetylpenicillamine, aminoguanidine, which is a more powerful inhibitor of inducible NO synthase (iNOS) than is endothelial NO synthase (eNOS), and N-nitro-L-arginine methyl ester (L-NAME), a more powerful inhibitor of eNOS than of iNOS. All drugs were infused intravenously during a period of 6 or 12 h in each group. Pancreatic tissue was removed at 6 and 12 h after creating the CDL. L-Arginine, S-nitroso-N-acetyl-penicillamine, and aminoguanidine treatment had no effect on the elevation of serum pancreatic enzymes, whereas L-NAME administration significantly exacerbated their elevation. Pathologically, L-NAME treatment resulted in a significantly worse histologic score at 6 and 12 h, especially in terms of the degree of hemorrhage, acinar cell necrosis, and microvascular thrombosis. Addition of L-arginine clearly reversed the effect of L-NAME. Neither the NO substrate nor NO donor could inhibit the progression of hemorrhagic pancreatitis in CDL-induced pancreatitis. Aminoguanidine had no effect on the severity of the pancreatitis. We therefore concluded that NO production by eNOS may play a significant role in preventing the development and progression of acute pancreatitis.
Nishino
T
T
Department of Gastroenterology, Tokyo Women's Medical University, School of Medicine, Japan.
Watanabe
S
S
Oyama
H
H
Fukuya
Y
Y
Hayashi
N
N
Kobayashi
M
M
D000208:Acute Disease; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001202:Ascitic Fluid; D004386:Duodenum / Q000601:surgery; D004487:Edema; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D008026:Ligation; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052250:Nitric Oxide Synthase Type III; D010195:Pancreatitis / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D006146:Guanidines; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D001120:Arginine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D010396:Penicillamine; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester