Nitric oxide synthase inhibition negates bombesin-induced gastroprotection.
BACKGROUND
Bombesin prevents gastric injury primarily by the release of endogenous gastrin. Gastroprotection by exogenous gastrin is negated by nitric oxide synthase inhibition, which implicates a role for nitric oxide as a protective mediator. Because both endothelial and inducible isoforms of this enzyme can play a role in mucosal defense, this study was done to examine the contrasting effects of 2 nitric oxide synthase inhibitors on bombesin-induced gastroprotection.


METHODS
Rats were given subcutaneous saline or bombesin (10-100 microg/kg) 30 minutes before they received a 1-mL orogastric bolus of acidified ethanol (150 mmol/L of hydrochloric acid/50% ethanol) and rats were killed 5 minutes later for assessment of macroscopic injury (mm(2)). Gastric mucosal blood flow was measured by laser Doppler. Endothelial, neural, and inducible nitric oxide synthase were assessed by using Western immunoblot.


RESULTS
Bombesin decreased gastric mucosal damage, and dose-dependently increased blood flow when compared with saline-treated rats. Endothelial but not neural or inducible nitric oxide synthase immunoreactivity was increased by bombesin. In additional studies, intraperitoneal administration of N(G)-nitro-l-arginine methyl ester (l-NAME, 5-10 mg/kg), a nonselective nitric oxide synthase inhibitor, negated bombesin-induced gastroprotection and hyperemia, whereas the selective inducible inhibitor aminoguanidine (45 mg/kg) did not. Subcutaneous (SC) l-arginine (300 mg/kg), but not d-arginine, abolished the effects of l-NAME.


CONCLUSIONS
Taken together, these data suggest that nitric oxide produced by the endothelial isoform of nitric oxide synthase plays an important role in mediating the gastroprotective and hyperemic actions associated with bombesin.
Castañeda
A A
AA
Department of Surgery, University of Texas-Houston Medical School, Houston, USA.
Kim
Y S
YS
Chang
L K
LK
Cui
Y
Y
Mercer
D W
DW
D000284:Administration, Oral; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001839:Bombesin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects / Q000473:pathology*; D006146:Guanidines / Q000494:pharmacology; D006851:Hydrochloric Acid / Q000008:administration & dosage / Q000633:toxicity*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects*
D004791:Enzyme Inhibitors; D006146:Guanidines; D000431:Ethanol; D001120:Arginine; D019001:Nitric Oxide Synthase; D001839:Bombesin; D006851:Hydrochloric Acid; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester