Aminoguanidine selectively decreases cyclic GMP levels produced by inducible nitric oxide synthase.
Overproduction of nitric oxide (NO) following induction of NO synthase in vascular smooth muscle by endotoxin and certain cytokines contributes to the vasodilation and hyporesponsiveness to vasopressors that characterize the septic circulation. Guanosine 3',5'-cyclic monophosphate (cGMP) mediates the effects of NO in vascular smooth muscle. Vessels from animals treated with endotoxin have elevated cGMP levels compared with control animals. Aminoguanidine has been proposed as a selective inhibitor of the inducible form of NO synthase. This study compares the effects of aminoguanidine on phenylephrine-induced contractions and cGMP levels in thoracic aortic rings from endotoxin treated (20 mg/kg intraperitoneally) with sham-treated (1 ml saline intraperitoneally) rats. Endotoxin-treatment depressed phenylephrine-induced contraction and raised tissue levels of cGMP. Aminoguanidine (100 microM and 1 mM) increased phenylephrine-induced tension and decreased cGMP levels in a dose-dependent manner in intact and endothelium-denuded aortas from endotoxin-treated rats but had no effect on vessels from sham-treated rats. These findings are consistent with the hypothesis that endotoxin treatment causes increased vascular production of endothelium-independent NO, which is associated with a diminished response to vasoconstrictors. Aminoguanidine decreases indices of NO production only after endotoxin treatment, providing further evidence that it is a selective inhibitor of inducible NO synthase.
Griffiths
M J
MJ
Unit of Critical Care, National Heart and Lung Institute, London, United Kingdom.
Messent
M
M
Curzen
N P
NP
Evans
T W
TW
D000818:Animals; D001013:Aorta, Thoracic / Q000737:chemistry / Q000187:drug effects; D006152:Cyclic GMP / Q000032:analysis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012477:Salmonella enteritidis
D004731:Endotoxins; D006146:Guanidines; D010656:Phenylephrine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; C004479:pimagedine