AMINOGUANIDINE SELECTIVELY DECREASES CYCLIC CMP 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 contribu tes to the vasodilation and hyporesponsiveness to vasopressors that ch aracterize the septic circulation. Guanosine 3',5'-cyclic monophosphat e (cGMP) mediates the effects of NO in vascular smooth muscle. Vessels from animals treated with endotoxin have elevated cGMP levels compare d with control animals. Aminoguanidine has been proposed as a selectiv e inhibitor of the inducible form of NO synthase. This study compares the effects of aminoguanidine on phenylephrine-induced contractions an d cGMP levels in thoracic aortic rings from endotoxin treated (20 mg/k g intraperitoneally) with sham-treated (1 ml saline intraperitoneally) rats. Endotoxin-treatment depressed phenylephrine-induced contraction and raised tissue levels of cGMP. Aminoguanidine (100 mu M and 1 mM) increased phenylephrine-induced tension and decreased cGMP levels in a dose-dependent manner in intact and endothelium-denuded aortas from e ndotoxin-treated rats but had no effect on vessels from sham-treated r ats. These findings are consistent with the hypothesis that endotoxin treatment causes increased vascular production of endothelium-independ ent NO, which is associated with a diminished response to vasoconstric tors. Aminoguanidine decreases indices of NO production only after end otoxin treatment, providing further evidence that it is a selective in hibitor of inducible NO synthase.