BENEFICIAL EFFECT OF SPM-5185, A CYSTEINE-CONTAINING NITRIC-OXIDE DONOR, IN RAT CAROTID-ARTERY INTIMAL INJURY

We studied the effects of an organic nitric oxide (NO) donor SPM-5185 in a rat carotid artery intimal injury model. Seven days after injury, the two end segments of the injured carotid arteries were studied for endothelial release of NO, and the middle segments were used for histological measurement of the intimal-to-medial (I/M) ratio and scanning electron microscopy of the luminal surface. The NO donor SPM-5185 or its non-NO-donating control compound SPM-5267 were infused intravenously at 30 mu g/d. Full vasorelaxant responses of rat carotid arterial rings were obtained with the endothelium-dependent vasodilators acetylcholine (ACh), A23187, and the endothelium-independent vasodilator acidified NaNO2 in sham-operated control rings. Impaired relaxation occurred with 10 mu mol/L ACh and 1 mu mol/L A23187 in injured rings but not in rings infused with SPM-5185 for 7 days. Relaxation to 100 mu mol/L acidified NaNO2 was not significantly different among any of the groups, indicating a normal vascular smooth muscle response after intimal injury. Morphometric analysis of injured carotid arteries given vehicle and SPM-5267 showed marked intimal thickening with an average I/M ratio of 0.78+/-0.03 and 0.74+/-0.05, respectively. SPM-5185 markedly attenuated intimal thickening, resulting in an I/M ratio of 0.13+/-0.03 (P<.01 from vehicle), representing an approximate to 82% inhibition of intimal thickening. SPM-5185 infusion resulted in accelerated regeneration of endothelial cells on the intimal surface at 7 days. SPM-5185 also markedly retarded the proliferation of cultured rat vascular smooth muscle cells at 7 days compared with SPM-5267 (P<.01). We conclude that a constant intravenous infusion of a subvasodilator dose of NO donor SPM-5185 significantly accelerates the functional recovery of the regenerating endothelium and also inhibits vascular smooth muscle cell proliferation, which contributes to myointimal thickening.