endogenous NOS inhibitors - endothelin-1 pathway for the vascular remodelling

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Abstract
Mechanisms of vascular remodelling process are complex and poorly understood. We describe herein the role of L-arginine-endogenous NOS inhibitors-endothelin-1 pathway for the vascular remodelling after endothelial denudation of the rabbit carotid artery. It is reportedly known that NO is a vasodilating substance, an inhibitor of platelet aggregation and adhesion, and an inhibitor of vascular smooth muscle cell proliferation and that endothelin-1, of which production is inhibited by NO, is a potent vasoconstrictor and a potent mitogen. An accumulation of endogenous inhibitors (L-NMMA and ADMA) in regenerated endothelial cells after the endothelial denudation was accompanied by the decreased NO generation, the increased endothelin-1 content within the vessel wall and the occurrence of intimal hyperplasia. Endothelin-1 content within the vessel wall was significantly increased after the exogenous L-NMMA administration for 2 weeks, suggesting that accumulated L-NMMA results in the decreased NO generation and, in turn, increases endothelin-1 content. Endothelin-1 facilitated the [3H]-L-NMMA uptake by endothelial cell and brought about the potentiation of L-NMMA-mediated inhibition of NO generation. These results strongly suggest that the L-arginine--endogenous NOS inhibitors--endothelin-1 pathway plays an active role for vascular remodelling.

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