ROLE OF NONSELECTIVE CATION CHANNELS AS CA2-1-INDUCED CONTRACTION ANDTHEIR SUPPRESSION BY NITRIC-OXIDE( ENTRY PATHWAY IN ENDOTHELIN)

The present study was carried out to clarify the role of nonselective cation channels as a Ca2+ entry pathway in the contraction and the inc rease in [Ca2+](i) induced by endothelin-1 in endothelium-denuded rat thoracic aorta rings, and their suppression by nitric oxide (NO). In C a2+-free medium, the endothelin-1-induced contraction was suppressed t o about 20% of control values, although the increase in [Ca2+](i) beca me negligible. The contraction and the increase in [Ca2+](i) monitored by fura 2 fluorescence were unaffected by a blocker of L-type voltage -operated Ca2+ channels nifedipine. A blocker of nonselective cation c hannels ropoxyl]-4-methoxyphenethyl]-1H-imidazole.HCl(SK&F 96365) supp ressed the endothelin-1-induced contraction and increase in [Ca2+](i) to the level similar to that after removal of extracellular Ca2+. SK&F 96365 had no further effect on the endothelin-l-induced contraction i n the absence of extracellular Ca2+. The endothelin-1-induced contract ion and increase in [Ca2+](i) were abolished by a donor of NO sodium n itroprusside. The effects of another NO donor 3-morpholinosydnonimine (SIN-1) were also tested and yielded essentially similar results to th ose for sodium nitroprusside on the endothelin-1-induced contraction. Furthermore, the inhibitory effects of sodium nitroprusside could be b locked with a guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a] quinoxalin-1-one (ODQ) at 30 mu M. These findings suggest that Ca2+ en try through nonselective cation channels but not voltage-operated Ca2 channels plays a critical role in the endothelin-1-induced increase i n [Ca2+](i) and the resulting contraction and that inhibition by NO of the endothelin-1-induced contraction is mainly the result of blockade of Ca2+ entry through these channels. (C) 1998 Elsevier Science B.V. All rights reserved.