Ca(2+) channels involved in endothelin-induced mitogenic response in carotid artery vascular smooth muscle cells.

Endothelin (ET)-1 activates two types of Ca(2+)-permeable nonselective cation channels (NSCC-1 and NSCC-2) and a store-operated Ca(2+) channel (SOCC) in rabbit internal carotid artery (ICA) vascular smooth muscle cells (VSMCs) in addition to the voltage-operated Ca(2+) channel (VOCC). These channels can be discriminated using the Ca(2+) channel blockers SK&F-96365 and LOE-908. SK&F-96365 is sensitive to NSCC-2 and SOCC, and LOE-908 is sensitive to NSCC-1 and NSCC-2. On the basis of sensitivity to nifedipine, a specific blocker of the L-type VOCC, VOCCs have a minor role in ET-1-induced mitogenesis. Both LOE-908 and SK&F-96365 inhibited ET-1-induced mitogenesis in a concentration-dependent manner, and the combination of LOE-908 and SK&F-96365 abolished it. The IC(50) values of these blockers for ET-1-induced mitogenesis correlated well with those of the ET-1-induced intracellular free Ca(2+) concentration responses. These results indicate that the inhibitory action of these blockers on ET-1-induced mitogenesis may be mediated by blockade of NSCC-1, NSCC-2, and SOCC. Collectively, extracellular Ca(2+) influx through NSCC-1, NSCC-2, and SOCC may be essential for ET-1-induced mitogenesis in ICA VSMCs.