Ca2+ channels involved in endothelin-induced mitogenic response in carotid artery vascular smooth muscle cells

Endothelin (ET)-1 activates twotypes of Ca²⁺-permeable nonselective cation channels(NSCC-1 and NSCC-2) and a store-operated Ca²⁺ channel(SOCC) in rabbit internal carotid artery (ICA) vascular smooth musclecells (VSMCs) in addition to the voltage-operated Ca²⁺channel (VOCC). These channels can be discriminated using the Ca²⁺ channel blockers SK&F-96365 and LOE-908. SK&F-96365 issensitive to NSCC-2 and SOCC, and LOE-908 is sensitive to NSCC-1 andNSCC-2. On the basis of sensitivity to nifedipine, a specific blocker of the L-type VOCC, VOCCs have a minor role in ET-1-inducedmitogenesis. Both LOE-908 and SK&F-96365 inhibited ET-1-inducedmitogenesis in a concentration-dependent manner, and the combination ofLOE-908 and SK&F-96365 abolished it. The IC₅₀ values ofthese blockers for ET-1-induced mitogenesis correlated well with thoseof the ET-1-induced intracellular free Ca²⁺concentration responses. These results indicate that the inhibitory action of these blockers on ET-1-induced mitogenesis may bemediated by blockade of NSCC-1, NSCC-2, and SOCC. Collectively,extracellular Ca²⁺ influx through NSCC-1, NSCC-2, and SOCCmay be essential for ET-1-induced mitogenesis in ICA VSMCs.