Pharmacological characterization of Ca2+ entry channels in endothelin-1-induced contraction of rat aorta using LOE 908 and SK&F 96365

1 We have recently shown that endothelin-1 (ET-1) activates two types of Ca 2+-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) an d store-operated Ca2+ channel (SOCC). These channels can be pharmacological ly discriminated using Ca2+ channel blockers such as SK&F 96365 and LOE 908 . Here we characterized Ca2+ entry channels involved in ET-1-induced contra ctions of rat thoracic aortic rings and increases in the intracellular free Ca2+ concentration ([Ca2+](i)) of single smooth muscle cells using these b lockers. 2 LOE 908 or a blocker of voltage-operated Ca2+ channel nifedipine had no e ffect on the contractions and increases in [Ca2+](i) induced by thapsigargi n or ionomycin, whereas SK&F 96365 abolished them. 3 The contractions and increases in [Ca2+](i) induced by ET-1 depended on e xtracellular Ca2+ but were resistant to nifedipine. The responses to lower concentrations (less than or equal to 0.1 nM) of ET-1 were abolished by eit her SK&F 96365 or LOE 908. The responses to higher concentrations (greater than or equal to 1 nM) were abolished by SK&F 96365, but were partially res istant to LOE 908. 4 SK&F 96365 inhibited the LOE 908-resistant contractions induced by higher concentrations of ET-1 with IC50 values similar to those for contractions induced by thapsigargin or ionomycin. 5 These results show that the contractions and increases in [Ca2+](i) of ra t aortic smooth muscles at lower concentrations of ET-1 involve only one Ca 2+ entry channel which is sensitive to SK&F 96365 and LOE 908 (NSCC-2), whe reas those at higher concentrations of ET-1 involve another Ca2+ entry chan nel which is sensitive to SK&F 96365 but resistant to LOE 908 (SOCC) in add ition to the former channel.