Endothelin-1 activates the R-type Ca2+ channel in vascular smooth-muscle cells.

Endothelin-1 (ET-1) induced a concentration-dependent sustained increase of intracellular calcium ([Ca2+]i) in single cells of rabbit aortic vascular smooth-muscle cells (VSMCs). This sustained [Ca2+]i increase was insensitive to the L-type Ca2+ antagonist nifedipine but was sensitive to isradipine and the presence of extracellular Ca2+. The ET(A) receptor antagonist BQ-123, ET-3, and the selective ETB agonist BQ-3020 had no effect on ET-1-induced sustained [Ca2+]i increase. Pretreatment with caffeine or ryanodine did not prevent the effect of ET-1 on [Ca2+]i. However, ET-1 did not induce further increases in the sustained [Ca2+]i increase induced by either high levels of extracellular potassium [K]0 or insulin, nor did ET-1 have any effect on potassium or L-type calcium channels. Our results suggest that the sustained [Ca2+]i increase induced by ET-1, as with insulin, was mainly due to activation of a nifedipine-insensitive but isradipine-sensitive steady-state, voltage-dependent R-type calcium channel via an as yet unidentified ET receptor.