Inhibitory effects of carvedilol on calcium channels in vascular smooth muscle cells

Carvedilol has hypotensive effects and inhibits agonist-induced cell proliferation of vascular smooth muscle and then prevents vascular remodeling. However, the basic mechanisms have not been clarified. We examined the effects of carvedilol on [Ca2+] mobilization and voltage-dependent L-type Ca2+ current (I-Ca.L) in vascular smooth muscle cells, and compared them with metoprolol. [Ca2+](i) was measured using fura-2 AM and patch clamp techniques in rat embryonic aortic smooth muscle cells (A7r5). In the presence of extracellular Ca2+, vasopressin and endothelin-1 increased [Ca2+](i) due first to the Ca2+ release from store sites, and subsequently Ca2+ entry. Carvedilol did not inhibit the Ca2+ release, but significantly suppressed the sustained rise due to Ca2+ entry concentration-dependently. Nifedipine and nicardipine (10 muM) partly inhibited the sustained rise. but carvedilol inhibited it more effectively than the Ca2+ channel blockers. Under voltage clamp conditions, carvedilol (0.2-10 muM) reversibly inhibited the I-Ca.L concentration-dependently without any changes in the current-voltage relationships of I-Ca.L. Carvedilol shifted the steady-state inactivation for I-Ca.L to more negative potentials and inhibited I-Ca.L in a voltage-dependent manner. In addition, carvedilol did not inhibit Ca2+ release front store sites induced by thapsigargin, but significantly inhibited the sustained rise due to capacitative Ca2+ entry unrelated to I-Ca.L. In contrast, metoprolol did not mimic these effects of carvedilol. These results provide evidence that carvedilol inhibits I-Ca.L and may also inhibit the channels for agonist (vasopressin and endothelin-1)-induced Ca2+ entry in vascular smooth muscle cells, which might contribute to the vasorelaxing and antiproliferative effects of carvedilol.