Nakajima Toshiaki, Ma Ji, Iida Haruko, Iwasawa Kuniaki, Jo Taisuke, Omata Masao, Nagai Ryozo
Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, Tokyo, Japan.
Jpn Heart J. 2003 Nov;44(6):963-78. doi: 10.1536/jhj.44.963.
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+]i mobilization and voltage-dependent L-type Ca2+ current (ICa.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. Nilfedipine and nicardipine (10 microM) partly inhibited the sustained rise, but carvedilol inhibited it more effectively than the Ca2+ channel blockers. Under voltage clamp conditions, carvedilol (0.2-10 microM) reversibly inhibited the ICa.L concentration-dependently without any changes in the current-voltage relationships of ICa.L. Carvedilol shifted the steady-state inactivation for ICa.L to more negative potentials and inhibited ICa.L in a voltage-dependent manner. In addition, carvedilol did not inhibit Ca2+ release from store sites induced by thapsigargin, but significantly inhibited the sustained rise due to capacitative Ca2+ entry unrelated to ICa.L. In contrast, metoprolol did not mimic these effects of carvedilol. These results provide evidence that carvedilol inhibits ICa.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.
卡维地洛具有降压作用，可抑制激动剂诱导的血管平滑肌细胞增殖，进而防止血管重塑。然而，其基本机制尚未阐明。我们研究了卡维地洛对血管平滑肌细胞中[Ca2+]i动员和电压依赖性L型Ca2+电流（ICa.L）的影响，并将其与美托洛尔进行比较。使用fura-2 AM和膜片钳技术在大鼠胚胎主动脉平滑肌细胞（A7r5）中测量[Ca2+]i。在细胞外Ca2+存在的情况下，血管加压素和内皮素-1首先通过从储存部位释放Ca2+增加[Ca2+]i，随后Ca2+内流。卡维地洛不抑制Ca2+释放，但能浓度依赖性地显著抑制由于Ca2+内流导致的持续升高。硝苯地平和尼卡地平（10 microM）部分抑制持续升高，但卡维地洛比钙通道阻滞剂更有效地抑制它。在电压钳条件下，卡维地洛（0.2 - 10 microM）浓度依赖性地可逆抑制ICa.L，且ICa.L的电流-电压关系无任何变化。卡维地洛将ICa.L的稳态失活电位向更负的方向移动，并以电压依赖性方式抑制ICa.L。此外，卡维地洛不抑制毒胡萝卜素诱导的储存部位Ca2+释放，但显著抑制与ICa.L无关的容量性Ca2+内流导致的持续升高。相比之下，美托洛尔不能模拟卡维地洛的这些作用。这些结果表明，卡维地洛抑制ICa.L，还可能抑制激动剂（血管加压素和内皮素-1）诱导的血管平滑肌细胞Ca2+内流通道，这可能是卡维地洛血管舒张和抗增殖作用的原因。
