Wang Y, Rosenberg R L
Department of Pharmacology, University of North Carolina, Chapel Hill 27599.
Mol Pharmacol. 1991 Nov;40(5):750-5.
Ethaverine is a derivative of papaverine used in the treatment of peripheral vascular disease and is thought to cause vasodilation by reducing intracellular Ca2+ concentrations in vascular smooth muscle cells. We tested its effects on single, dihydropyridine-sensitive, L-type calcium channels from porcine cardiac muscle, incorporated into planar lipid bilayers. L-type calcium channels were activated by step depolarizations from a holding potential of -60 mV to a test potential of 0 mV, and unitary currents carried by 100 mM BaCl2 were recorded. Channel activity was enhanced by the presence of the dihydropyridine agonist (+)-202-791 (0.5 microM) and the activated alpha subunit of the stimulatory GTP-binding protein, Gs. We found that 0.3-30 microM ethaverine on either side of the channel caused a reduction in the channel open probability (EC50 approximately 1 microM), with the higher concentrations inhibiting channel activity almost completely. In addition, the ethaverine caused a small reduction in the unitary current amplitude of single open channels (approximately 20%). To test whether the effect of ethaverine on open probability was due to a displacement of the dihydropyridine agonist, we studied the effect of ethaverine on the binding of [3H]nitrendipine to cardiac sarcolemma and found that ethaverine inhibited [3H]nitrendipine binding with a Ki of approximately 8.5 microM. Ethaverine also inhibited the binding of [3H]diltiazem and [3H]verapamil, with Ki values of 1-2 microM. Because ethaverine is structurally related to verapamil, it is likely that ethaverine acts by binding to the verapamil binding sites on the L-type calcium channels to inhibit channel activation and dihydropyridine binding.
乙磺酸戊胺酯是一种用于治疗外周血管疾病的罂粟碱衍生物，被认为通过降低血管平滑肌细胞内的钙离子浓度来引起血管舒张。我们测试了它对整合到平面脂质双分子层中的猪心肌单个二氢吡啶敏感的L型钙通道的作用。L型钙通道通过从-60 mV的保持电位逐步去极化到0 mV的测试电位来激活，并记录由100 mM氯化钡携带的单位电流。二氢吡啶激动剂(+)-202-791(0.5 microM)和刺激性GTP结合蛋白Gs的活化α亚基的存在增强了通道活性。我们发现，通道两侧0.3 - 30 microM的乙磺酸戊胺酯会导致通道开放概率降低(半数有效浓度约为1 microM)，较高浓度几乎完全抑制通道活性。此外，乙磺酸戊胺酯使单个开放通道的单位电流幅度略有降低(约20%)。为了测试乙磺酸戊胺酯对开放概率的影响是否是由于二氢吡啶激动剂的置换，我们研究了乙磺酸戊胺酯对[3H]尼群地平与心肌肌膜结合的影响，发现乙磺酸戊胺酯抑制[3H]尼群地平结合，其抑制常数约为8.5 microM。乙磺酸戊胺酯还抑制[3H]地尔硫卓和[3H]维拉帕米的结合，抑制常数值为1 - 2 microM。由于乙磺酸戊胺酯在结构上与维拉帕米相关，乙磺酸戊胺酯可能通过与L型钙通道上的维拉帕米结合位点结合来抑制通道激活和二氢吡啶结合。
