Matsuda K, Lozinskaya I, Cox R H
Bockus Research Institute, Graduate Hospital, Philadelphia, PA 19146, USA.
Am J Hypertens. 1997 Nov;10(11):1231-9. doi: 10.1016/s0895-7061(97)00225-2.
The observation that organic Ca2+ channel blockers are more effective in lowering blood pressure and peripheral resistance in hypertensive compared to normotensive subjects suggests that there is a greater contribution from voltage-gated Ca2+ channels (CaL) to vascular force maintenance in hypertensive arteries. This study tests this hypothesis by comparing the effects of Bay k 8644 and nisoldipine on basal force development, contractile responses to norepinephrine and serotonin, and Ca2+ currents (ICa) in mesenteric artery (MA) from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). MA rings were used to record isometric contractions at Lmax. Single cells were isolated by collagenase plus elastase for measurement of CaL properties by patch-clamp methods. Contractile responses to Bay k 8644 were larger and more sensitive in SHR than WKY, and were larger in endothelium-denuded compared to intact rings. In SHR, the addition of 10 nmol/L Bay k 8644 increased contractile sensitivity to norepinephrine (NE) and serotonin (5HT), and increased maximum response to 5HT. In WKY, 10 nmol/L Bay k 8644 produced a small increase in 5HT sensitivity with no effect on maximum response, and had no effect on NE responses. In the presence of 1 mumol/L nisoldipine, the maximum response and the sensitivity to both NE and 5HT were decreased in both WKY and SHR with the inhibitory effects of nisoldipine being larger in SHR than WKY. Peak ICa was larger in SHR, and current-voltage curves were shifted toward more negative voltages compared to WKY. Bay k 8644 increased ICa in both WKY and SHR myocytes with no apparent difference in the magnitude of its effect when expressed as a percent of control ICa. These results suggest that CaL contribute significantly to tonic force maintenance as well as to agonist responses in MA from both WKY and SHR, but with a much larger contribution in SHR. Differences in the sensitivity of CaL to Bay k 8644 were not responsible for the differences in contractile responses to this agonist.
与血压正常的受试者相比，有机钙通道阻滞剂在降低高血压患者的血压和外周阻力方面更有效，这一观察结果表明，电压门控钙通道（CaL）对高血压动脉血管张力维持的贡献更大。本研究通过比较Bay k 8644和尼索地平对Wistar-Kyoto大鼠（WKY）和自发性高血压大鼠（SHR）肠系膜动脉（MA）的基础张力发展、对去甲肾上腺素和5-羟色胺的收缩反应以及钙电流（ICa）的影响，来验证这一假设。MA环用于记录Lmax时的等长收缩。通过胶原酶加弹性蛋白酶分离单个细胞，采用膜片钳方法测量CaL特性。与WKY相比，SHR对Bay k 8644的收缩反应更大且更敏感，与完整环相比，内皮剥脱环的收缩反应更大。在SHR中，添加10 nmol/L Bay k 8644可增加对去甲肾上腺素（NE）和5-羟色胺（5HT）的收缩敏感性，并增加对5HT的最大反应。在WKY中，10 nmol/L Bay k 8644使5HT敏感性略有增加，对最大反应无影响，对NE反应无影响。在存在1 μmol/L尼索地平的情况下，WKY和SHR对NE和5HT的最大反应和敏感性均降低，尼索地平对SHR的抑制作用大于WKY。SHR的ICa峰值更大，与WKY相比，电流-电压曲线向更负的电压方向移动。Bay k 8644增加了WKY和SHR心肌细胞的ICa，以对照ICa的百分比表示时，其作用幅度无明显差异。这些结果表明，CaL对WKY和SHR的MA中的张力维持以及激动剂反应有显著贡献，但在SHR中的贡献要大得多。CaL对Bay k 8644敏感性的差异不是对该激动剂收缩反应差异的原因。
