Callera G E, Varanda W A, Bendhack L M
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Department of Physiology, Faculty of Medicine, University of São Paulo, Ribeirão Preto, São Paulo.
Hypertension. 2001 Sep;38(3 Pt 2):592-6. doi: 10.1161/hy09t1.096248.
Arteries from hypertensive rats show a greater contraction in response to Ca(2+) channel activator and an increased sensitivity to Ca(2+) entry blockers compared with those of normotensive rats. These facts suggest an altered Ca(2+) influx through membrane channels. In this study, this hypothesis was tested by direct activation of voltage-gated Ca(2+) channels using Bay K 8644, a dihydropyridine sensitive large conductance (L-type) Ca(2+) channel opener in aortas from 2-kidney, 1-clip (2K1C) hypertensive rats. Because the membrane potential of smooth muscle cells is an important regulator of the conformational state of L-type Ca(2+) channels and, consequently, dihydropyridine affinity, the effect of 10 mmol/L KCl on the responses to Bay K 8644 was also studied. Maximal contraction (ME) and sensitivity to Bay K 8644 were greater in 2K1C rats than in 2K normotensive rats (ME, 1.77+/-0.15 versus 1.25+/-0.19 g; negative log molar value [pD(2)], 8.27+/-0.07 versus 7.92+/-0.08). When the KCl concentration was increased from 4.7 to 10 mmol/L in the bathing medium, no differences were observed in the contractile effect of Bay K 8644 between 2K1C and 2K (ME, 1.28+/-0.13 versus 1.14+/-0.21 g; pD(2), 8.56+/-0.08 versus 8.38+/-0.07). The cell resting membrane potential of 2K1C aorta vascular smooth muscle cells were less negative than in 2K (-35.19+/-4.91 versus -48.32+/-1.88 mV). Basal intracellular Ca(2+) concentration (Ca(2+)) was greater in cultured vascular smooth muscle cells from 2K1C than from 2K (293.4+/-25.83 versus 205.40+/-12.83 nmol/L). In 2K1C, Bay K 8644 induced a larger increase in Ca(2+) than in 2K (190.60+/-45.65 versus 92.57+/-14.67 nmol/L), and in 10 mmol/L KCl, this difference was abolished (134.90+/-45.12 versus 125.20+/-32.17 nmol/L). The main conclusion of the present work is that the increased contractile response to Bay K 8644 in 2K1C aortas is due to an increased Ca(2+) influx through voltage-gated Ca(2+) channels.
与正常血压大鼠的动脉相比，高血压大鼠的动脉对Ca(2+)通道激活剂表现出更大的收缩反应，并且对Ca(2+)内流阻滞剂的敏感性增加。这些事实表明通过膜通道的Ca(2+)内流发生了改变。在本研究中，使用Bay K 8644（一种对二氢吡啶敏感的大电导（L型）Ca(2+)通道开放剂）直接激活2肾1夹（2K1C）高血压大鼠主动脉中的电压门控Ca(2+)通道，对这一假设进行了检验。由于平滑肌细胞的膜电位是L型Ca(2+)通道构象状态的重要调节因子，因此也是二氢吡啶亲和力的重要调节因子，所以还研究了10 mmol/L KCl对Bay K 8644反应的影响。2K1C大鼠的最大收缩（ME）和对Bay K 8644的敏感性高于2K正常血压大鼠（ME，1.77±0.15对1.25±0.19 g；负对数摩尔值[pD(2)]，8.27±0.07对7.92±0.08）。当浴液中KCl浓度从4.7 mmol/L增加到10 mmol/L时，2K1C和2K之间Bay K 8644的收缩效应未观察到差异（ME，1.28±0.13对1.14±0.21 g；pD(2)，8.5
