Cellular Pharmacology of Hyperpolarization-Relaxation Coupling

通过测定犬或猪冠状动脉或基底动脉平滑肌细胞内钙离子浓度([Ca^&lt；2+&gt；]i)的变化，探讨大电导钙激活钾通道(BK)和三磷酸腺苷敏感性钾通道(K&lt；ATP&gt；)参与动脉张力调节的可能机制。静息状态下，左旋克罗卡林降低[Ca~(2+)]_i和音调。左克罗卡林可抑制5-羟色胺引起的[Ca~(2+)]_i升高和收缩，其作用最强于尼卡地平。左克罗卡林的抑制作用可被格列本脲阻断，但不能被四乙基铵或伊比利亚毒素阻断。左旋克罗卡林可降低收缩蛋白的钙敏感性。因此，左克罗卡林可作为治疗蛛网膜下腔出血后迟发性血管痉挛的候选药物，因为在犬的基底动脉中，左克罗卡林不依赖于…的状态而降低[Ca~(2+)]_i和血管张力。K~(+)通道开放剂引起的超极化对激动剂刺激或高KCI去极化所产生的Ca~(2+)运动和收缩的抑制作用的阐明如下：K~(2+)通道开放剂使质膜超极化时，电压依赖性的L型钙通道失活，钙离子内流减少。质膜的超极化对膜相关酶磷脂酶C的活性也有抑制作用。与激动剂受体有关的IP_3的产生和IP_3诱导的细胞内钙释放被K~(+)通道开放剂对质膜的超极化所抑制。收缩元件Ca~(2+)~(2+)敏感性的电压依赖性。此外，不同K~(+)通道开放剂引起的膜超极化对犬冠状动脉的松弛作用大于对[Ca~(2+)]_i的影响，因此，膜电压可能调节细胞内酶活性，包括收缩元件。因此，在血管张力的控制中应考虑这一信号转导的新方面。较少

The involvement of large conductance Ca^<2+>-activated K^+ channels (BK) and ATP-sensitive K^+ (K_<ATP>) channels in regulation of arterial tone was examined by measuring the change in intracellular Ca^<2+> concentration ([Ca^<2+>]_i) simultaneously with force of contraction in the canine or porcine coronary or basilar arterial smooth muscles. At resting condition, levcromakalim reduced [Ca^<2+>]_i and tone. Levcromakalim suppressed the serotonin-induced increases in [Ca^<2+>]_i and contraction, the maximum effects of which were much greater than those of nicardipine. The inhibitory effects of levcromakalim were blocked by glibenclamide but not by tetraethylammonium or iberiotoxin. Levcromakalim may reduce the Ca^<2+>-sensitivity of the contractile proteins. Thus, levcromakalim can be a candidate of therapeutic agents for delayd vasospasm after subarachnoid hemorrhage, since in the canine basilar artery levcromakalim reduces [Ca^<2+>]_i and vascular tone independently of the states of … More BK channels.The elucidation of the inhibitory of the hyperpolarization induced by K^+ chnnel openers on the Ca^<2+> movements and force of contraction produced by either the stimulation with agonists or depolarization with high KCI has shown as following : When the plasma membrane is hyperpolarized by K^+ channel openers, voltage-dependent L-type Ca^<2+> channels are deactivated and the influx of Ca^<2+> is decreased. The hyperpolarization of the plasma membrane also has another inhibitory effects on the membrane-associated enzyme activity, phospholipase C.The IP_3 production and IP_3-induced Ca^<2+> release from intracellular stores related with the stimulation of the agonist receptors are inhibited by the hyperpolarization of the plasma membrane by K^+ channel openers. The voltage-dependence of the Ca^<2+> sensitivity of contractile elements. Furthermore, membrane hyperpolarization induced by various K^+ channel openers, relaxd canine coronary arteries more profoundly than decreased [Ca^<2+>]_i.Thus, the membrane voltage may regulate intracellular enzyme activities, including contractile elements. This new facet of signal transduction therefore should be considered in the control of vascular tone. Less