Cellular Pharmacology of Hyperpolarization-Relaxation Coupling

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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