Studies performed to elucidate the inhibitory mechanisms of the hyperpolarization induced by K
+ channel openers on the Ca
2+ movements and force of contraction produced by either the stimulation of thromboxane A
2 receptors or depolarization with high KCl have shown the following: When the plasma membrane is hyperpolarized by K
+ channel openers, voltage-dependent Ltype Ca
2+ channels are deactivated and the influx of Ca
2+ is decreased, as is the case with the KCl-induced Call influx. The hyperpolarization of the plasma membrane also has other inhibitory effects on phospholipase C, a membrane-associated enzyme activity. The IP
3 production and IP
3-induced Ca
2+ release from intracellular stores, which is related to the stimulation of the agonist receptors, are inhibited by the hyperpolarization of the plasma membrane by K
+ channel openers. Recently, we showed that the Ca
2+ sensitivity of the contractile elements was voltage dependent. Furthermore, membrane hyperpolarization induced by various K
+ channel openers relaxed canine coronary arteries more profoundly than decreased [Ca
2+]
i. Thus, the membrane voltage may regulate intracellular enzyme activities, including contractile elements. Therefore, this new facet of signal transduction should be considered in the control of vascular tone. The evolutional relationships of various K
+ channels are also discussed.
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