Molecular pharmacologycal investigations on K channel openers-New

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Effects of newly synthesized K channel openers, nicorandil, cromakalim and pinacidil on smooth muscle cells of the rabbit and rat portal vein, mesenteric artery and vein were investigated using the microelectrode, voltage clamp and patch clamp methods. The membrane potential of smooth muscle cells of the rabbit mesenteric artery was -7OmV and that of the portal vein was -55mV. Above three agents consistently hyperpolarized the membrane and increased the ionic conductance of the membrane. When the current-voltage relation-ships were compared before and after application of these agents, all agents increased the membrane resistance and both relation curves cross at about -8OmV. This means that the hyperpolarization induced by nicorandil, pinacidil and cromakalim was due to increase in the K permeability of the membrane. Using the voltage clamp method, when nicorandil, cromakalim or pinacidil was applied at the holding potantial of -40mV, the outward current generated in a concentration d … More ependent manner. This outward current was slightly inhibited by application of tetraethyl-ammonium (TEA) and markedly inhibited by 4-aminopyridine (4-AP). These potential changes were very sensitive to intracellular (cytosilic) Ca. When rectangular depolarization pulse or ramp current (-120V - +140mV) was applied, the K current was consistently enlarged. These outward current evoked by these three agents were blocked by preapplication of glibencalmide. When the patch clamp method was applied on fragmented membranes (inside out patch), the cytosolic Ca sensitive K channels were recorded, i.e. large conductance (280pS) and small conductance (30pS) of the Ca dependent K current. The former was more sensitive to TEA that 4-AP and the latter was more sensitive to 4-AP than TEA. ATP (over 1mM) inhibited the generation of the 3OpS K channel and blocked this channel with of 1OmM ATP. Nicorandil, pinacidil and cromakalim accelerated the generation of the 30pS K channel and these actions of Ca channel openers were blocked by pre- application of glibenclamide. These K channel openers the open probability and prolonged the open time of the ATP-sensitive Ca dependent K channel. Therefore, we concluded that K channel openers acts on the 30pS Ca dependent ATP sensitive K channel. Nicorandil possessed aproperty of nitroglycerine-like action, pinacidil a property of dihydropyridine sensitive Ca antagonistic action and pinacidil a property of synthesis inhibitor of inositol 1,4,5-trisphosphate. Such actions with the K channel opening may merit as anti-anginal and anti-hypertensive agents. Less