LEVCROMAKALIM-INDUCED MODULATION OF MEMBRANE POTASSIUM CURRENTS, INTRACELLULAR CALCIUM AND MECHANICAL-ACTIVITY IN RAT MESENTERIC-ARTERY

In freshly-dispersed cells from rat mesenteric artery, levcromakalim (1 and 10 mu M) induced a non-inactivating potassium current (I-KCO), an event which was associated with increased current noise. I-KCO was fully inhibited in the presence of 10 mu M glibenclamide. Stationary fluctuation analysis of the current noise associated with I-KCO induced by levcromakalim at a holding potential of -10 mV indicated that the unitary conductance of the underlying K-channels was 10.2 pS at 0 mV under the quasi-physiological conditions of the experiment. In isolated arterioles both levcromakalim (10 nM-10 mu M) and nifedipine (10 nM-10 mu M) each elicted full, concentration-dependent, parallel reductions of the increases in [Ca2+](i) (assessed using fura-2) and tension induced by 10 mu M noradrenaline. However, the effects of both drugs on KCl-induced increases in tension and in [Ca2+](i), did not follow a simple relationship. Levcromakalim relaxed KCl- and noradrenaline-induced sustained contractions with a similar potency. This was in contrast to nifedipine which was approximately 20 times more potent against KCl-induced contractions. It is concluded that levcromakalim relaxes rat mesenteric arterioles primarily by the opening of a small conductance, glibenclamide-sensitive K-channel. An additional action of levcromakalim is suggested by its relative inability to suppress the increase in [Ca2+](i) produced by 30 mM K+-PSS.