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 microM) induced a non-inactivating potassium current (IKCO), an event which was associated with increased current noise. IKCO was fully inhibited in the presence of 10 microM glibenclamide. Stationary fluctuation analysis of the current noise associated with IKCO 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 microM) and nifedipine (10 nM-10 microM) each elicited full, concentration-dependent, parallel reductions of the increases in [Ca2+]i (assessed using fura-2) and tension induced by 10 microM 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.
Criddle
D N
DN
School of Biological Sciences, University of Manchester, UK.
Greenwood
I A
IA
Weston
A H
AH
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019806:Cromakalim; D004594:Electrophysiology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D011189:Potassium Chloride; D009543:Nifedipine; D002118:Calcium; D009638:Norepinephrine