BRL 38227 (levcromakalim)-induced hyperpolarization reduces the sensitivity to Ca2+ of contractile elements in canine coronary artery

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Abstract
Potassium (K+) channel openers decrease intracellular free Ca2+ concentrations ([Ca2+]i) by hyperpolarizing the membrane and deactivating the Ca2+-channels. To examine whether the hyperpolarization produced by K+-channel openers has other effects on the mechanical activity of vascular smooth muscle, we investigated the effects of levcromakalim (BRL 38227) on membrane potential, [Ca2+]i, as measured with fura-2, and force of contraction induced by 30 mmol/l KCl-physiological salt solution (PSS), in canine coronary arteries. BRL 38227 hyperpolarized the membrane and reduced increases in [Ca2+]i and in contractile force induced by 30 mmol/l KCl-PSS. The [Ca2+]i-contractile force curve, determined in the presence of BRL 38227, was located to the right of the control curve determined by decreasing extracellular Ca2+ concentrations ([Ca2+]o) in 30 mmol/l KCl-PSS. The [Ca2+ i-contractile force curve, determined by decreasing extracellular K+ concentrations ([K+]o), was also located to the right of that determined by decreasing [Ca2+]o in 30 mmol/l KCl-PSS. The effect of BRL 38227, a reduction in the Ca 2+-sensitivity of contractile elements, was antagonized by the ATP-sensitive K+-channel blocker, glibenclamide (10−6 or 10−5 mol/1). These results suggest that the membrane hyperpolarization induced by BRL 38227, or the repolarization caused by reducing ([K+]o), decreases the Ca2+-sensitivity of contractile elements of vascular smooth muscle.