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

Summary

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.