K⁺ Channel-opening action and KRN2391-induced reduction of Ca²⁺ sensitivity of arterial smooth muscle

To clarify the vasodilating mechanism of KRN2391, a novel vasodilator having a combined nitrate-like and K⁺ channel-opening action, we investigated its effects on membrane potentials, intracellular Ca²⁺ concentrations ([Ca²⁺](i)) and force of contraction in canine coronary artery. KRN2391 hyperpolarized the membrane of arterial smooth muscle cells in 5 and 30 mM KCl-physiological salt solutions. KRN2391 reduced the increases in [Ca²⁺](i) and force of contraction induced by 30 mM KCl- physiological salt solution and the effect on [Ca²⁺](i) was almost abolished by 10^-5 M glibenclamide, although the effect on force of contraction was only partially inhibited. The [Ca²⁺](i)-force curves in the presence of KRN2391 or the selective K⁺ channel openers Ki4032 and cromakalim were shifted to the right, as compared to the control curve determined by varying the extracellular Ca²⁺ concentration ([Ca²⁺](o)). This finding indicates that these substances reduce the Ca²⁺ sensitivity of contractile elements (Ca²⁺ desensitization). The Ca²⁺-desensitizing action of KRN2391 was partly antagonized by 10^-5 M glibenclamide. There was no interaction between nitroglycerin and cromakalim or Ki4032. These results suggest that, in addition to the nitrate-like action, the opening of the K⁺ channel by KRN2391 reduces not only [Ca²⁺](i) but also the Ca²⁺ sensitivity of contractile elements, resulting in vasodilatation.