Evidence that pinacidil may promote the opening of ATP‐sensitive K+ channels yet inhibit the opening of Ca2+‐activated K+ channels in K+ ‐contracted canine mesenteric artery

Abstract

1 The effects of cromakalim and pinacidil on contraction and ⁸⁶Rb efflux were investigated in strips of canine mesenteric artery. 2 Cromakalim and pinacidil relaxed arterial strips precontracted with 20.9 mm K⁺ with pD₂ values of 6.56 and 5.88, respectively. 3 High (above 10 μm) concentrations of pinacidil, but not cromakalim, relaxed arterial strips bathed by a medium containing 65.9 mm K⁺, and inhibited Ca²⁺-induced contractions in strips bathed by a medium containing 80 mm K⁺. These findings suggested that pinacidil may act as an inhibitor of Ca²⁺ influx. 4 In arterial strips preloaded with ⁸⁶Rb, cromakalim and pinacidil increased the basal ⁸⁶Rb efflux. 5 When the effects of cromakalim and pinacidil on ⁸⁶Rb efflux were determined in arterial strips contracted with 65.9 mm K⁺, both drugs increased ⁸⁶Rb efflux. The increase in ⁸⁶Rb efflux induced by pinacidil was much smaller than that induced by cromakalim. Under the same conditions, nifedipine decreased ⁸⁶Rb efflux. 6 After the addition of nifedipine to arterial strips contracted with 65.9 mm K⁺, pinacidil produced a greater increase in ⁸⁶Rb efflux than in the absence of nifedipine, whereas the effects of cromakalim were the same for the two conditions. Therefore, the effects of pinacidil on ⁸⁶Rb efflux may be the resultant of two opposing effects: an increased ⁸⁶Rb efflux due to the opening of ATP-sensitive K⁺ channels, and a decreased efflux due to the closing of Ca²⁺-activated K⁺ channels. 7 In causing relaxation, cromakalim was competitively antagonized by glibenclamide with a pA₂ value of 7.16. However, glibenclamide antagonism of pinacidil was not of the simple competitive type, suggesting that inhibition of Ca²⁺ influx may contribute to the relaxant action of pinacidil. 8 It may be concluded that although the ability of pinacidil to increase ⁸⁶Rb efflux via ATP-sensitive K⁺ channel opening was similar to that of cromakalim, the inhibition of Ca²⁺ influx by pinacidil may reduce the opening of Ca²⁺-activated K⁺ channels in K⁺-contracted arterial strips.