Characterization of responses to cromakalim and pinacidil in smooth and cardiac muscle by use of selective antagonists

Abstract

1 In dog isolated coronary artery (precontracted with endothelin, 10 nm) cromakalim (0.1–30μm) and pinacidil (1–30μm) produced concentration-dependent vasorelaxant responses. The effects of these compounds could be blocked by glibenclamide (3μm), phentolamine (30 μm) or alinidine (30 μm) to a similar extent, indicating that both agents alter vascular tone through the same mechanism in this preparation. 2 The ability of the antagonists glibenclamide, phentolamine and alinidine to block the response to cromakalim in a number of smooth muscle types from the guinea-pig was determined. Cromakalim (0.1–30 μm) produced concentration-dependent relaxant responses in thoracic aorta (precontracted with endothelin, 30 nm), ileum (precontracted with K⁺, 25 mm) and trachea (spontaneously contracted). Responses to cromakalim in all tissues could be blocked by the three antagonists. However, significantly higher concentrations of the antagonists were required to block responses in the thoracic aorta than in the ileum or trachea. Given that the rank order of potency of the antagonists was similar in all tissues (i.e. glibenclamide > phentolamine = alinidine), this result may suggest vascular K⁺ channels opened by cromakalim are quantitatively but not qualitatively different in vascular compared with non-vascular smooth muscle. Glibenclamide was approxmately 10 times more potent than phentolamine or alinidine. 3 Cromakalim had minimal functional effects on the rat spontaneously beating right atrial (rate) or electrically driven left ventricular strip (force) preparations. Similarly the three antagonists studied failed to alter force generation in the right ventricular strip. However alinidine and phentolamine did produce a dose-related bradycardia in the spontaneously beating right atria. This effect appears to be unrelated to blockade of the K⁺ channel opened by cromakalim since glibenclamide, the most potent K⁺ channel antagonist studied, failed to produce the same response. 4 It would appear that the K⁺ channel opened by cromakalim is present in a number of vascular and non-vascular smooth muscle. Based on the potency of the three antagonists studied, there appears to be little heterogeneity in the process activated by cromakalim in vascular and non-vascular smooth muscle.