Effect of cromakalim on KCl-, noradrenaline- and angiotensin II-induced contractions in the rat pulmonary artery.

The effect of cromakalim on vascular reactivity was studied in rat isolated pulmonary arterial strips. Cromakalim (0.1-1 microM) inhibited contractions induced by low (20-30 mM) KCl concentrations in a concentration-dependent manner. It had no effect on those elicited by 60-100 mM KCl. However, a higher concentration of cromakalim (10 microM) slightly decreased (-5 to -10%) KCl efficacy. Contractions induced by noradrenaline (NA, 0.01-1 microM) and angiotensin II (AII, 0.5-50 nM) were reduced by cromakalim (0.1-10 microM). The maximal response to NA and AII was decreased by 54 +/- 6.4% and 70 +/- 5.8% (n = 5), respectively, in the presence of 10 microM cromakalim. The inhibitory effect of cromakalim was not dependent on the presence of vascular endothelium. After blockade of calcium influx by verapamil (10 microM), cromakalim had no further effect on NA- and AII-induced contractions. Cromakalim (0.1-1 microM) had no effect on the amplitude of the transient contraction evoked by NA and AII in Ca(2+)-free solution. The inhibitory effect of cromakalim (1 microM) was reversed by glibenclamide (1-10 microM) and phentolamine (5-100 microM) which, however, did not alter the relaxant effect of verapamil (1 microM), papaverine (1 microM) or theophylline (1 mM). Contractions induced by NA and AII in the presence of tetraethylammonium (TEA, 10 mM) were also depressed by cromakalim. These results show that cromakalim is a potent anticonstrictor agent in the pulmonary circulation. As in other smooth muscles, its mechanism of action involves an interaction with potassium channels at the vascular smooth muscle cell membrane level.