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Effects of Ca2+ antagonists and K+-channel activators on K+-induced contractions in the rat aorta
Abstract:
1. In the rat aortic ring with endothelium, suspended in a K+-free salt solution containing 1.25 mM Ca2+, the concentration-response curve to K+ (2-50 mM) was characterized by an initial small contractile phase occurring at 2-5 mM (Emax 1 = 0.67 +/- 0.18 g, n = 9) followed by a plateau (4-8 mM) and then a secondary contractile response (Emax2 = 1.64 +/- 0.13 g). 2. (-)-Bay k 8644 (0.01-0.3 microM) increased greatly the maximum of the first and only slightly that of the second contractile phase to K+. 3. In preparations treated with 0.3 microM (-)-Bay k 8644, only the contractile responses to low concentrations of K+ were inhibited by RP 49356 (0.1-1.0 microM), cromakalim (0.1-1.0 microM), nicorandil (1-10 microM), minoxidil sulphate (10 microM) or HA 1004 (1 microM). 4. In contrast, nitrendipine (0.01-0.1 microM) and diltiazem (1.0 microM) inhibited contractile responses to all concentrations of K+, whereas bucindolol (3 microM), dihydralazine (100 microM) and cinnarizine (1.0 microM) depressed only the second phase of the K+ concentration-response curve. 5. These results indicate that the enhancement by (-)-Bay k 8644 of the contractile response to low K+ (2-10 mM) is possibly due to activation of voltage-operated calcium channels (VOCs). The inhibition by purported K+ channel activators (cromakalim, RP 49356, nicorandil, minoxidil sulphate) of these contractions is compatible with membrane hyperpolarization mediated by an increase in outward K+ current. This mechanism would lead to VOC closure and therefore a fall in free cytosolic Ca2+. 6. Thus, the determination of the effects of myorelaxant agents on the concentration-response curve to K+ in the presence of (-)-Bay k 8644, is a novel and simple functional approach to the discrimination quantitatively and qualitatively of activators of K+ channels from other classes of compounds (such as calcium entry blockers) or vasodilators with an as yet undetermined cellular mechanism (e.g. bucindolol).