DIFFERENCES BETWEEN THE EFFECTS OF CROMAKALIM AND NIFEDIPINE ON AGONIST-INDUCED RESPONSES IN RABBIT AORTA

1 The effects of cromakalim on endothelium-denuded rabbit aortic strips were compared with those of the calcium (Ca2+) entry blocking agent, nifedipine. 2 Pre-incubation with cromakalim or nifedipine had no significant effect on the initial phasic component of noradrenaline (NA)-induced responses. 3 Cromakalim (0.3-10-mu-M), but not nifedipine, inhibited the maintained tonic contractions produced by NA. The effects of cromakalim were antagonized by raising extracellular [K+] or by glibenclamide. 4 Nifedipine inhibited contractions produced by KCl (40 mM) whereas cromakalim had no effect. 5 In Ca2+-free physiological salt solution (PSS), cromakalim produced a significant inhibition of both the refilling of and the release of Ca2+ from NA-releasable Ca2+ stores, whereas nifedipine was ineffective. 6 In tissues preloaded with K-42+ cromakalim (0.3-10-mu-M) produced a concentration-dependent increase in the K-42+ efflux rate coefficient. NA (0.3-mu-M) also produced an increase in the rate of efflux of K-42+, an effect which was not antagonized by nifedipine (0.3-mu-M). 7 When microelectrodes were used, cromakalim (1-10-mu-M) produced a maintained concentration-dependent membrane hyperpolarization. However, low concentrations of cromakalim (< 1-mu-M) which relaxed the aorta had no effect on membrane potential. NA had no significant effect on membrane potential. 9 It is concluded that the ability of cromakalim to relax NA-induced contractions in rabbit aorta is not exerted by the indirect closure of nifedipine-sensitive Ca2+ channels. Instead, cromakalim may exert a direct inhibitory action on Ca2+ uptake into and release from Ca2+ stores and additionally inhibit the pathway through which Ca2+ passes from the extracellular fluid to intracellular Ca2+ stores.