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 microM), 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 42K+ cromakalim (0.3-10 microM) produced a concentration-dependent increase in the 42K+ efflux rate coefficient. NA (0.3 microM) also produced an increase in the rate of efflux of 42K+, an effect which was not antagonized by nifedipine (0.3 microM). 7. When microelectrodes were used, cromakalim (1-10 microM) produced a maintained concentration-dependent membrane hyperpolarization. However, low concentrations of cromakalim (less than 1 microM) 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.
Bray
K M
KM
Department of Physiological Sciences, School of Biological Sciences, University of Manchester.
Weston
A H
AH
Duty
S
S
Newgreen
D T
DT
Longmore
J
J
Edwards
G
G
Brown
T J
TJ
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001578:Benzopyrans / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D019806:Cromakalim; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D001578:Benzopyrans; D011758:Pyrroles; D019806:Cromakalim; D009543:Nifedipine; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine