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KMID : 0390119950350020063
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Journal of Pusan Medical College
1995 Volume.35 No. 2 p.63 ~ p.74
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Characterization of Bimakalim as a K+ Channel Opener in Canine Coronary Artery
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Abstract
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The importance of K+ channel activation is widely reported in terms of maintenance of membrane potential and the functional regulation of cardiovascular system. Recently, cromakalim, a benzopyran derivative, is known as a K+ channel activator. It
is
accepted that relaxant effect of cromakalim is ascribed to the membrane hyperpolarization in association with increased K+ conductance, thereby indirectly inhibiting Ca2+ influx through the voltage-dependent Ca2+ channel.
Bimakalim(EMD 52692) has a non-chiral benzopyran structure, in which the nucleus possesses characteristically the double bond between C3-C4 It is more potent than cromakalim and has high selectively to coronary and cerebral blood vessels.
In the present study, it was aimed to characterize the relaxant action of bimakalim compared with that of cromakalim.
1. In the canine coronary artery, artery, bimakalim(1 nM~30 μM) and cromakalim(10 nM~30μM) caused the concentration-dependent relaxation with EC50 of 3.45±0.83×10E-8 M and 1.90±0.20×10E-7M, respectively. Bimakalim is more potent than
cromakalim
by 5.5-fold.
2. The concentration-relaxant response curves of cromakalim and bimakalim was shifted to the right by pretreatment with glibenclamide(0.1, 0.3 and 1.0μM). By Schild-polt analysis, the pA2 value of glibenclamide against cromakalim was 7.85 with
the
slope of 0.95(not different from unity), indicating the competitive antagonism, and that against bimakalim was 7.96 with the slope of 1.37, suggeting non-competitive antagonism.
3. Bimakalim as well as cromakalim did not inhibit the Ca2+ influx through the voltage-dependent Ca2+ channel.
4. Either cromakalim-or bimakalim-induced relaxation of the phenylephrine contraction was reversed by posttreatment with glibenclamide.
5. The relaxant effect of bimakalim was not affected by Ba2+, tetraethylmammonium and 4-aminopyridine.
6. In the ATP-depleted coronary arterial strips(treated with 2-deoxyglucose and oligomycin), glibenlamide-enhancement of phenylephrine conraction was observed in 6 among 14 cases(42%). Additional application of bimakalim to non-responding
ATP-depleted
strips consistently exerted a glibenclamide-enhancement.
Based on these results, it is concluded that in canine coronary arterial smooth muscle, bimakalim as well as cromakalim activated the glibenclamide-sensitive K+ channels distinct from the ATP-sensitive K+ channels. Bimakalim was more potent than
cromakalim. The difference of the potency between two agents may the potency between two agents may the ascribed to the difference of inhibitory action on the intrancellular Ca2+ release rather than that on Ca2+ efflux.
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