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Modulation of vasodilatation to levcromakalim by hypoxia and EDRF in the rabbit isolated ear: a comparison with pinacidil, sodium nitroprusside and verapamil
Author(s) -
Randall Michael D.,
Griffith Tudor M.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13581.x
Subject(s) - pinacidil , sodium nitroprusside , vasodilation , verapamil , chemistry , cromakalim , potassium channel opener , papaverine , pharmacology , endothelium derived relaxing factor , potassium channel , medicine , anesthesia , endocrinology , nitric oxide , calcium , agonist , biochemistry , glibenclamide , receptor , organic chemistry , diabetes mellitus
1 We have used an isolated buffer‐perfused preparation of the rabbit ear to investigate the effects of hypoxia and inhibition of endothelium‐derived relaxing factor (EDRF) synthesis on the vasodilator responses to the potassium channel opener, levcromakalim (the active (−)‐enantiomer of cromakalim). The results obtained with levcromakalim have been compared with those for pinacidil, sodium nitroprusside and verapamil. 2 Levcromakalim relaxed preconstricted preparations with an EC 50 = 343 ± 41 n m and R max = 80.3 ± 6.4%. Under hypoxic conditions the concentration‐response curve was significantly ( P < 0.01) shifted to the left with an EC 50 = 118 ± 16 n m and R max = 89.9 ± 2.7%. Hypoxia did not influence relaxation to either pinacidil, sodium nitroprusside or verapamil. 3 Inhibition of EDRF synthesis with 100 μ m N G ‐nitro‐ l ‐arginine methyl ester ( l ‐NAME) also significantly ( P < 0.001) increased the vasodilator potency of levcromakalim (EC 50 = 56 ± 5 n m ), and caused a similar shift in the concentration‐response curve to sodium nitroprusside. It did not influence vasodilatation to either verapamil or pinacidil. The potentiation of vasodilator responses to levcromakalim by l ‐NAME was reversed by an excess of l ‐arginine. 4 Impairment of oxidative phosphorylation with 400 n m carbonyl cyanide m ‐chlorophenylhydrazone significantly ( P < 0.05) increased the potency of levcromakalim (EC 50 = 120 ± 20 n m ) but did not influence vasodilatation to pinacidil or endothelium‐dependent relaxations to acetylcholine. 5 Vasodilatation to levcromakalim was augmented both by hypoxia and by inhibition of EDRF activity. Since impairment of oxidative phosphorylation increased the potency of levcromakalim but did not alter EDRF activity then the mechanism responsible for hypoxic facilitation of responses to levcromakalim is likely to be due to reduced ATP levels in hypoxic smooth muscle cells rather than a change in EDRF activity. These results suggest that levcromakalim may selectively dilate both hypoxic vessels and vessels with impaired EDRF activity. The results also point to important differences in the pharmacology of levcromakalim and pinacidil.