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Cardiovascular Research 1998 37(3):791-798; doi:10.1016/S0008-6363(97)00262-9
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Enhancement of the vasorelaxant potency of nicorandil by metabolic inhibition and adenosine in the pig coronary artery

Christina S Davie and Nicholas B Standen*

Ion Channel Group, Department of Cell Physiology and Pharmacology, University of Leicester, PO Box 138, Leicester LE1 9HN, UK

* Corresponding author. Tel. (+44-116) 252 3302; Fax (+44-116) 252 5045; E-mail: nbs@le.ac.uk

Objective: Nicorandil is used clinically to treat angina and acts in part by opening ATP-sensitive K+ channels whose opening is also enhanced by metabolic compromise. We have therefore investigated whether treatments that mimic conditions in ischaemia can increase the potency of nicorandil to dilate coronary arteries. Methods: Ring segments from pig small coronary arteries were mounted on a myograph, contracted with 20 mM K+ Krebs solution containing 200 nM BAYK 6844, and relaxations to cumulative doses of nicorandil were measured. Results and Conclusions: Nicorandil produced a dose-dependent relaxation with a mean pEC50 (–log EC50, M) of 4.76±0.02. Inhibition of metabolism with carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 100 nM) or by removal of extracellular glucose significantly increased the potency of nicorandil (pEC50s of 5.11±0.08 and 5.08±0.06, p<0.05 in each case). The adenosine analogue 2-chloroadenosine (2-CA, 300 nM) had a similar effect (pEC50=5.17±0.06, p<0.05). Reducing extracellular pH to 6.8 also significantly increased the potency of nicorandil, but to a smaller extent. Glibenclamide reduced the potency of nicorandil (pEC50=3.81±0.01, n=7), and abolished its enhancement by CCCP, zero glucose, 2-CA or pH 6.8 solution. 2-CA did not affect the potency of nicorandil in relaxing contractions to 80 mM K+ or the potency of glyceryl trinitrate. We conclude that the potency of nicorandil to cause coronary vasorelaxation is increased under conditions of metabolic inhibition. This effect appears to result from the K+ channel opening action of the drug, and may have significant consequences for its therapeutic effectiveness.

KEYWORDS Coronary artery; Nicorandil; Potassium channel; Adenosine; Pig; Ischaemia


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