Dual mechanism of the relaxing effect of nicorandil by stimulation of cyclic GMP formation and by hyperpolarization.
In addition to previous results from our laboratory showing that nicorandil relaxed vascular smooth muscle by increasing cyclic GMP levels, it was shown to activate K-channels as well, an effect that also leads to relaxation. In the present study, we attempted to differentiate quantitatively between these two effects in isolated bovine coronary artery strips with simultaneous isotonic measurement of length and radioimmunoassay (RIA) determination of cyclic GMP. When the strips were contracted by the thromboxane A2 analogue U 46619 (1 microM) with 10 microM methylene blue added, nicorandil produced 30-50% relaxation without significant changes in cyclic GMP. When in U 46619-contracted strips the hyperpolarizing effect of nicorandil was suppressed by increasing extracellular K+ to 80.4 mM (30-fold), nicorandil caused only 52% relaxation, whereas cyclic GMP increases were not significantly suppressed. Quantitative separation of both mechanisms of relaxation by nicorandil was further achieved through calculation of the cyclic GMP-mediated component from a correlation between increases in cyclic GMP and percentage of relaxation as produced by nicorandil under conditions of inhibited hyperpolarization, i.e., in strips contracted with 1 microM U 46619 or 26.8 mM K+ (10-fold) and exposed to either 30-fold K+ or 10 mM Ba2+. Under both conditions, similar correlations between cyclic GMP and relaxation were obtained. Because U 46619, in addition to its contractile effect, partially antagonized the relaxation by nicorandil without changing cyclic GMP, the correlation was corrected for this effect and indicated a participation of cyclic GMP in the overall relaxant response of approximately 30-40% at low and less than or equal to 80-90% at high concentrations of nicorandil.
Kukovetz
W R
WR
Institute of Pharmacodynamics and Toxicology, University of Graz, Austria.
Holzmann
S
S
Braida
C
C
Pöch
G
G
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001464:Barium / Q000494:pharmacology; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects; D006152:Cyclic GMP / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D008751:Methylene Blue / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D009599:Nitroprusside / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D015221:Potassium Channels; D011450:Prostaglandin Endoperoxides, Synthetic; D014665:Vasodilator Agents; D009599:Nitroprusside; D001464:Barium; D009536:Niacinamide; D020108:Nicorandil; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D011188:Potassium; D008751:Methylene Blue