title: Regional differences in the vasorelaxant effects of nicorandil and amlodipine on isolated porcine coronary arteries.
abstract: The vasorelaxant effects of nicorandil, a K(+)-channel opener, and amlodipine, a dihydropyridine-type Ca(2+)-channel blocker, were investigated on partially and maximally K(+)-depolarized ring preparations from the porcine left anterior descending coronary artery. By comparing vascular responses in the proximal and distal parts of the epicardial segment, the scope of the study was to evaluate regional differences in the action of nicorandil and amlodipine. Nicorandil (10(-7)-10(-4) M) shifted the K+ concentration-response curves to the right and depressed the maximal contractile responses in a concentration-dependent manner, consistent with K(+)-channel opening and secondary non-K(+)-channel opening mechanisms of action. Nicorandil had a significantly more potent relaxant effect in the proximal compared to the distal arterial rings contracted with 85 mM K+. Pretreatment with methylene blue (10(-5) M) did not significantly influence the regional difference in the action of nicorandil. Amlodipine (10(-9)-10(-6) M) had a significantly more potent and effective inhibitory and relaxant effect than nicorandil under the same conditions. In contrast to nicorandil, the effect of amlodipine was more prominent in the distal compared to the proximal vessel rings. The cumulative addition of extracellular Ca2+ exhibited a more potent contractile response in the distal rather than in the proximal rings. Nicorandil totally and amlodipine partly eliminated the contractile responses to the lowest concentration of Ca2+. The inhibitory effect of amlodipine on the contractile responses to higher Ca2+ concentrations was more pronounced than that of nicorandil. The results show that there are regional differences in the responsiveness of porcine coronary arteries to Ca2+, nicorandil and amlodipine. Our findings indicate that the regional difference in nicorandil-induced vasodilation was caused neither by the K(+)-channel opening nor by the nitrate-like mechanism of action, but could be due to a direct Ca(2+)-influx blocking effect of the drug.
authors.affiliation: Institute of Pharmacology, University of Aarhus, United Kingdom.
authors.forename: L B
authors.initials: LB
authors.lastname: Tankó
authors.forename: E O
authors.initials: EO
authors.lastname: Mikkelsen
authors.forename: O
authors.initials: O
authors.lastname: Frøbert
authors.forename: J P
authors.initials: JP
authors.lastname: Bagger
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008751:Methylene Blue / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D010496:Pericardium; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D015221:Potassium Channels; D014665:Vasodilator Agents; D017311:Amlodipine; D009536:Niacinamide; D020108:Nicorandil; D006162:Guanylate Cyclase; D011188:Potassium; D002118:Calcium; D008751:Methylene Blue