Calcitonin gene-related peptide relaxes porcine coronary arteries via cyclic AMP-dependent mechanisms, but not activation of ATP-sensitive potassium channels.
We investigated the relaxant mechanisms of calcitonin gene-related peptide (CGRP) in endothelium-denuded porcine coronary arteries. Intracellular free calcium concentration ([Ca++]i) was measured simultaneously with force by the fura-2 microfluorimetric method. CGRP (10(-9) to 10(-7) M) or isoproterenol (10(-8) to 10(-5) M) produced a concentration-dependent relaxation of arterial rings precontracted with 30 mM KCl with only a slight decrease in [Ca++]i. In contrast, cromakalim (3 x 10(-7) to 3 x 10(-5) M), an ATP-sensitive potassium channel opener, reduced [Ca++]i and force in a parallel manner. When the arteries were precontracted with 90 mM KCl, the relaxant effects of CGRP and isoproterenol were attenuated, whereas that of cromakalim was abolished. In arteries precontracted with 90 mM KCl, reduction of extracellular calcium concentrations from 2.5 to 0.1 mM recovered the relaxant effects of CGRP and isoproterenol, but not that of cromakalim. All three relaxants reduced both [Ca++]i and force in arteries precontracted with endothelin-1 (10(-8) M). Glibenclamide (10(-5) M) inhibited the decrease in [Ca++]i and the relaxation caused by cromakalim, but had virtually no effect on those produced by CGRP or isoproterenol. In arteries precontracted with 30 mM KCl and relaxed maximally by isoproterenol (10(-5) M), CGRP (10(-7) M) failed to produce any relaxant effect, whereas cromakalim (10(-5) M) reduced [Ca++]i and force further. The inhibitor of phosphodiesterase, 3-isobutyl-1-methylxanthine, potentiated the decreases in [Ca++]i and relaxations caused by CGRP and isoproterenol, but not those by cromakalim.(ABSTRACT TRUNCATED AT 250 WORDS)
Kageyama
M
M
Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
Yanagisawa
T
T
Taira
N
N
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D019806:Cromakalim; D000242:Cyclic AMP / Q000378:metabolism*; D016232:Endothelins / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects
D001578:Benzopyrans; D016232:Endothelins; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide; D007545:Isoproterenol; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine