Relaxant mechanisms of cyclic AMP-increasing agents in porcine coronary artery.
We investigated the relaxant mechanisms of the cyclic AMP (cAMP)-increasing agents, isoproterenol, T-0509, forskolin and 3-isobutyl-1-methylxanthine (IBMX), on porcine coronary arteries contracted with U46619 (300 nM), a thromboxane A2 analogue, or 30 mM KCl, by measuring force simultaneously with intracellular Ca2+ concentration ([Ca2+]i) or cAMP and cyclic GMP (cGMP) levels. In U46619-contracted arteries, these agents decreased [Ca2+]i and force of contraction to almost the same extent in a concentration-dependent manner, whereas in KCl-contracted arteries these agents, except IBMX at higher concentrations, produced a relaxation with little change in [Ca2+]i. These agents all elevated tissue cAMP levels, and in addition, IBMX at higher concentrations increased cGMP levels. In Ca(2+)-free medium, these agents produced a concentration-dependent inhibition of Ca2+ release from intracellular Ca2+ stores induced by U46619 but not by 25 mM caffeine. Isoproterenol at a high concentration (3 microM) transiently decreased [Ca2+]i but steadily relaxed KCl-contracted arteries. This decrease in [Ca2+]i, but not the relaxation was inhibited by ryanodine and caffeine treatments. These results suggest that the relaxant mechanism of these agents on KCl-contracted arteries is mainly due to phosphorylation of myosin light chain kinase via cAMP-dependent protein kinase, resulting in a reduction of the Ca2+ sensitivity of contractile elements. Their relaxant mechanism in U46619-contracted arteries seems due to the inhibition of signal transduction of the agonist, resulting in a decrease in [Ca2+]i and inhibition of the Ca2+ sensitization.
Yamagishi
T
T
Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
Yanagisawa
T
T
Satoh
K
K
Taira
N
N
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D013552:Swine; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011450:Prostaglandin Endoperoxides, Synthetic; D014665:Vasodilator Agents; D012433:Ryanodine; D005576:Colforsin; D013928:Thromboxane A2; D011189:Potassium Chloride; C025342:RP333; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000242:Cyclic AMP; D006152:Cyclic GMP; D007545:Isoproterenol; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine