Relaxant mechanisms of cyclic AMP-increasing agents in porcine coronary artery

Toshio Yamagishi, Teruyiki Yanagisawa, Keisuke Satoh, Norio Taira

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

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 Ca2+-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 μM) 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.

Original languageEnglish
Pages (from-to)253-262
Number of pages10
JournalEuropean Journal of Pharmacology
Volume251
Issue number2-3
DOIs
Publication statusPublished - 1994 Jan 14

Keywords

  • Ca concentration, intracellular
  • Ca sensitivity of contractile elements
  • Coronary artery
  • Thromboxane A
  • cAMP
  • β-Adrenoceptor

ASJC Scopus subject areas

  • Pharmacology

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