Functional relevance of the changes in cyclic AMP accumulation.

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Functional relevance of the change in cAMP accumulation was examined in the isolated rat cardiac myocyte and papillary muscle.Methods: Effects of isoproterenol (ISP), phophodiesterases (PDE) and ISP in the presence of PDE inhibitors on force of contraction were examined in relation to the effects on cAMP metabolism. Force of contraction was measured in the isolated rat right papillary muscle (37ﾟC, 1Hz). Rat heart cell was isolated by method of Powell and Twist and the cAMP content was determined by radioimmunoassay. Results: The extent of cAMP accumulation induced by submaximal concentration of ISP and IBMX (a non-selective PDE inhibitor) was 2.4 and 4.8-fold, respectively. However, IBMX-induced positive inotropic effect (PIE) was less effective than that of ISP. IBMX elicited cAMP accumulation and PIE by itself, and enhanced the ISP-induced cAMP accumulation and PIE. A PDE type-III selective inhibitor (milrinone) elicited cAMP accumulation and PIE by itself. Whereas milrinone scarcely affected the ISP-induced cAMP accumulation and PIE. A PDE type-IV selective inhibitor (Ro 20-1724) did not elicit the cAMP accumulation and PIE by itself, but it potentiated the cAMP accumulation and PIE induced by ISP more effectively than IBMX. Thus increased intracellular cAMP concentration is not necessarily reflected to the augmentation of contractile force. The present results suggest that cAMP and isoenzymes of PDE in the different intracellular compartments share differential physiologic relevance in regulation of myocardial contractility.