THE EFFECT OF REDUCED MYOCARDIAL CYCLIC-AMP CONTENT ON THE RESPONSE TO MILRINONE IN THE ISOLATED GUINEA-PIG HEART

Background: Cardiac beta receptor down-regulation is associated with a reduction of tissue cyclic adenosine monophosphate (AMP) content. Mil rinone exerts its effects by inhibiting the metabolism of existing cyc lic AMP. The purpose of this study was to evaluate the effect of reduc ed myocardial cyclic AMP content on the pharmacologic action of milrin one. Methods: A reduction of myocardial cyclic AMP content was produce d by creating catecholamine depletion in the hearts of adult guinea pi gs with intraperitoneal reserpine. Control animals received the reserp ine vehicle. Isolated heart perfusion was maintained with modified Kre bs buffer, and hearts were paced at 270 beats/min. A latex balloon and transducer-tipped catheter were inserted into the left ventricle. Iso volemic work was maintained at a constant balloon volume. Hearts from control and reserpine treated animals were perfused for 20 minutes wit h buffer containing either no milrinone, 1.7 x 10(-6), or 1.0 x 10(-4) mol/L milrinone (n = 12 for each dose). Maximal positive and negative dP/dt were assessed. The hearts were then frozen and cyclic AMP was m easured. Results: Cyclic AMP content was significantly lower in the re serpine-treated hearts at each milrinone concentration (0.33 +/- 0.01 vs 0.46 +/- 0.01; 0.33 +/- 0.01 vs 0.53 +/- 0.01; 0.30 +/- 0.01 vs 0.6 1 +/- 0.02 pmol/mg wet weight, p < 0.05). Milrinone significantly incr eased positive and negative dP/dtmax (p < 0.05), but no difference was observed between control and reserpine-treated hearts. Conclusions: E ndogenous catecholamine depletion reduces myocardial cyclic AMP conten t but does not attenuate the response to milrinone in the isolated hea rt.