Differential alteration of cardiotonic effects of EMD 57033 and β-adrenoceptor agonists in volume-overload rabbit ventricular myocytes

Background: We investigated the effects of EMD 57033, a prototype Ca²⁺ sensitizer, and β-adrenoceptor agonists in ventricular myocytes isolated from the volume-overload (V-O) heart failure model of the rabbit. Methods and Results: V-O cardiac hypertrophy was induced in rabbits by the formation of an arterio-venous shunt between the carotid artery and jugular vein 12 to 15 weeks after the operation. Ventricular myocytes were enzymically isolated from normal and V-O rabbit hearts. The myocyte was loaded with a fluorescence Ca²⁺ dye, indo-1, and Ca²⁺ transients, and cell lengths were measured simultaneously. V-O myocytes were significantly larger than control myocytes. Duration of Ca²⁺ transients and cell shortening was significantly longer in the V-O myocytes than in control myocytes. Effects of cardiotonic interventions, including EMD 57033, isoproterenol, and dobutamine, on Ca²⁺ transients and cell shortening in V-O myocytes were compared with those in control rabbit myocytes. Isoproterenol and dobutamine increased the systolic cell shortening and peak Ca²⁺ transients and abbreviated the duration of cell shortening and Ca²⁺ transients. These responses were markedly attenuated in V-O myocytes. By contrast, the response of cell shortening to EMD 57033 was unaltered, and the Ca²⁺ sensitizing effect of EMD 57033 was rather enhanced in V-O myocytes. Conclusion: Our results indicate that the effectiveness of Ca²⁺ sensitizers is maintained in the V-O rabbit hypertrophy and heart failure model in contrast to the blunted response to β-adrenoceptor agonists, which provides an insight on therapeutic strategy with Ca²⁺ sensitizers for the treatment of contractile dysfunction in congestive heart failure.