Background: We investigated the effects of EMD 57033, a prototype Ca2+ sensitizer, and beta-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 beta-adrenoceptor agonists, which provides an insight on therapeutic strategy with Ca2+ sensitizers for the treatment of contractile dysfunction in congestive heart failure.