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


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.


CONCLUSIONS
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.
Sugawara
H
H
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Sakurai
K
K
Atsumi
H
H
Nakada
S
S
Tomoike
H
H
Endoh
M
M
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004280:Dobutamine / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007545:Isoproterenol / Q000627:therapeutic use*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009210:Myofibrils / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D011817:Rabbits; D013829:Thiadiazines / Q000627:therapeutic use*
D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D013829:Thiadiazines; C070609:EMD 53998; D004280:Dobutamine; D007545:Isoproterenol