Pacing-Overdrive Dog
نویسندگان
چکیده
The functional integrity of the (3and a-adrenergic stimulatory pathways in a rapid ventricular pacing model of congestive heart failure in dogs was investigated; normal dogs served as controls. Total (-adrenergic receptor density was 35% lower (p<O.O1) in the pacing-overdrive dogs, and the (-adrenergic receptor-mediated stimulation of adenylate cyclase (Vm.) was found to be 68% and 72% lower (p<O.O1) in the left and right ventricles of the paced dogs. In addition, the basal adenylate cyclase activity was found to be 56% and 68% lower (p<O.O1) in the left and right ventricles of the failing heart. Similarly, the V., of 5'-guanylylimidodiphosphate (GppNHp) and forskolin stimulation of adenylate cyclase activity was significantly lower, 70%o and 55%, respectively (p <0.01), in both ventricles of the paced dogs. However, although the concentration yielding half-maximal velocity for (-agonist and GppNHp stimulation of adenylate cyclase was similar in both groups, that for forskolin stimulation of the enzyme was significantly increased (p<0.O1). Pertussis toxin-mediated ADP-ribosylation ofmembranes from control and failing hearts revealed a significant decrease in the inhibitory guanine nucleotide binding protein content (48±9%Yo, p<O.Ol) in the hearts ofthe paced dogs. Moreover, although the pertussis toxin treatment increased the basal and the forskolin-stimulated adenylate cyclase activity in both normal and failing heart membranes, the adenylate cyclase activity remained significantly depressed in the failing heart after pertussis toxin treatment (p<0.01). Consistent with the depressed adenylate cyclase activity, mechanical studies on isolated papillary muscles and trabeculae revealed a decrease in baseline total tension (from 7.0±0.7 to 3.8±0.4 g/mm2,p<0.01) and dT/dt (from 26±8 to 13±1 g/mm2/sec, p<0.01) in the pacing-overdrive model. Tension generation and dT/dt observed in the paced dogs in response to increasing concentrations of forskolin demonstrated a rightward shift in the dose-response curve and a decrease in maximal forskolin stimulation (p<0.01). Similarly, maximal tension and dT/dt in the presence of isoproterenol was significantly lower than in the normal dogs (p<0.01). The decrease in j3-adrenergic responsiveness was accompanied by a decrease and rightward shift in o!l-adrenergic responsiveness (increase in tension was 1.1±0.1 g/mm2 in paced dogs versus 2.1±0.1 g/mm2 in controls, p<0.01). This decrease in a,-adrenergic responsiveness occurred despite no change in receptor density, suggesting that the abnormality resides beyond the receptor. We suggest that a decrease in adenylate cyclase reactivity contributes to the blunted ,&adrenergic response to catecholamine stimulation in the pacing-overdrive model of heart failure. These abnormalities to the /3-adrenergic signal transduction pathway were accompanied by a decrease in activity of the membrane-bound enzyme Na+,K+-ATPase (p<0.01). These defects may be a reflection of more widespread dysfunction of sarcolemmal-bound enzymes and may play a role in the decrease in contractility and the development of heart failure in this model. (Circulation Research 1991;69:332-343)
منابع مشابه
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