-Adrenergic Contractile Response in Rabbit Hearts

Whereas mobilization of intracellular Ca 2 1 stimulates neuronal adenylyl cyclase via Ca 2 1 /calmodulin, mobilized Ca 2 1 directly inhibits adenylyl cyclase in other tissues. To determine the physiologic role of the Ca 2 1 -dependent interaction between Na 1 /Ca 2 1 exchange and b -adrenergic signal transduction in the intact heart, digoxin (0.3 mg/kg) was administered intravenously in rabbits. 30 min after the administration, digoxin impaired the peak left ventricular dP/dt response to dobutamine infusions by up to 38% as compared with control rabbits. This impairment was not caused by changes in either b -adrenergic receptor number or in the functional activity of stimulatory guanine nucleotide-binding protein. It was associated with 33–36% reductions in basal and stimulated adenylyl cyclase activities. Animals treated with calcium gluconate (20 mg/kg/min for 30 min) also demonstrated similar reductions in adenylyl cyclase activities. In addition, increasing the free Ca 2 1 concentration progressively inhibited adenylyl cyclase activity in the control, digoxin-treated, and calcium gluconate–treated sarcolemma preparations in vitro. Moreover, digoxin and calcium gluconate pretreatment blunted the increase in cAMP in myocardial tissue after dobutamine infusion in vivo. Thus, digoxin rapidly reduces b -adrenergic contractile response in rabbit hearts. This reduction may reflect an inhibition of adenylyl cyclase by Ca 2 1 mobilized via Na 1 /Ca 2 1 exchange. ( J. Clin. Invest. 1996. 97:6–13.)