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Nagai, K. et al.

Digoxin reduces beta-adrenergic contractile response in rabbit hearts. Ca(2+)-dependent inhibition of adenylyl cyclase activity via Na+/Ca2+ exchange.

Whereas mobilization of intracellular Ca2+ stimulates neuronal adenylyl cyclase via Ca2+/calmodulin, mobilized Ca2+ directly inhibits adenylyl cyclase in other tissues. To determine the physiologic role of the Ca(2+)-dependent interaction between Na+/Ca2+ exchange and beta-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 beta-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 Ca2+ 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 beta-adrenergic contractile response in rabbit hearts. This reduction may reflect an inhibition of adenylyl cyclase by Ca2+ mobilized via Na+/Ca2+ exchange.[1]

References

Digoxin reduces beta-adrenergic contractile response in rabbit hearts. Ca(2+)-dependent inhibition of adenylyl cyclase activity via Na+/Ca2+ exchange. Nagai, K., Murakami, T., Iwase, T., Tomita, T., Sasayama, S. J. Clin. Invest. (1996) [Pubmed]

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