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.
Department of Internal Medicine, Kyoto University Hospital, Japan.
K
K
Nagai
T
T
Murakami
T
T
Iwase
T
T
Tomita
S
S
Sasayama
D009597:4-Nitrophenylphosphatase / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002125:Calcium Gluconate / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology*; D000242:Cyclic AMP / Q000032:analysis; D003864:Depression, Chemical; D004077:Digoxin / Q000494:pharmacology*; D004280:Dobutamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D017136:Ion Transport; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D019831:Sodium-Calcium Exchanger; D016276:Ventricular Function
D000067956:Adenylyl Cyclase Inhibitors; D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D011943:Receptors, Adrenergic, beta; D019831:Sodium-Calcium Exchanger; D004280:Dobutamine; D004077:Digoxin; D000242:Cyclic AMP; D009597:4-Nitrophenylphosphatase; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D002125:Calcium Gluconate; D002118:Calcium