Amiodarone. Biochemical aspects and haemodynamic effects

The mechanisms underlying the non-competitive beta-antagonistic properties of amiodarone were investigated, and the haemodynamic responses to exercise following the administration of oral amiodarone or intravenous propranolol were compared in dogs with a healed myocardial infarction submitted to a graded treadmill exercise. In radioligand binding studies, amiodarone, up to 10 mumol/L did not compete with 125I-iodocyanopindolol for binding to rat heart beta-adrenoceptors. Exposure of cardiac membranes to greater concentrations of amiodarone induced a significant decrease in the number of beta-adrenoceptors without affecting their affinity for 125I-iodocyanopindolol. Similar results were observed ex vivo, in rats after single or multiple dose administration. When added in vitro to rat heart membranes, amiodarone non-competitively inhibited the activation of adenylate cyclase by isoprenaline, glucagon and secretin. Stimulation of adenylate cyclase by those agents which act at more internal sites in the sarcolemmal membrane such as GppNHp, sodium fluoride or forskolin, was much less affected by amiodarone. In dogs performing at a submaximal work level, amiodarone significantly reduced heart rate and tended to increase coronary flow and to reduce left ventricular end-diastolic pressure, but did not affect left ventricular dP/dt. During submaximal exercise, propranolol had similar effects on heart rate, but dramatically reduced myocardial contractility.