Effects of Amiodarone and L8040, Novel Antianginal and Antiarrhythic Drugs, on Cardiac and Coronary Haemodynamics and on Cardiac Intracellular Potentials

Abstract

1. The effects on the coronary and systemic haemodynamics of intravenous and intracoronary injections of two benzfuran derivatives, amiodarone and its brominated analogue (L8040), were studied in open-chest anaesthetized dogs. The effects of L8040 on cardiac intracellular potentials after 6 weeks of 20 mg/kg intraperitoneal injections in rabbits were also investigated. 2. Both compounds produced dose-related and quantitatively similar decreases in coronary vascular resistance following their intracoronary administration; threshold effects occurred with about 0-25 mg of each drug and maximal effects with 4 mg. Larger intracoronary doses produced measurable systemic effects. 3. Intravenous injections of amiodarone and L8040 (2-5-10 mg/kg) produced dose-related decreases in heart rate and aortic pressure with a fall in total peripheral resistance. The left ventricular output was either unaffected or increased with a consistent augmentation in stroke volume. 4. The bradycardia produced by both drugs was associated with prolongation of the P-R interval of the electrocardiogram with no significant effect on the QRS duration or the Q-T interval. 5. Each drug produced a decrease in the total peripheral vascular resistance with no change in left ventricular end diastolic pressure except after 10 mg/kg doses which led to an increase in this parameter. 6. Cardiac contractile force and peak LV dp/dt were reduced by both drugs in a dose-related manner. 7. Chronic intraperitoneal administration of L8040 in rabbits caused a prolongation of the duration of the atrial and ventricular intracellular potential without an effect on the maximal rate of depolarization. 8. The effect of amiodarone or L8040 on the coronary circulation and arterial pressure may be attributed to their vasodilator properties but their depressant actions on cardiac contractile force and peak LV dp/dt with an increase in left ventricular end diastolic pressure at high doses, also suggest intrinsic negative inotropic propensity for both compounds. 9. It is concluded that the overall effects on coronary and systemic haemodynamics of amiodarone and its brominated analogue are likely to permit a favourable influence on the balance of oxygen supply and demand in myocardial ischaemia; in addition, their actions on sino-atrial and atrio-ventricular conduction as well as those on cardiac repolarization suggest potential antiarrhythmic properties which merit investigation.

Electrophysiological Effects of Dronedarone (SR33589), a Noniodinated Benzofuran Derivative, in the Rabbit Heart

“…30 It is noteworthy that the brominated analogue (without the iodine) of AM has been shown to have identical class III antiarrhythmic actions comparable to those of AM. 31,32 Thus, the data raise the possibility that neither the presence of a halogen nor its type might be the basis for the unique electrophysiological properties of benzofuran derivatives as a class for the propensity to homogeneously increase the duration of the cardiac action potential. Our data in the present study demonstrating that the long-term effects of SR, a nonhalogenated benzofuran derivative, closely resemble not only those of long-term AM but also those reported for hypothyroidism.…”

Acute effects of amiodarone upon the canine sinus node and atrioventricular junctional region.

“…In man (3,4,7,(11)(12)(13)15) and in experimental animals (2, 33) amiodarone's chronotropic effect has been variously described as positive (11,13,25), negative (3,4,15,(32)(33)(34), or biphasic, with a brief initial increase soon followed by a long-lasting bradycardia (12 (3,10,37). The present study is in accord with these observations made in man and further confirms that the effective concentrations of amiodarone are similar in both dogs (25,33) and humans (11,13,38 (42), then another explanation must be found for the negative chronotropic action of amiodarone.…”

“…Whereas the acute hemodynamic effects abate rapidly after intravenous administration (2,11,13), reported maximal antiarrhythmic efficacy after per os administration appears to be achieved after several days or weeks (4,5,7,8,15,16). Amiodarone prolongs the duration of the action potential without concomitantly changing the resting membrane potential (10,14,17), yet it is still not clear whether amiodarone's antiarrhythmic properties can be ascribed to these electrophysiologic changes (18).…”

“…Parenteral administration of the benzfuran derivative as a pseudosolution in dogs (2,10) and with tween 80 in man (11) causes a prompt decrease in peripheral and coronary vascular resistance. (2,10).…”

“…Parenteral administration of the benzfuran derivative as a pseudosolution in dogs (2,10) and with tween 80 in man (11) causes a prompt decrease in peripheral and coronary vascular resistance. (2,10). The ensuing reflexly mediated response usually includes a brief increase in heart rate (11)(12)(13) that often obscures the direct negative chronotropic (14) and inotropic (2) action of amiodarone.…”