Effects of amiodarone and L8040, novel antianginal and antiarrhythmic drugs, on cardiac and coronary haemodynamics and on cardiac intracellular potentials.
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.
D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents; D001572:Benzofurans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects*; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D011437:Propylamines / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D001572:Benzofurans; D011437:Propylamines; D013876:Thiophenes; D000638:Amiodarone