The beneficial effect of amrinone on acute drug-induced heart failure in the anaesthetised dog.

Amrinone, a positive inotropic-vasodilator agent, was administered to anaesthetised dogs in an attempt to reverse heart failure induced by drugs possessing negative inotropic properties. Propranolol, a beta-adrenergic blocker; verapamil, a calcium slow-channel blocker procainamide, a type 1 antiarrhythmic agent; or sodium pentobarbital, a barbituate; administered as a bolus injection and/or infusion, produced a sustained depression in canine cardiac function. Cardiac depression was characterised by a greater than 40% reduction in cardiac contractile force (CF) and maximum left ventricular pressure development (LV dp/dtmax), a 30 to 50% reduction in cardiac output (CO) and concomitant increases in mean central venous or mean right atrial blood pressures (CVP, RAP, respectively). Amrinone, when administered intravenously as a bolus injection (1 or 3 mg X kg-1) plus an infusion (0.03 or 0.1 mg X kg-1 X min-1) reversed the depression in cardiac function by increasing CF, CO and LV dp/dtmax and decreasing preload CVP or RAP in all four drug-induced failure models. Due to the vasodilator properties of amrinone, afterload, total peripheral resistance (TPR), was reduced in verapamil and procainamide failures as well as in propranolol failure, the only model where TPR increases. In another model of heart failure, in which ouabain-induced arrhythmias preceded procainamide toxicity, amrinone was also an effective cardiotonic agent. Ouabain's inotropic effect was studied in propranolol-induced heart failure. Although an increase in LV dp/dtmax and a decrease in CVP were noted, ouabain (40 micrograms X kg-1 iv) increased TPR and had little effect on the depression in CF and CO. Drug-induced models of heart failure were useful pharmacological tools for evaluating the cardiotonic agent's ability to overcome severe cardiac depression. In propranolol-, verapamil-, procainamide-, and pentobarbital-induced cardiac toxicity, amrinone could be of therapeutic value.

Cardiotonic activity of milrinone, a new and potent cardiac bipyridine, on the normal and failing heart of experimental animals.

Milrinone (Win 47203) is a potent cardiac bipyridine with inotropic and vasodilator properties. Its effects were studied in anesthetized and unanesthetized dogs and in isolated cardiac tissues from guinea pigs. In the anesthetized dog, the intravenous injection of milrinone (0.01-0.1 mg/kg) increased cardiac contractile force (CF) (23 +/- 6.1 to 87 +/- 8.9%), maximum left ventricular pressure development (24 +/- 5.8 to 119 +/- 16.1%), and cardiac output (16 +/- 4.5 to 33 +/- 8.9%), with less than a 30% increase in heart rate (HR). Significant decreases in systolic and diastolic blood pressures were seen at 0.3-3 mg/kg i.v. Oral doses of milrinone (0.1-1.0 mg/kg), in unanesthetized dogs, increased cardiac CF by 35 +/- 7.0 to 99 +/- 17.0%, with a maximum increase in HR of 40 +/- 7.1% and no significant change in blood pressure. Milrinone was effective in the presence of ouabain and dopamine without enhancing their arrhythmogenic properties. It was also effective in reversing propranolol-, verapamil-, or pentobarbital-induced heart failure. The inotropic response does not seem to involve the stimulation of the autonomic receptors, the release of endogenous catecholamines, histamine, or prostaglandins, or the inhibition of Na+,K+-adenosine triphosphatase. Milrinone is an inhibitor or cardiac adenosine 3',5'-monophosphate (cAMP) phosphodiesterase, with resultant increases in cardiac cAMP levels. However, the time course for this increase does not seem to correspond to the increase in muscle developed tension, and, therefore, it is unlikely to be responsible for the initiation of the inotropic response. Milrinone is a potent cardioactive agent which should be beneficial in the treatment of acute and chronic congestive heart failure.