Pharmacology of the bipyridines: amrinone and milrinone

Abstract

The cardiovascular bipyridines amrinone and milrinone are positive inotropic agents with vasodilator properties. When their effects on the heart and circulation were studied in both isolated cardiac tissues and anesthetized animals, milrinone was found to be 30 times more potent than amrinone. The inotropic response of isolated atria and papillary muscles to the bipyridines was characterized by increases in isometric tension and in the rates of tension development and relaxation. In the anesthetized dog, amrinone (1.0 mg/kg iv) and milrinone (0.03 mg/kg iv) caused significant increases in left ventricular dP/dtmax, cardiac output, and heart rate, significant decreases in pulmonary arterial pressure, and no change in systemic blood pressure. Studies to elucidate the mechanism(s) of action of the bipyridines indicated that Ca++ and cyclic AMP (cAMP) play important roles. The inotropic response to milrinone was modified by changes in the rate of stimulation and the concentration of extracellular Ca++ and by depolarization with high K+ or pretreatment with a calcium-channel blocker. Reduction of the extracellular Na+ concentration of 75% of normal potentiated the inotropic response of papillary muscles to low concentrations of milrinone, suggesting possible activation of the Na+-Ca++ exchange mechanism. These results suggest that milrinone may stimulate the influx of Ca++ into the cardiac cell. The bipyridines are phosphodiesterase inhibitors that increase cardiac cAMP levels. However, a time-course analysis of the changes in cAMP levels during the inotropic response to the bipyridines indicated that the increase in isometric tension development preceded the increase in cAMP. Our data suggest that more than one mechanism may be involved in the initiation and maintenance of the inotropic response to the bipyridines.