Antagonistic effect of morphine on the positive inotropic response of ouabain on the isolated rabbit heart.

Abstract

The antagonistic effect of morphine on the positive inotropic response of ouabain was studied in 96 isolated rabbit hearts, using a modified Langendorff preparation. Decreased calcium (Ca) in the perfusate resulted in increased depression of peak left ventricular dP/dt by morphine (10(-4) gm/ml), and the number of beats required to reach the depression was proportionally reduced with the reduction of calcium chloride from 2.16 mM to 0.54 mM. Likewise, the positive inotropic effect of ouabain (10(-6) gm/ml) was proportionally reduced by the same reduction of calcium chloride concentration in the perfusate, but the number of beats required to reach the cardiotonic effect was proportionally increased with Ca deficiency. The opposing effects of ouabain and morphine were mutually antagonistic regardless of the order of drug administration. When the hearts had been previously exposed to morphine, ouabain stimulation was no longer beat-dependent. Following prior exposure to ouabain, the beat-dependency of morphine depression on the heart also was partially antagonized. These results suggest that the level of maximal dP/dt during morphine depression or ouabain stimulation is directly related to the extracellular concentration of Ca. The number of beats required to attain the depression or stimulation is probably a reflection of the rate at which equilibrium is established between the mobile fraction of extracellular and intracellular Ca, since transmembrane movement of Ca is believed to occur during each beat. A possible common site of morphine and ouabain effect may be the cellular membrane, where ionic flux occurs.