Myocardial actions of milrinone: characterization of its mechanism of action.

The effect of milrinone on hemodynamic, pharmacologic, and key metabolic processes involved in regulating myocardial cellular calcium was evaluated in an attempt to characterize the mechanism of action of this compound. Data from open-chest dog preparations and isolated guinea pig and rat heart preparations showed that milrinone causes a significant increase in contractility (+ dP/dt of left ventricular pressure) and coronary blood flow. Based on evidence from the Langendorff heart preparations, this positive inotropic effect of milrinone may be related in part to the drug's significant effect on positive chronotropy. However, the coronary-dilating action by milrinone appears to be direct and independent of positive chronotropy. Biochemical studies demonstrated that milrinone appears to have little effect on cardiac subcellular Ca++ transport systems. Preliminary findings indicate, however, that milrinone may play a role in initiating an earlier spontaneous release of Ca++ from the sarcoplasmic reticulum. The implications of these and other results in relation to the drug's mechanism of action are discussed.