RELATIONSHIP BETWEEN MYOCARDIAL MILRINONE CONTENT AND ITS ACUTE HEMODYNAMIC AND ELECTROPHYSIOLOGIC EFFECTS

One of the major determinants of the short-term effects of many cardio active drugs is the concentration of the drug specifically within the myocardium. However, no information regarding the disposition of the p hosphodiesterase inhibitor milrinone in the heart is available. We the refore determined the time course of short-term myocardial milrinone u ptake from paired transcoronary sampling and simultaneous coronary sin us blood flow after a I-mg intravenous bolus in patients undergoing di agnostic cardiac catheterization. In accordance with this intention, a sensitive, reproducible method for the determination of milrinone in human whole-blood samples was developed. The reverse-phase high-perfor mance liquid chromatographic method described used a C-18 column with UV-absorbance detection at 326 nm, with a limit of detection of 0.6 ng /ml, and was highly reproducible. The short term hemodynamic and elect rophysiologic effects of the drug also were determined. Significant in creases in spontaneous heart rate and LV+dP/dt(max) (at constant heart rate) were observed, accompanied by reductions in mean arterial press ure, systemic vascular resistance, and PR interval, without significan t changes in atrioventricular nodal or ventricular effective refractor y periods. Peak content (1.89 +/- 0.30% of injected dose) was rapidly attained, 0.56 +/- 0.06 min after milrinone injection. Time of peak ef fects was significantly delayed (7-10 min after injection) relative to time of peak myocardial milrinone content. Residual myocardial milrin one content was 69.1 +/- 5.7% of maximum 12.5 min after injection. It is concluded that both myocardial uptake and the onset of positive ino tropic effects after intravenous injection of milrinone were very rapi d. However, there was significant hysteresis between peak myocardial c ontent and subsequent hemodynamic effects.