Relationship between myocardial milrinone content and its acute hemodynamic and electrophysiologic effects

One of the major determinants of the short-term effects of many cardioactive drugs is the concentration of the drug specifically within the myocardium. However, no information regarding the disposition of the phosphodiesterase inhibitor milrinone in the heart is available. We therefore determined the time course of short-term myocardial milrinone uptake from paired transcoronary sampling and simultaneous coronary sinus blood flow after a 1-mg intravenous bolus in patients undergoing diagnostic 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-performance liquid chromatographic method described used a C18 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 electrophysiologic effects of the drug also were determined. Significant increases in spontaneous heart rate and LV+dP/dtmax (at constant heart rate) were observed, accompanied by reductions in mean arterial pressure, systemic vascular resistance, and PR interval, without significant changes in atrioventricular nodal or ventricular effective refractory periods. Peak content (1.89 +/- 0.30% of injected dose) was rapidly attained, 0.56 +/- 0.06 min after milrinone injection. Time of peak effects was significantly delayed (7-10 min after injection) relative to time of peak myocardial milrinone content. Residual myocardial milrinone 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 inotropic effects after intravenous injection of milrinone were very rapid. However, there was significant hysteresis between peak myocardial content and subsequent hemodynamic effects.