Effect of Milrinone (Corotrope) on the Contractility of Isolated Dog Ventricular Muscle

The bipyridine milrinone (Corotrope) is a new positive inotropic agent for treatment of congestive heart failure. The dose-response curves on electrically paced isolated dog ventricular trabeculae on contractile force were determined with single as well as cumulative dosages of milrinone. These dose-response curves differed both quantitatively and qualitatively. The "single-dose, dose-response" curve shows a flattening out in the dosage range of 1-5 micrograms/ml, which was followed by a second "single-dose, dose-response" curve between 5-50 micrograms milrinone/ml bathing fluid. The maximal response obtained at 50 micrograms/ml with the single dose-response was 1.44 +/- 0.15 g (132 +/- 9%), while with the cumulative dose-response maximum contractile change attained at 1 microgram/ml was 0.58 g (40 +/- 7%). This difference is possibly due to the tachyphylaxis produced by the first dose of milrinone which reduced the effects of the second dose. The biphasic dose-response to milrinone was converted to a monophasic one by raising [Ca2+] from 1.8-4.5 mM. A statistical analysis of the single-dose, dose-response curve was conducted by applying a third-degree polynomial fitted by least squares; the curve gave a statistically significant fit with the experimentally obtained data. This suggests that the plateau observed is not due to random variation and that the single-dose, dose-response curve consists of at least two portions. This point was further substantiated by showing that the Ca2+ channel blockers had an effect on the low dosages of milrinone (less than 2.5 micrograms/ml) but had no significant effect on the dosages above 5 micrograms/ml. Milrinone increases the rate of relaxation and decreases the time for 50 and 90% relaxation. The data suggest that milrinone may act on two different types of calcium channels.