Understanding the hemodynamic effects of milrinone in normal and failing hearts: an experimental study using the circulatory equilibrium framework in canines.

Abstract

Milrinone, a phosphodiesterase III inhibitor, exerts positive inotropic and vasodilatory effects via cyclic adenosine monophosphate-mediated signaling pathways. However, its comprehensive hemodynamic impact, particularly on venous return, remains incompletely characterized. Using the generalized circulatory equilibrium framework, we investigated the cardiovascular effects of milrinone in normal and heart failure (HF) canine models. Ten beagle dogs (5 normal, 5 with acute left HF induced by left coronary microembolization) were studied under general anesthesia and open-chest conditions. Milrinone was administered intravenously at 0.5 µg·kg·min. From the circulatory equilibrium framework, we derived the effective stressed blood volume (SBV) and the logarithmic slope (SL) of the left ventricular (LV) output curve, which indicates LV pumping capability. Milrinone infusion reduced SBV from 31.6 ± 1.3 to 26.5 ± 1.7 mL/kg in the normal model and from 35.7 ± 3.0 to 32.1 ± 3.6 mL/kg in the HF model, with a significant main effect of drug (= 0.004) but no model × drug interaction in two-way ANOVA (= 0.531). In the normal group, SL was unchanged [61.6 ± 1.6 to 62.2 ± 3.5 mL·min·kg], resulting in decreases in aortic pressure (AP) and cardiac output (CO). In contrast, in the HF group, milrinone increased SL [18.3 ± 3.1 to 30.2 ± 4.3 mL·min·kg], with a significant model × drug interaction (= 0.044). As a result, AP and CO were preserved, while left atrial pressure was reduced. In conclusion, in the HF canine model, milrinone improves the circulatory equilibrium point by enhancing LV pumping function and reducing SBV.Analysis using a generalized circulatory equilibrium framework demonstrates that milrinone reduces stressed blood volume, shifting the venous return curve downward in both normal and heart failure (HF) models. In contrast, milrinone shifts the cardiac output (CO) curve upward only in the HF model. Left atrial pressure is reduced without CO reduction in the HF model, whereas CO decreases in the normal model. These findings indicate that circulatory equilibrium responses to milrinone depend on cardiac function.