Biochemical Mechanisms for the Inotropic Effect of the Cardiotonic Drug Milrinone

Publisher Website
Google Scholar
Abstract
Milrinone is a new inotropic agent for the treatment of refractory congestive heart failure. Our understanding of the mechanism(s) of action of this synthetic cardiotonic drug is incomplete. We examined the effects of milrinone and the parent compound amrinone on sarcoplasmic reticulum function (45Ca-uptake and Ca-ATPase); radioligand binding to adenosine, .beta.-adrenergic, and cholinergic muscarinic receptors; cyclic AMP accumulation; and inhibition of various forms of cyclic AMP phosphodiesterases. Comparisons were made to observe how these effects correlate with the inotropic response of heart. Milrinone was shown to be a potent phosphodiesterase inhibitor that was 40 times more potent than amrinone and 10 times more potent at inhibiting the high-affinity (Km = 0.23 .mu.M) form (Ki = 22 .mu.M) than the low-affinity (Km = 140 .mu.M) form (Ki = 225 .mu.M) of cyclic AMP phosphodiesterase in heart. The potency of milrinone as a phosphodiesterase inhibitor was the same in the presence and absence of calcium. Concentrations of milrinone that increased cyclic AMP accumulation also produced positive inotropy. A comparison of milrinone with amrinone and methylxanthines revealed the order of potency to be isobutylmethylxanthine > milrinone > theophylline > caffeine > amrinone. Milrinone and amrinone had no effect on 45Ca-uptake or Ca-ATPase activity in myocyte sarcoplasmic reticulum. However, milrinone did bind weakly to adenosine receptors (KD = 466 .mu.M) but not to cholinergic muscarinic or .beta.-adrenergic receptors. Also, in combination with isoproterenol high concentrations of milrinone blocked the negative inotropic response to the adenosine agonist phenylisopropyladenosine. These results indicate that milrinone is a phosphodiesterase inhibitor and probably exerts its inotropic effect by inhibiting a low Km form of phosphodiesterase.