INHIBITION OF CARDIOVASCULAR LOW-KM CAMP PHOSPHODIESTERASE ACTIVITY BY MEDORINONE

Medorinone (5‐methyl‐1, 6‐naphthyridin‐2(1H)‐one) is a structurally novel cardiotonic/vasodilator agent. The purpose of the present study was to evaluate the effects of medorinone on subcellular systems involved in the contractile‐relaxation processes of cardiac and vascular smooth muscle (VSM); cyclic nucleotide phosphodiesterase (PDE), Ca2+‐regulated contractile proteins, and sarcolemmal Na+‐K+ ATPase. Medorinone produces concentration‐related inhibition (IC50 values between 0.38 and 1.3 μ) of the cGMP‐inhibitable, low‐Km cAMP PDE (peak III PDE from a DEAE‐cellulose column) present in guinea pig and canine cardiac and vascular smooth muscle. The potency of medorinone is similar to that of milrinone and papaverine, less than CI‐930, and greater than imazodan, piroximone, and amrinone. Medorinone is approximately 300–400 × less potent an inhibitor of the low‐Km cAMP PDE. Medorinone appears to be a non‐linear mixed inhibitor of the low‐Km cAMP PDE having a Ki value of approximately 0.3 μM. Medorinone is also an equipotent inhibitor (IC50 values between 0.23 and 0.35 μM) of the low‐m cAMP PDE present in soluble and particulate fractions obtained from normal and myopathic human hearts, with no differences in potency observed between normal and myopathics. Medorinone (10 and 100 μM) does not affect VSM myosin light chain phosphorylation or VSM actomyosin superprecipitation. Moreover, medorinone does not affect cardiac myofibrillar ATPase activity or cardiac sarcolemmal Na+‐K+ ATPase activity. In summary, these data are consistent with the hypothesis that inhibition of the low‐Km cAMP PDE isozyme by medorinone in cardiac and vascular smooth muscle is a mechanism by which this agent produce both positive cardiac inotropy and VSM relaxation. Copyright © 1990 Wiley‐Liss, Inc.