Inhibition of guinea pig aortic sarcolemmal Ca 2+ ‐Mg 2+ ATPase and cAMP phosphodiesterase activity by milrinone

Milrinone is a positive inotrope/vasodilator that inhibits cardiovascular low K m cAMP phosphodiesterase (PDE) and not Na + −K + ATPase activity. To explore other possible mechanisms of action, we quantitated the effects of milrinone on Ca 2+ ‐stimulated Mg 2+ ATPase activity in guinea pig aortic smooth muscle plasma membranes. Milrinone inhibited Ca 2+ ‐ stimulated activity, but not basal activity, in aortic microsomes. Maximum inhibition (70%) occurred at 1 μM, which coincided with the inflection of a parabolic dose‐response curve. In a sarcolemmal‐enriched (F1) aortic preparation, 1 μM cAMP, 1 μM Cl‐930 (another low K m cAMP PDE inhibitor), and 100 μM W‐7 (a calmodulin antagonist) all inhibited Ca 2 ‐stimulated Mg 2+ ATPase activity. This F1 preparation contained cAMP PDE activity which was inhibited by 1 μM milrinone (26%) and 1 μM Cl‐930 (40%) but not by 100 μM W‐7. The inhibition of F1 Ca 2+ ‐Mg 2+ ATPase activity by 1 μM milrinone could be diminished by increasing the concentration of CaCl 2 in reaction mixtures. In sum, these studies show that milrinone can inhibit vascular sarcolemmal Ca 2+ ‐stimulated Mg 2+ ATPase activity. However, inhibition may be direct or direct or may be secondary to cAMP PDE inhibition in vascular sarcolemma, since inhibition also occurs with cAMP and another low‐K m cAMP PDE inhibitor, Cl‐930.