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Inhibition of guinea pig aortic sarcolemmal Ca 2+ ‐Mg 2+ ATPase and cAMP phosphodiesterase activity by milrinone
Author(s) -
O'Connor Bernard,
Silver Paul J.
Publication year - 1990
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430190408
Subject(s) - milrinone , sarcolemma , chemistry , phosphodiesterase , medicine , endocrinology , atpase , inotrope , biochemistry , enzyme , membrane , biology
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.