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Summary. We investigated the basis for the difference in the cardiotonic effects of the PDE3 inhibitors cilostazol and milrinone in the rabbit heart. Cilostazol displayed greater selectivity than milrinone for inhibition of cAMP-PDE activity in microsomal vs cytosolic fractions from rabbit heart. This difference was due to the inhibition of significantly less cytosolic cAMP-PDE activity by cilostazol compared to milrinone. A combination of cilostazol (>15 [mu]M) and the PDE4 selective inhibitor, rolipram (5 [mu]M), inhibited levels of cytosolic cAMP-PDE activity similar to those inhibited by milrinone on its own. This suggested that milrinone inhibited PDE4 in addition to PDE3 activity. In isolated rabbit cardiomyocytes, milrinone (>10 [mu]M) caused greater elevations in intracellular cAMP and calcium than cilostazol. In the presence of rolipram, however, the cAMP and calcium elevating effects of cilostazol and milrinone were similar. Therefore, in rabbit heart, partial inhibition of PDE4 by milrinone contributed to greater increases in cardiomyocyte cAMP and calcium levels than cilostazol. PDE4 activity in failing human heart was lower than in rabbit heart and there was no significant difference in the inhibition of human cytosolic cAMP-PDE by cilostazol and milrinone. Our results suggest that in normal rabbit heart inhibition of PDE4 by milrinone may partly contribute to the greater cardiotonic effect of milrinone when compared to cilostazol. However, the lower level of PDE4 activity in failing human heart suggests that factors other than inhibition of PDE4 by milrinone may contribute to differences in cardiotonic action when compared to cilostazol.
KeyWords. phosphodiesterase, cilostazol, milrinone, cAMP, calcium, cardiomyocyte, heart
Introduction
PDE3, also known as the cGMP-inhibited PDE, is a target for several drugs that have positive inotropic, vasodilatory, and antithrombotic effects [1]. Inhibitors of PDE3 activity such as amrinone, enoximone and milrinone are in clinical use for acute treatment of congestive heart failure (CHF) [2], while cilostazol (Pletal-R ) is used for effective treatment of symptoms of intermittent claudication (IC), a manifestation of lower-extremity peripheral arterial occlusive disease [3-9]. Chronic use of amrinone, enoximone and milrinone in CHF patients has been associated with decreased survival through mechanisms that remain uncertain [10]. It has been suggested that uncontrolled elevation of cAMP may contribute to adverse effects. This notion is supported by the observation that patient survival is reduced by treatment with...