Mechanisms of positive inotropic action of flosequinan, hydralazine, and milrinone on mammalian myocardium

Abstract

Flosequinan is an arterial and venous dilator that also has a positive inotropic effect at relatively higher doses. The purpose of this study was to determine the mechanism of this positive inotropic effect in ferret papillary muscles loaded with the Ca 2+ indicator, aequorin. Over the range of doses from 10 −6 to 10 −3 M, flosequinan produced a 61±9% increase in peak tension that was accompanied by a corresponding increase in [Ca 2+] i. This positive inotropic effect was not selectively blocked by addition to the perfusate of procaine 0.6 μM, tetrodotoxin 10 −6 M or by verapamil, 5×10 −8 M. In contrast, the positive inotropic effect of flosequinan, but not milrinone or hydralazine, was potentiated by prior addition of ouabain 3 nM to enhance intracellular Ca 2+ via reduction of the Na +/Ca 2+ exchange. Moreover, antagonists of Na +/Ca 2+ exchange, including cadmium 10 μM, amiloride 600 μM and choline substitution for 1/3 Na + in the perfusate, blocked the response to flosequinan but not hydralazine or milrinone. These results indicate that flosequinan produces a positive inotropic effect by reduction of Na +/Ca 2+ exchange in mammalian myocardium. Moreover, flosequinan has the potential to interact synergistically with other positive inotropic agents such as digoxin that affect Na +/Ca 2+ exchange by direct or indirect actions.