In Vivo Evidence of Positive Inotropism of EMD 57 033 Through Calcium Sensitization

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Abstract
The previous separation of the racemic cardiotonic thiadiazinone derivative EMD 53 998 yielded two enantiomers with different pharmacologic properties: EMD 57 033, a potent Ca2+ sensitizer with some residual phosphodiesterase III (PDE III) inhibition, and EMD 57 439, a pure PDE III inhibitor. Although numerous in vitro studies demonstrated the ability of EMD 57 033 to increase the responsiveness of cardiac contractile proteins to Ca2+, in vivo evidence for such an action is lacking. Because there is no possibility of directly proving Ca2+ sensitization in vivo, we attempted to exclude PDE III inhibition as a major contributing component of the positive inotropic action of EMD 57 033. In anesthetized rats, EMD 57 033 increased left ventricular (LV) first derivative of change in systolic pressure over time (dP/dt max) without affecting blood pressure. In contrast, the PDE III-inhibitory enantiomer EMD 57 439 decreased blood pressure. The pattern of hemodynamic effects in anesthetized dogs revealed similar differences between EMD 57 033 and PDE inhibitors. Thus the increase in LVdP/dt max in response to EMD 57 033 was not accompanied by changes of heart rate and blood pressure. As expected for PDE inhibitors, pimobendan and milrinone increased cardiac contractile force in dogs, concomitant, however, with tachycardia, hypotension, and a decrease in total peripheral resistance. When regional contractility was measured separately in two different areas of the dog myocardium, the positive inotropic action of the PDE inhibitors pimobendan and milrinone was antagonized by local coronary infusion of acetylcholine. The cardiotonic effect of the Ca2+ sensitizer EMD 57 033 was entirely resistant to inhibition by acetylcholine. In conscious dogs, β-blockade markedly attenuated the increase in LVdP/dt max produced by two different doses of the PDE III inhibitor EMD 57 439. In contrast, a dose of EMD 57 033 equieffective in positive inotropic action with the lower dose of EMD 57 439 remained unaffected by 2+. Of special importance is the finding that this Ca2+ sensitizer at appropriate doses may be able to improve systolic function without adverse effects on diastolic function, as indicated by a slight decrease in left ventricular end-diastolic pressure.