Inotropic response to DPI 201-106 in the failing human heart

Abstract

The present study was designed to characterize the positive inotropic response to DPI 201-106 in isolated papillary muscle strips obtained from heart failure patients undergoing surgery. The positive inotropic responses to isoprenaline and milrinone and cardiac β-adrenoceptor density were also determined. DPI 201-106 increased the force of contraction in papillary muscle strips from patients with moderate (NYHA II-III) and severe (NYHA IV) heart failure, in a concentration-dependent manner. This positive inotropic effect was more pronounced in tissues from NYHA IV patients. Furthermore, these responses were greater than those produced by milrinone or isoprenaline. The positive inotropic efects of isoprenaline and milrinone were reduced in NYHA IV compared to NYHA II-III. Consistently, there was also a smaller density of β-adrenoceptors in myocardium from NYHA IV than in NYHA II-III. The positive inotropic effect of Ca2+ was similar in tissue from both groups of patients. The positive inotropic effect of DPI 201-106 was not antagonized by adenosine or carbachol whereas both compounds reduced the positive inotropic effect of isoprenaline. DPI 201-106 did not increase the Ca2+-sensitivity of chemically skinned ventricular fibres, whereas a significant increase of the Ca2+-sensitivity was obtained with trifluoperazine. It is concluded that DPI 201-106 produces significant positive inotropic effects in tissue excised from the failing human heart. The lack of inhibition by adenosine and carbachol might contribute to its greater effectiveness in NYHA IV than NYHA II-III and indicates that its mechanism of action is cyclic AMP-independent. A sensitization of the contractile proteins to Ca2+ does not appear to be important for the positive inotropic action of DPI 201-106 in the failing human heart.