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

Abstract

1 The present study was designed to characterize the positive inotropic response to in isolated papillary muscle strips obtained from heart failure patients undergoing surgery.2 The positive inotropic responses to isoprenaline and milrinone and cardiac fl-adrenoceptor density were also determined. 3 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 effects of isoprenaline and milrinone were reduced in NYHA IV compared to NYHA II-III. Consistently, there was also a smaller density of fi-adrenoceptors in myocardium from NYHA IV than in NYHA II-III. The positive inotropic effect of Ca2l was similar in tissues from both groups of patients. 4 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.5 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. 6 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.

Myofilament Calcium Regulation in Human Myocardium

“…Although differences in experimental findings have been reported by investigators who used agents targeted at myofilament calcium sensitivity, 8,41 we propose that adaptational changes may not always be detected by standard steady-state calcium-force relationship determinations. Differences in isotype, structural interaction, phosphorylation level, or intracellular milieu may alter apparent myofibrillar calcium responsiveness in human myocardium.…”

Synthesis and Structure-Activity Relationships of 6-Heterocyclic-Substituted Purines as Inactivation Modifiers of Cardiac Sodium Channels

“…The organics were dried over MgS04 and then concentrated under vacuum to give a foam (4.5 g) which was chromatographed over silica gel with 1% MeOH/CH2Cl2. The first product eluted was recrystallized in EtOH to afford 730 mg (17%) of (S)-56: mp 156-158 °C; [a]D = +3.7°(c = 1, MeOH); NMR (300 MHz, CDCI3) <5 8.68 (s, 1H), 8.33 (dd, Ji = J2 = 2.07 Hz, 2H), 8.20 (s, 1H), 7.37 (d, J = 6.32 Hz, 4H), 7.25 (t, J = 7.18 Hz, 4H), 7.18 (t, J = 5.44 Hz, 2H), 6.42 (dd, Ji=Ji = 2.15 Hz, 2H), 4.45 (dd, Ji = 14.1 Hz, J2 = 1. 13 Hz, 1H), 4.20 (dd, Ji = 7.…”