The new compound, LASSBio 294, increases the contractility of intact and saponin-skinned cardiac muscle from Wistar rats

1 A new compound designated as LASSBio 294 (L-294), 3,4-methylenedioxybenzoyl-2-thienylhydrazone, was synthesized as an alternative therapeutic for cardiac dysfunction. 2 L-294 increased in a dose-dependent manner the spontaneous contractions of isolated hearts from Wistar rats with maximal effect (128.0 +/-0.7% of control) observed at 25 muM. 3 The positive inotropic effect of L-294 was also observed in electrically stimulated cardiac tissues from Wistar rats. The maximal increment of twitches, at 200 muM, was 163.1 +/- 18.4% for atrial, 153.5 +/- 28.5% for papillary and 201.5 +/- 18.5% for ventricular muscles. 4 In saponin skinned ventricular cells: (a) L-294 present in the period of sarcoplasmic reticulum (SR) loading with Ca2+ shifted the dose and caffeine-induced contracture curve; (b) L-294 (100 mum) increased 40% the Ca2+ uptake into SR; (c) L-294 did not significantly alter the sensitivity of contractile proteins to Ca2+ in SR-disrupted skinned ventricular cells. 5 Retrograde perfusion of the isolated heart from Wistar rats with L-294 (100 muM) did not cause any significant change in rhythm, heart rate (control, 220 +/- 14.7 b.p.m.; 246 +/- 24.6 b.p.m. for L-294), PR interval (control, 66.0 +/-2.4 ms; 64.0 +/-2.3 ms for L-294) or QRS duration (control, 28.8 +/-3.4 ms; 32.0 +/-2.0 ms for L-294). 6 These results suggest a novel mechanism for a positive cardioinotropic effect through an interaction with the Ca2+ uptake/release process of the SR. The effect of L-294 could be explained by a pronounced increased accumulation of Ca2+ into the SR.