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

A new compound designated as LASSBio 294 (L‐294), 3,4‐methylenedioxybenzoyl‐2‐thienylhydrazone, was synthesized as an alternative therapeutic for cardiac dysfunction. 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 μ M . 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 μ M , was 163.1±18.4% for atrial, 153.5±28.5% for papillary and 201.5±18.5% for ventricular muscles. In saponin skinned ventricular cells: (a) L‐294 present in the period of sarcoplasmic reticulum (SR) loading with Ca 2+ shifted the dose and caffeine‐induced contracture curve; (b) L‐294 (100 μ M ) increased 40% the Ca 2+ uptake into SR; (c) L‐294 did not significantly alter the sensitivity of contractile proteins to Ca 2+ in SR‐disrupted skinned ventricular cells. Retrograde perfusion of the isolated heart from Wistar rats with L‐294 (100 μ M ) 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). These results suggest a novel mechanism for a positive cardioinotropic effect through an interaction with the Ca 2+ uptake/release process of the SR. The effect of L‐294 could be explained by a pronounced increased accumulation of Ca 2+ into the SR.British Journal of Pharmacology (2001) 134 , 603–613; doi: 10.1038/sj.bjp.0704291