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 microM. 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 microM, 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 Ca(2+) shifted the dose and caffeine-induced contracture curve; (b) L-294 (100 microM) 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. 5. Retrograde perfusion of the isolated heart from Wistar rats with L-294 (100 microM) 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 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.
Sudo
R T
RT
Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Bloco J, Sala 14, Cidade Universitária, Rio de Janeiro, Brazil. ntsudo@farmaco.ufrj.br
Zapata-Sudo
G
G
Barreiro
E J
EJ
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000187:drug effects; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D012503:Saponins / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D016276:Ventricular Function
D002316:Cardiotonic Agents; D006835:Hydrazones; C439284:LASSBio 294; D012503:Saponins; D013876:Thiophenes