LASSBio-294, A Compound With Inotropic and Lusitropic Activity, Decreases Cardiac Remodeling and Improves Ca(2+) Influx Into Sarcoplasmic Reticulum After Myocardial Infarction.
American journal of hypertension 2010 Jul 29; In press
Costa D DG, da Silva J JS, Kümmerle A AE, Sudo R RT, Landgraf S SS, Caruso-Neves C, Fraga C CA, de Lacerda Barreiro E EJ, Zapata-Sudo G
Programa de Desenvolvimento de Fármacos, ICB, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
BackgroundMyocardial infarction (MI) is commonly associated with cardiac hypertrophy, reduced Ca(2+) uptake into the sarcoplasmic reticulum (SR) and impaired myocardial relaxation. Treatment to prevent MI-associated complications is currently lacking. The purpose of the present study was to investigate the remodeling and function of hearts subjected to experimental MI and to evaluate the response to treatment with a new thienylhydrazone: 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294), which has demonstrated positive inotropic properties.MethodsLASSBio-294 (2 mg/kg) or vehicle (dimethyl sulfoxide) was administered daily by intraperitoneal injection for 4 weeks in sham-operated rats and rats with MI. Cardiac remodeling and hemodynamic parameters were monitored through histological and intraventricular pressure analyses. Intracellular Ca(2+) regulation (uptake and release) and the sensitivity of contractile proteins to Ca(2+) were evaluated by determining the contractile response of saponin-skinned cardiac cells from infarcted hearts.ResultsCardiac hypertrophy occurred at 4 weeks post-MI and was partially reverted by treatment with LASSBio-294. LASSBio-294 treatment also reduced the nuclear density, collagen volume fraction, and left ventricular end-diastolic pressure (LV EDP) induced by MI. MI led to reduced Ca(2+) uptake from the SR, but did not modify the Ca(2+) release or the Ca(2+)-force relationship. LASSBio-294 restored SR function and enhanced the sensitivity of contractile proteins to Ca(2+).ConclusionLASSBio-294 is a promising candidate for improving intracellular Ca(2+) regulation and preventing MI-induced cardiac dysfunction, which could potentially prevent heart failure (HF).American Journal of Hypertension (2010). doi:10.1038/ajh.2010.157.
Keywords: LASSBio-294