LASSBio-294, a compound with inotropic and lusitropic activity, decreases cardiac remodeling and improves Ca2 influx into sarcoplasmic reticulum after myocardial infarction

Abstract

Background Myocardial infarction (MI) is commonly associated with cardiac hypertrophy, reduced Ca2+ 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 (2mg/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 Ca2+ regulation (uptake and release) and the sensitivity of contractile proteins to Ca2+ 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 Ca2+ uptake from the SR, but did not modify the Ca2+ release or the Ca2+-force relationship. LASSBio-294 restored SR function and enhanced the sensitivity of contractile proteins to Ca2+. ConclusionLASSBio-294 is a promising candidate for improving intracellular Ca2+ regulation and preventing MI-induced cardiac dysfunction, which could potentially prevent heart failure (HF). © 2010 American Journal of Hypertension, Ltd.