LASSBio-294, A compound with inotropic and lusitropic activity, decreases cardiac remodeling and improves Ca²(+) influx into sarcoplasmic reticulum after myocardial infarction.
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.


METHODS
LASSBio-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 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.


RESULTS
Cardiac 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(+).


CONCLUSIONS
LASSBio-294 is a promising candidate for improving intracellular Ca²(+) regulation and preventing MI-induced cardiac dysfunction, which could potentially prevent heart failure (HF).
Costa
Daniele G
DG
ICB, Universidade Federal do Rio de Janeiro, Brazil.
da Silva
Jaqueline S
JS
Kümmerle
Arthur E
AE
Sudo
Roberto T
RT
Landgraf
Sharon S
SS
Caruso-Neves
Celso
C
Fraga
Carlos A M
CA
de Lacerda Barreiro
Eliezer J
EJ
Zapata-Sudo
Gisele
G
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects*
D002316:Cardiotonic Agents; D006835:Hydrazones; C439284:LASSBio 294; D013876:Thiophenes; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium