title: Contractile response of norepinephrine is modulated by caspase-3 in adult rat ventricular myocytes isolated from septic rat heart.
abstract: Sepsis accounts for 50% of intensive care unit deaths due to cardiac dysfunction. The cellular mechanisms following norepinephrine (NE) during sepsis are undefined. Using a septic adult rat ventricular myocyte (ARVM) paradigm, we examined the molecular mechanism responsible for the blunted contractile response of NE. We tested the hypothesis that NE-induced increases in active caspase-3 contribute to sepsis-induced ARVM contractile dysfunction. Single ARVMs were isolated from hearts harvested from sham and septic male rats. The contractile properties and expression of caspase-3 cascade proteins were determined in ARVMs treated with NE with and without QVD-OPH, prazosin and atenolol to characterize the effect of NE on their mechanical properties. Septic ARVMs exhibited a significant decrease in peak shortening (PS) compared to sham ARVMs. The effect of NE on the PS of the sham ARVMs was more pronounced compared to the septic ARVMs, suggesting a blunted contractile response of NE. NE in the presence of QVD-OPH ameliorated the sepsis-induced decrease in PS at 18h but not at 1h, while the effect of NE on sepsis-induced contractile response remained unaffected at 18h by prazosin and atenolol. An up-regulated expression of caspase-3 in NE-treated septic ARVMs was reversed by QVD-OPH, as seen by the increased number of septic ARVMs exhibiting caspase-3 fluorescence. Transfection of ARVMs using caspase-3 siRNA blocked sepsis-induced up-regulation of caspase-3 and increased PS following NE treatment. These data suggest that caspase-3 inhibition ameliorated sepsis-induced decreased ARVM contractility and blocked the blunted contractile response of NE.
authors.affiliation: Cardionome Laboratory, Department of Biomedical Sciences, Texas A&M Health Science Center Baylor College of Dentistry, Dallas, TX 75246, United States.
authors.forename: Mani
authors.initials: M
authors.lastname: Chopra
authors.forename: Avadhesh C
authors.initials: AC
authors.lastname: Sharma
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001262:Atenolol / Q000494:pharmacology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D009638:Norepinephrine / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000139:chemically induced / Q000503:physiopathology*
chemical_list: D000316:Adrenergic alpha-Agonists; D000590:Amino Acid Chloromethyl Ketones; D011804:Quinolines; C468548:quinoline-val-asp(OMe)-CH2-OPH; D001262:Atenolol; D053148:Caspase 3; D009638:Norepinephrine; D011224:Prazosin