title: Role of myocardial inducible nitric oxide synthase in contractile dysfunction and beta-adrenergic hyporesponsiveness in rats with experimental volume-overload heart failure.
abstract: BACKGROUND
  Whereas nitric oxide (NO) has been implicated in the pathophysiology of heart failure (HF), the significance and functional role of different NO synthase (NOS) isoforms in this pathology are controversial. Our aim was to study in the myocardium of rats with volume-overload-induced HF the expression, activity, and localization of endothelial (eNOS) and inducible (iNOS) isoforms and the involvement of iNOS in depressed cardiac contractile properties, intracellular Ca(2+) ([Ca(2+)](i)) transients, and beta-adrenergic hyporesponsiveness.
  
  
  RESULTS
  HF was induced by aortocaval fistula (ACF). Compensated and decompensated subgroups of HF were selected on the basis of daily sodium excretion. ACF induced cardiac hypertrophy in rats with compensated (36%) and decompensated (76%) HF. Whereas in HF rats, cardiac eNOS expression and activity were unchanged, iNOS expression and activity increased approximately 2-fold. iNOS immunostaining was observed in ventricular myocytes of compensated and decompensated HF rats but not in controls. Isoproterenol-positive inotropic and lusitropic effects were markedly attenuated in papillary muscle of HF rats, more pronouncedly in decompensated than in compensated rats. Isoproterenol-induced increases in the rates of [Ca(2+)](i) activation and relaxation were also depressed in ACF rats. Selective iNOS blockade by N-(3-(aminomethyl)benzylacetamidine improved the attenuated beta-adrenergic responsiveness in HF rats.
  
  
  CONCLUSIONS
  Our findings indicate that myocardial iNOS is activated in rats with volume-overload HF and suggest that increased iNOS activity contributes to depressed myocardial contractility and beta-adrenergic hyporesponsiveness.
authors.affiliation: Bruce Rappaport Faculty of Medicine, The Rappaport Institute, The Bernard Katz Center for Cell Biophysics, Technion, Haifa, Israel.
authors.forename: Olga
authors.initials: O
authors.lastname: Gealekman
authors.forename: Zaid
authors.initials: Z
authors.lastname: Abassi
authors.forename: Irit
authors.initials: I
authors.lastname: Rubinstein
authors.forename: Joseph
authors.initials: J
authors.lastname: Winaver
authors.forename: Ofer
authors.initials: O
authors.lastname: Binah
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001164:Arteriovenous Fistula / Q000150:complications; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002306:Cardiac Volume; D006332:Cardiomegaly / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010210:Papillary Muscles / Q000187:drug effects / Q000201:enzymology; D051381:Rats
chemical_list: D000318:Adrenergic beta-Agonists; D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D007545:Isoproterenol; D002118:Calcium