title: Overexpression myocardial inducible nitric oxide synthase exacerbates cardiac dysfunction and beta-adrenergic desensitization in experimental hypothyroidism.
abstract: BACKGROUND
  Altered nitric oxide synthase (NOS) has been implicated in the pathophysiology of heart failure (HF). Recent evidence links hypothyroidism to the pathology of HF. However, the precise mechanisms are incompletely understood. The alterations and functional effects of cardiac NOS in hypothyroidism are unknown. We tested the hypothesis that hypothyroidism increases cardiomyocyte inducible NOS (iNOS) expression, which plays an important role in hypothyroidism-induced depression of cardiomyocyte contractile properties, [Ca(2+)]i transient ([Ca(2+)]iT), and β-adrenergic hyporesponsiveness.
  
  
  RESULTS
  We simultaneously evaluated LV functional performance and compared myocyte three NOS, β-adrenergic receptors (AR) and SERCA2a expressions and assessed cardiomyocyte contractile and [Ca(2+)]iT responses to β-AR stimulation with and without pretreatment of iNOS inhibitor (1400 W, 10(-5)mol/L) in 26 controls and 26 rats with hypothyroidism induced by methimazole (~30 mg/kg/day for 8 weeks in the drinking water). Compared with controls, in hypothyroidism, total serum T3 and T4 were significantly reduced followed by significantly decreased LV contractility (EES) with increased LV time constant of relaxation. These LV abnormalities were accompanied by concomitant significant decreases in myocyte contraction (dL/dtmax), relaxation (dR/dtmax), and [Ca(2+)]iT. In hypothyroidism, isoproterenol (10(-8)M) produced significantly smaller increases in dL/dtmax, dR/dtmax and [Ca(2+)]iT. These changes were associated with decreased β1-AR and SERCA2a, but significantly increased iNOS. Moreover, only in hypothyroidism, pretreatment with iNOS inhibitor significantly improved basal and isoproterenol-stimulated myocyte contraction, relaxation and [Ca(2+)]iT.
  
  
  CONCLUSIONS
  Hypothyroidism produces intrinsic defects of LV myocyte force-generating capacity and relaxation with β-AR desensitization. Up-regulation of cardiomyocyte iNOS may promote progressive cardiac dysfunction in hypothyroidism.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Shao
authors.affiliation: Section on Cardiovascular Medicine, Wake Forest School of Medicine Winston-Salem, North Carolina, United States; Wake Forest, Institute for Regenerative Medicine, Winston-Salem, North Carolina, United States.
authors.forename: Heng-Jie
authors.initials: HJ
authors.lastname: Cheng
authors.affiliation: Department of Orthopaedic Surgery, Wake Forest School of Medicine Winston-Salem, North Carolina, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Callahan
authors.affiliation: Section on Cardiovascular Medicine, Wake Forest School of Medicine Winston-Salem, North Carolina, United States.
authors.forename: Dalane W
authors.initials: DW
authors.lastname: Kitzman
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: liweimin_2009@163.com.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Li
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Section on Cardiovascular Medicine, Wake Forest School of Medicine Winston-Salem, North Carolina, United States. Electronic address: ccheng@wakehealth.edu.
authors.forename: Che Ping
authors.initials: CP
authors.lastname: Cheng
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D007037:Hypothyroidism / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000378:metabolism*
chemical_list: D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat
keywords: Beta-adrenergic receptor agonists; Calcium; Cells; Nitric oxide synthase; Thyroid hormone