title: Neuronal nitric oxide synthase inhibition improves diastolic function and reduces oxidative stress in ovariectomized mRen2.Lewis rats.
abstract: OBJECTIVE
  The loss of estrogen in mRen2.Lewis rats leads to an exacerbation of diastolic dysfunction. Because specific neuronal nitric oxide synthase (nNOS) inhibition reverses renal damage in the same model, we assessed the effects of inhibiting neuronal nitric oxide on diastolic function, left ventricular remodeling, and the components of the cardiac nitric oxide system in ovariectomized (OVX) and sham-operated mRen2.Lewis rats treated with N5-(1-imino-3-butenyl)-L-ornithine (L-VNIO; 0.5 mg/kg per day for 28 d) or vehicle (saline).
  
  
  METHODS
  Female mRen2.Lewis rats underwent either bilateral oophorectomy (OVX; n = 15) or sham operation (or surgical procedure) (sham; n = 19) at 4 weeks of age. Beginning at 11 weeks of age, the rats were randomized to receive either L-VNIO or vehicle.
  
  
  RESULTS
  The surgical loss of ovarian hormones, particularly estrogen, led to exacerbated hypertension, impaired myocardial relaxation, diminished diastolic compliance, increased perivascular fibrosis, and increased relative wall thickness. The cardiac tetrahydrobiopterin-to-dihydrobiopterin levels were lower among OVX rats compared with sham-operated rats, and this altered cardiac biopterin profile was associated with enhanced myocardial superoxide production and decreased nitric oxide release. L-VNIO decreased myocardial reactive oxygen species production, increased nitrite concentrations, attenuated cardiac remodeling, and improved diastolic function.
  
  
  CONCLUSIONS
  Impaired relaxation, diastolic stiffness, and cardiac remodeling were found among OVX mRen2.Lewis rats. A possible mechanism for this unfavorable cardiac phenotype may have resulted from a deficiency in available tetrahydrobiopterin and subsequent increase in nNOS-derived superoxide and reduction in nitric oxide synthase metabolites within the heart. Selective nNOS inhibition with L-VNIO attenuated cardiac superoxide production and limited remodeling, leading to improved diastolic function in OVX mRen2.Lewis rats.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1009, USA.
authors.forename: Jewell A
authors.initials: JA
authors.lastname: Jessup
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Alex F
authors.initials: AF
authors.lastname: Chen
authors.forename: Tennille D
authors.initials: TD
authors.lastname: Presley
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Kim-Shapiro
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Leanne
authors.initials: L
authors.lastname: Groban
mesh_terms: D000818:Animals; D003971:Diastole / Q000187:drug effects*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D054144:Heart Failure, Diastolic / Q000378:metabolism / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D004791:Enzyme Inhibitors; C111862:N(5)-(1-imino-3-butenyl)ornithine; D009569:Nitric Oxide; D009952:Ornithine; D019001:Nitric Oxide Synthase