title: Genetic variants on rat chromosome 8 exhibit profound effects on hypertension severity and survival during nitric oxide inhibition in spontaneously hypertensive rats.
abstract: BACKGROUND
  Hypertension and mortality is aggravated by nitric oxide inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHRs) but not in Munich Wistar Frömter (MWF) rats. MWF rats carry major albuminuria quantitative trait loci on rat chromosome (RNO) 6 and RNO8; susceptibility of SHRs to L-NAME is enhanced by transfer of RNO6 from MWF rats into the SHR background. Here, we tested whether the sensitivity to L-NAME in SHRs is affected by transfer of RNO8 from MWF rats in consomic SHR-8(MWF) rats.
  
  
  METHODS
  In study 1, we analyzed survival in male SHR and SHR-8(MWF) rats in response to 18 weeks of treatment with either normal drinking water (vehicle-treated) or water containing 20mg/L L-NAME. In study 2, we analyzed blood pressure and renal damage in both strains in response to 6 weeks of treatment with L-NAME compared with vehicle-treated groups.
  
  
  RESULTS
  In study 1, starting after 6 weeks of treatment with L-NAME, mortality reached 90% in SHRs in contrast with the group of L-NAME treated SHR-8(MWF) rats (P < 0.0001) in which all rats survived similar to vehicle-treated rats. In study 2, L-NAME resulted in a more pronounced increase in mean arterial blood pressures in SHRs compared with SHR-8(MWF) rats (216 ± 6 vs. 180 ± 11 mm Hg; P < 0.05). In contrast, tubulointerstitial kidney damage was even lower in SHRs compared with SHR-8(MWF) rats after L-NAME treatment (P < 0.05), whereas albuminuria was not different between strains.
  
  
  CONCLUSIONS
  The blood pressure increase and impaired survival of SHRs in response to nitric oxide inhibition is profoundly influenced by genes on RNO8.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Charité Centrum für Therapieforschung, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schütten-Faber
authors.forename: Leonard
authors.initials: L
authors.lastname: Schulte
authors.forename: Johannes
authors.initials: J
authors.lastname: Unland
authors.forename: Peter
authors.initials: P
authors.lastname: Kossmehl
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D033481:Chromosomes, Mammalian; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000633:toxicity*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010641:Phenotype; D040641:Quantitative Trait Loci; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics*; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
keywords: albuminuria; blood pressure; genetics; hypertension; kidney; nitric oxide; survival.