title: Chronic clofibrate administration prevents saline-induced endothelial dysfunction and oxidative stress in young Sprague-Dawley rats.
abstract: OBJECTIVE
  High salt intake causes hypertension and endothelial dysfunction in young Sprague-Dawley rats. Clofibrate (clof) prevents this salt induced hypertension. We asked whether clof can prevent salt-induced endothelial dysfunction, and if so, its mechanism. We also questioned whether high salt intake can induce endothelial dysfunction without hypertension in older animals.
  
  
  METHODS
  Young (Y, 5 weeks) and old (O, 53 weeks) male Sprague-Dawley rats were given either vehicle (Con, 20 mM Na2CO3) or 0.9% NaCl (Sal) to drink for three weeks. Some young rats received clof (80 mg/d) in their drinking fluid. After three weeks, we measured mean arterial pressure (MAP), endothelial function, by comparing hypotensive responses to acetylcholine (ACh, endothelium dependent) and sodium nitroprusside (SNP, endothelium independent), plasma total nitrite+nitrate levels (PNOx), by the Griess reaction, and aortic superoxide production by lucigenin chemiluminescence.
  
  
  RESULTS
  Carotid artery MAP did not change in O. Sal-Y developed hypertension: 133+/-3 vs. 114+/-2 mmHg, P < 0.001, which was prevented by clof: 105+/-2 mmHg. ACh induced a similar dose dependent hypotensive response in Con-O and Sal-O that was inhibited by L-NAME (100mg/kg i.v.). Responses to ACh were blunted in Sal-Y but not in Con-Y. Further, L-NAME inhibited ACh responses only in Con-Y. The response to SNP was similar in all animals. Importantly, the ACh-induced hypotensive response was potentiated in clof+Sal-Y, an effect which was attenuated by blocking calcium-activated potassium channels (KCa) with a combination of apamin (50 ug/kg i.v.) + charybdotoxin (50 ug/kg i.v.), but not by L-NAME. PNOx was reduced in Sal-Y compared to Con-Y (2.09+/-0.26 vs. 4.8+/-0.35 microM, P < 0.001), but not in Sal-O. Aortic superoxide production was higher (P < 0.001) in Sal-Y (2388+/-40 milliunits/mg/min) than Sal-O (1107+/-159 milliunits/mg/min), but was reduced by clof (1378+/-64 milliunits/mg/min; P < 0.001).
  
  
  CONCLUSIONS
  High salt intake increases oxidative stress in young animals, leading to impaired nitric oxide activity and endothelial dysfunction. Clofibrate prevents endothelial dysfunction partly through reduced O2 - formation but mainly via selective activation of KCa channels. Older animals are resistant to both salt induced hypertension and oxidative stress.
authors: Department of Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5 Canada.
authors: Sowndramalingam
authors: S
authors: Sankaralingam
authors: Kaushik M
authors: KM
authors: Desai
authors: Thomas W
authors: TW
authors: Wilson
mesh_terms: D000818:Animals; D000838:Anions; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002254:Carbonates / Q000494:pharmacology; D002339:Carotid Arteries / Q000473:pathology; D002994:Clofibrate / Q000494:pharmacology*; D004727:Endothelium / Q000187:drug effects / Q000473:pathology*; D006973:Hypertension / Q000517:prevention & control; D008297:Male; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012492:Salts / Q000009:adverse effects*; D017673:Sodium Chloride, Dietary / Q000494:pharmacology
chemical_list: D000838:Anions; D000924:Anticholesteremic Agents; D002254:Carbonates; D012492:Salts; D017673:Sodium Chloride, Dietary; C005686:sodium carbonate; D002994:Clofibrate; D010100:Oxygen