Chronic clofibrate administration prevents salineinduced endothelial dysfunction and oxidative stress in young Sprague-Dawley rats

Abstract

Clin Invest Med 2008; 31 (2): E62-E70. AbstractPurpose: 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 M, 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.High salt intake can result in the development of hypertension in some humans 1 and animals. 2,3 High salt intake has also been reported to cause endothelial dysfunction, with or without a change in blood pressure. [4][5][6] Endothelial dysfunction is characterized by reduced endothelium dependent vascular relaxation. 7 Endothelium dependent vascular relaxa-

Reduced hyperpolarization of endothelial cells following high dietary Na+: effects of enalapril and tempol

“…Previously published data from several groups indicate that an HSD (6–10% NaCl) administered for a period of 2–4 weeks (protocols similar to that used in the present study) to Wistar and Sprague‐Dawley rats resulted in increased arterial pressure . In addition, tempol has been shown to reverse the blood pressure increase .…”

“…Previously published data from several groups indicate that an HSD (6-10% NaCl) administered for a period of 2-4 weeks (protocols similar to that used in the present study) to Wistar and Sprague-Dawley rats resulted in increased arterial pressure. 1,9,[49][50][51] In addition, tempol has been shown to reverse the blood pressure increase. 50,51 Administration of an HSD with a lower salt content (1% NaCl for 12 days) to Sprague-Dawley rats produced no increase in blood pressure and did not alter endothelium-dependent relaxation of aortic rings.…”

Clofibrate, a Peroxisome Proliferator–Activated Receptor-Alpha (PPARα) Agonist, and Its Molecular Mechanisms of Action against Sodium Fluoride–Induced Toxicity

“…The fibrates including clofibrate are a class of drugs that have been established to lower high blood cholesterol and prevent cardiovascular diseases [48,54,88]. Interestingly, previous studies have reported the antihypertensive effect of clofibrate on spontaneously hypertensive rats (SHR), salt-loaded hypertensive rats and salineinduced endothelial dysfunction [17,78,97]. The renin-angiotensin-aldosterone system (RAAS) plays an important role in regulating blood pressure and body fluid, which contribute to the pathophysiology of hypertension and cardiovascular/renal diseases [5,6,61].…”

Clofibrate Relaxes the Longitudinal Smooth Muscle of the Mouse Distal Colon through Calcium-Mediated Desensitisation of Contractile Machinery

“…Clofibrate, a synthetic ligand of PPAR-␣ , is a useful drug in the treatment of several pathologies associated with dyslipidemia. Recent studies have shown that clofibrate is able to induce hypotensive responses following vasodilation [6,7] . Experimental studies and expert opinions have emphasised that cardiovascular disease prevention can be improved by strategies that include the long-term use of clofibrate.…”