Abstract
In humans, hypercholesterolemia and hypertension are associated with endothelial dysfunction. Here, we assess whether hypercholesterolemia induces endothelial dysfunction in rats with pre-existing hypertension. Spontaneously hypertensive rats (SHR) and normotensive controls (WKY) were fed with a high-cholesterol diet for 12 weeks, and endothelial function was assessed in isolated thoracic aortic rings. In SHR and WKY rats, the hypercholesterolemic diet resulted in the elevation of total cholesterol and low-density lipoprotein levels by approximately 2.5- and 4.5-fold, respectively. However, in aorta, the basal nitric oxide (NO) production—as assessed by the magnitude of l-NG-nitroarginine methyl ester-induced vasoconstriction as well as the NO-dependent relaxation induced by acetylcholine or histamine—were not diminished either in SHR or in WKY rats fed with the hypercholesterolemic diet. Interestingly, prostacyclin (PGI2) production in aortic rings from SHR rats was higher than in the aorta from WKY rats. However, the hypercholesterolemic diet had no further effects on PGI2 production in the aorta either of SHR or WKY rats. The monocyte chemoattractant protein 1 level in plasma was slightly elevated in SHR and WKY rats fed with the hypercholesterolemic diet compared with their normocholesterolemic counterparts. In summary, even in the presence of pre-existing hypertension, hypercholesterolemia fails to modify NO-dependent and PGI2-dependent endothelial function in SHR rats; it also does not induce a robust inflammatory response. Both are prerequisites for the development of atherosclerosis.
Footnotes
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This work was supported by the Polish Ministry of Science and Information Society Technologies (MNiI) (Grants P05A 003 25 and PBZ-KBN-101/T09/2003/6) and by a Professorial grant from the Foundation for Polish Science to S.C. (SP/04/04).
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doi:10.1124/jpet.105.098798.
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ABBREVIATIONS: NO, nitric oxide; SHR, spontaneously hypertensive rats; WKY, Wistar-Kyoto rats; PGI2, prostacyclin; MCP-1, monocyte chemoattractant protein 1; BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; ACh, acetylcholine; SNAP, S-nitroso-N-acetyl-penicillamine; l-NAME, l-NG-nitroarginine methyl ester; 6-keto-PGF1α, 6-keto-prostaglandin F1α; EDCF, endothelium-derived contracting factor; COX, cyclooxygenase; ORO, oil red O; SQ 29548, [1S(1α,2α(Z),3α,4α)]-7-[3-[[2-[(phenylamino) carbonyl]hydrazino]methyl]-7-oxabicy-clo[2.2.1] hept-2-yl]-5-heptenoic acid; apoE, apolipoprotein E.
- Received November 18, 2005.
- Accepted March 16, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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