Relationship between hypercholesterolaemia, endothelial dysfunction and hypertension.
OBJECTIVE
We have previously shown that in the rat a diet high in cholesterol and deficient in vitamin E and selenium results in hypercholesterolaemia and increased lipid oxidation. We utilized this model to determine whether rats given this diet develop impaired endothelium-dependent relaxation mediated by nitric oxide (NO) in mesenteric and in renal vessels. In addition, we tested whether the impairment is due to (i) decreased endothelial NO synthase activity, (ii) increased NO inactivation and/or (iii) increased production of the endothelium-derived constricting factors thromboxane A2/prostaglandin H2 and endothelin-1. We also investigated whether endothelial dysfunction induced by dyslipidaemia increases the sensitivity for the development of hypertension in response to high dietary salt.


METHODS
Male Dahl salt-sensitive (DSS) rats were divided into three groups and received a standard diet (control group), a high (4%) cholesterol diet (HChol), or a high cholesterol diet deficient in the anti-oxidants vitamin E and selenium (HChol-Def). The NaCl content of these diets was 0.5%. After 18 weeks we studied endothelium-dependent relaxation in response to acetylcholine (ACh) in aortas and in isolated perfused preparations of mesenteric arteries and kidneys. In some experiments, ifetroban, a thromboxane A2/prostaglandin H2 receptor antagonist, was added to the organ bath or the perfusion buffer. Vascular responses to endothelin-1 as well as to BQ-123, an endothelin A receptor blocker, were studied in the isolated perfused kidneys. In addition, two extra groups of rats were fed a diet high in sodium chloride (2%): one of the groups received the normal cholesterol diet whereas the other group received the diet high in cholesterol and deficient in vitamin E and selenium.


RESULTS
Compared to normocholesterolemic rats, responses to ACh were significantly impaired in aortas, mesenteric arteries and kidneys of HChol-Def rats (P < 0.01). Endothelial NO synthase activity (conversion of [14C]L-arginine to [14C]L-citrulline) was similar in aortas of control, HChol and HChol-Def rats; thus suggesting that impaired endothelium-dependent relaxation in the HChol-Def rats was not due to decreased cNOS catalytic activity. Ifetroban improved the impaired endothelium-dependent relaxation in mesenteric vessels, but not in aortas and kidneys. Endothelin-1 (ET-1: 10(-13)-10(-11) mol/l) elicited NO-mediated relaxations in kidneys of control rats but not in kidneys of HChol-Def; blockade of ET-1 with BQ-123, an ET(A) receptor blocker, did not improve NO-mediated relaxation of HChol-Def. Despite impaired endothelium-dependent relaxation in renal and mesenteric vessels, HChol-Def DSS rats failed to develop hypertension (systolic blood pressure 144 +/- 1 in control and 150 +/- 2 mmHg in HChol-Def) but manifested a significant increase in sensitivity to the pressor effects of a high (2% NaCl) dietary salt content during the initial 10 weeks of the study, although the final blood pressure at 18 weeks was similar in both groups.


CONCLUSIONS
These studies support the notion that (i) products of lipid oxidation may reduce NO bioactivity without affecting endothelial NO synthase mass or catalytic activity, (ii) the mechanisms involved in the endothelial dysfunction induced by hypercholesterolaemia and oxidized lipids may differ among vascular beds, and (iii) decreased NO bioavailability does not necessarily result in systemic hypertension, but it may enhance the sensitivity to the hypertensinogenic effect of dietary salt.
Department of Medicine, Veterans Affairs Medical Center and University of Minnesota Medical School, Minneapolis 55417, USA.
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Hayakawa
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Raij
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000201:enzymology; D001794:Blood Pressure; D001835:Body Weight; D004032:Diet; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006937:Hypercholesterolemia / Q000150:complications* / Q000378:metabolism; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010477:Perfusion; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000378:metabolism; D051381:Rats; D013928:Thromboxane A2 / Q000378:metabolism
D019332:Endothelin-1; D016232:Endothelins; D011463:Prostaglandins H; D009569:Nitric Oxide; D044262:Prostaglandin H2; D013928:Thromboxane A2; D019001:Nitric Oxide Synthase; D000109:Acetylcholine