Hypercholesterolemia is associated with more rapid development of atherosclerosis, and hypertension is frequently associated with abnormal vascular function. Therefore, to investigate the role of hypercholesterolemia and hypertension on vascular function, we studied three groups of male rats (aged 6 wk): normotensive Wistar-Kyoto rats (WKY) as a control group and spontaneously hypertensive rats (SHR) receiving either standard diet (SD; SHR-SD) or high-cholesterol (1%) diet (ChD; SHR-ChD). Vascular reactivity was tested on isolated aortic rings at 4 wk and at 3 and 6 mo of diet. At 3 mo, endothelium-dependent relaxation to acetylcholine (ACh) and ADP was significantly reduced in SHR-ChD but not in SHR-SD compared with WKY. At 6 mo, relaxations to ACh were further impaired in both SHR groups compared with WKY. Endothelium-independent vasodilation to nitroglycerin (NTG) was not different in the three groups of animals throughout 6 mo of diet. In additional experiments, we evaluated vascular reactivity in rats fed with ChD enriched with an excess of vitamin D [atherogenic diet (AD)] capable of producing vascular atherosclerotic lesions. In particular, we studied three additional groups of WKY and SHR rats fed with SD, AD, or AD plus a nonhypotensive dose of the calcium antagonist nitrendipine (Nit). Vasodilation to ACh and ADP was significantly blunted in WKY-AD compared with WKY-SD, whereas it was partially improved in WKY-Nit. There were no differences in endothelium-independent relaxation to NTG in the three WKY groups. In contrast, SHR-AD showed a marked reduction of endothelium-dependent and -independent vasodilation, but only endothelium-dependent vasodilation was preserved by addition of Nit to the diet. These data suggest that the development of vascular dysfunction in rat genetic hypertension is accelerated by ChD, in absence of detectable vascular lesions. Our study also shows that AD alters both vascular smooth muscle and endothelium-dependent relaxation. Low doses of Nit partially preserve endothelium-dependent vasodilation but do not affect the impairment of smooth muscle function in these rats.
Differential effects of losartan and doxazosin on vascular function in senescent spontaneously hypertensive rats