Overexpression of vascular endothelin-1 and endothelin-A receptors in a fructose-induced hypertensive rat model

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Abstract
To examine the temporal relationship between hyperinsulinemia and hypertension in the fructosehypertensive rat model and to study the function of endothelin-1 (ET-1) in fructose-induced hypertension. Since ET-1 induces insulin resistance in conscious rats, we tested the hypothesis that both hyperinsulinemia and hypertension developed in the fructose-hypertensive rat model might be the sequelae of an elevated tissue content of ET-1 and ETA receptors. Systolic hypertension was induced within 3 weeks in male Sprague–Dawley rats fed on a fructose-rich diet. After continual monitoring of blood pressure and plasma insulin concentrations, the animals were killed at the end of experiment to determine plasma levels of ET-1, the contractile response of aortic rings to ET-1, and ET-1 and ETA receptor gene expressions. In a separate experiment, BQ-610 was administered to lower the effect of ET-1 in rats with fructose-induced hypertension. Compared with control rats given normal chow, the fructose-fed rats developed systolic hypertension after 3 weeks of the diet (127 ± 3.7 versus 110 ± 5.5 mmHg, P < 0.01) and hyperinsulinemia both before (107.1 ± 32.5 versus 48.5 ± 14.3 pmol/l, P < 0.005) and after (96.6 ± 63.7 versus 50.4 ± 5.6 pmol/l, P < 0.05) they became hypertensive. Although plasma ET-1 levels did not differ between the rat groups, aortic ring contraction–concentration curves, indicating vessel contractility in response to ET-1, were significantly greater in these rats than in controls (F1,72 = 12.34, P < 0.00077). Messenger RNA extracted from the tail arteries and blotted with both ET-1 and ETA probes showed that fructose-fed rats had greater ET-1 and ETA-receptor gene expression than control rats. Concomitant administration of BQ-610 to rats fed on a fructose diet significantly reduced the hypertension. These findings suggest that elevated vascular expression of ET-1 and ETA receptor genes may mediate the development of hypertension and hyperinsulinemia in rats fed a fructose-rich diet.