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Endothelin-1 modulates angiotensin II in the development of hypertension in fructose-fed rats

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Abstract

Two of the most potent vasoconstrictors, endothelin-1 (ET-1) and angiotensin II (Ang II), are upregulated in fructose hypertensive rats. It is unknown whether an interrelationship exists between these peptides that may contribute to the development of fructose-induced hypertension. The objective of this study was to investigate the existence of an interaction between the endothelin and renin angiotensin systems that may play a role in the development of fructose-induced hypertension. High fructose feeding and treatment with either bosentan, a dual endothelin receptor antagonist, or with L-158,809, an angiotensin type 1 receptor antagonist, were initiated simultaneously in male Wistar rats. Systolic blood pressure, fasted plasma parameters, insulin sensitivity, plasma Ang II, and vascular ET-1-immunoreactivity were determined following 6 weeks of high fructose feeding. Rats fed with a high fructose diet exhibited insulin resistance, hyperinsulinemia, hypertriglyceridemia, hypertension, and elevated plasma Ang II. Treatment with either bosentan or L-158,809 significantly attenuated the rise in blood pressure with no effect on insulin levels or insulin sensitivity in fructose-fed rats. Bosentan treatment significantly reduced plasma Ang II levels, while L-158,809 treatment significantly increased vascular ET-1-immunoreactivity in fructose-fed rats. Thus, treatment with the endothelin receptor antagonist prevented the development of fructose-induced hypertension and decreased plasma Ang II levels. These data suggest that ET-1 contributes to the development of fructose-induced hypertension through modulation of Ang II levels.

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Acknowledgements

The authors thank Drs. G Kargacin, U Kumar, and L Marzban for consultation in the immunohistochemistry and Dr. CB Verchere for use of the microscope. Thanks to Drs. M Clozel and M Iglarz from Actelion Pharmaceuticals Ltd. and Dr. R Schwartz from Merck Research Laboratories for the generous gift of bosentan and L-158,809, respectively. The technical assistance of Dr. L Yao, P Rajput, K Potter, and VG Yuen is gratefully acknowledged. This project was supported by the Heart and Stroke Foundation of British Columbia and Yukon. LTT was a recipient of a Graduate Research Scholarship in Pharmacy from the Health Research Foundation of Canada’s Research-Based Pharmaceutical Companies and the Canadian Institute for Health Research and a Pacific Century Graduate Scholarship from the University of British Columbia.

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  1. Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada

    L. T. Tran, K. M. MacLeod & J. H. McNeill

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Tran, L.T., MacLeod, K.M. & McNeill, J.H. Endothelin-1 modulates angiotensin II in the development of hypertension in fructose-fed rats. Mol Cell Biochem 325, 89–97 (2009). https://doi.org/10.1007/s11010-008-0023-z

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