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VASCULAR AND HYPERTENSION

Endothelin-Mediated Vasoconstriction in Early Atherosclerosis Is Markedly Increased in ApoE^–/– Mouse but Prevented by Atorvastatin

Janet J. Maguire^*,1, Katherine E. Wiley^*, Rhoda E. Kuc^*, Victoria E. A. Stoneman, Martin R. Bennett and Anthony P. Davenport^*

^* Clinical Pharmacology Unit and Division of Cardiovascular Medicine, Level 6 Centre for Clinical Investigation, Box 110, Addenbrooke’s Hospital, Cambridge, CB2 2QQ, UK

To whom requests for reprints should be addressed at ¹ Clinical Pharmacology Unit, Level 6 Centre for Clinical Investigation, Box 110, Addenbrooke’s Hospital, Cambridge, CB2 2QQ, UK. E-mail: jjm1003{at}medschl.cam.ac.uk

Abstract

We have discovered that endothelin-1 (ET-1) vasoconstriction is significantly enhanced in aortas of young (8–16-week-old) apolipoprotein E–deficient (ApoE^–/–) mice devoid of atherosclerotic lesions (maximum response expressed as a percentage of the mean response to 100 mM KCl (E_MAX) = 55.7% ± 19.5% KCl, n = 5) compared to age-matched C57BL/6/J control animals (E_MAX = 12.6% ± 2.5% KCl, n = 8), indicating that alterations in the endothelin system may contribute to disease progression, at least in this animal model. There was no difference in the potency of ET-1 to contract aorta from the two groups (C57BL/6/J pD₂ = 8.74 ± 0.30; ApoE^–/– pD₂ = 8.50 ± 0.15, P > 0.05). This increased response was specific to ET-1, as it was not observed with phenylephrine or U46619, nor was it due to a non–receptor mediated increase in contractile sensitivity, as there was no change in response to KCl between the two groups. [¹²⁵I]ET-1 bound with subnanomolar affinity (K_D) to aorta (K_D == 0.018 ± 0.002 nM, n == 4) and, with an order of magnitude lower affinity, to heart (K_D == 0.47 ± 0.05, n == 5) of C57BL/6/J mice with binding densities (B_MAX) of 9.3 ± 2.4 fmol mg^–1protein and 100 ± 14 fmol mg^–1 protein, respectively. Alterations in vascular reactivity to ET-1 could not be explained by increased endothelin receptor density or affinity, as these were not altered in aorta (K_D == 0.011 ± 0.003 nM; B_MAX == 10.1 ± 3.9 fmol mg^–1, n == 4) and heart (K_D == 0.43 ± 0.04 nM; B_MAX == 115 ± 26 fmol mg^–1, n == 6) of ApoE^–/– animals. The ratio of ET_A to ET_B receptors in heart of control and ApoE^–/– mice was similar, comprising 89% and 85% ET_A receptors, respectively. In isolated aorta from ApoE^–/– mice on the Western diet, which more closely resembled more advanced stages of the disease in man, the augmented ET-1 vasoconstrictor response was maintained (E_MAX == 25.2% ± 6.8% KCl, n == 9); however, it was completely prevented in animals that had received 10 weeks of oral atorvastatin (30 mg kg^–1 day^–1) (E_MAX == 4.0% ± 1.5% KCl, n == 5), a concentration that was chosen because it did not affect plasma cholesterol and triglyceride levels. Therefore, this protective prevention of enhanced ET-1 vasoconstriction in ApoE^–/– mice by atorvastatin was independent of its lipid-lowering properties.

Key Words: ApoE^–/– mouse • endothelin-1 • atherosclerosis • vasoconstriction • atorvastatin