Endothelin-Mediated Vasoconstriction In Early Atherosclerosisis Markedly Increased In Apoe(-/-) Mouse But Prevented By Atorvastatin

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 m M KCI (E-MAX) = 55.7% +/- 19.5% KCI, n = 5) compared to age-matched C57BU6/J control animals (EMAX = 12.6% +/- 2.5% KCI, 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 (C57BU6/J pD(2) = 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 KCI between the two groups. [125 I]ET-1 bound with subnanomolar affinity (KD) to aorta (KD = 0-018 0.002 nM, n = 4) and, with an order of magnitude lower affinity, to heart (KD = 0.47 +/- 0.05, n = 5) of C57BU6/J mice with binding densities (B-MAX) of 9.3 +/- 2.4 fmol mg(-1) protein 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, BMAX = 115 +/- 26 fmol mg(-1), n = 6) of ApoE(-/-) animals. The ratio of ETA to ETB receptors in heart of control and ApoE-/- mice was similar, comprising 89% and 85% ETA 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 (EMAX = 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.