Abstract-Rupture of vulnerable plaques is the main cause of acute cardiovascular events. However, mechanisms responsible for transforming a stable into a vulnerable plaque remain elusive. Angiotensin II, a key regulator of blood pressure homeostasis, has a potential role in atherosclerosis. To study the contribution of angiotensin II in plaque vulnerability, we generated hypertensive hypercholesterolemic ApoE Ϫ/Ϫ mice with either normal or endogenously increased angiotensin II production (renovascular hypertension models). Hypertensive high angiotensin II ApoE Ϫ/Ϫ mice developed unstable plaques, whereas in hypertensive normal angiotensin II ApoE Ϫ/Ϫ mice plaques showed a stable phenotype. Vulnerable plaques from high angiotensin II ApoE Ϫ/Ϫ mice had thinner fibrous cap (PϽ0.01), larger lipid core (PϽ0.01), and increased macrophage content (PϽ0.01) than even more hypertensive but normal angiotensin II ApoE Ϫ/Ϫ mice. Moreover, in mice with high angiotensin II, a skewed T helper type 1-like phenotype was observed. Splenocytes from high angiotensin II ApoE Ϫ/Ϫ mice produced significantly higher amounts of interferon (IFN)-␥ than those from ApoE Ϫ/Ϫ mice with normal angiotensin II; secretion of IL4 and IL10 was not different. In addition, we provide evidence for a direct stimulating effect of angiotensin II on lymphocyte IFN-␥ production. These findings suggest a new mechanism in plaque vulnerability demonstrating that angiotensin II, within the context of hypertension and hypercholesterolemia, independently from its hemodynamic effect behaves as a local modulator promoting the induction of vulnerable plaques probably via a T helper switch.

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Objective: The aim of this study was to compare the response to NO-mediated vasodilators in vivo and in vitro during chronic NO synthase inhibition. Methds: NG-Nitro-L-arginine-methyl ester (L-NAME, 0.4 g/l) or vehicle was administered in the drinking water for 6 weeks to male Wistar rats weighing 220-240 g. The effect of acetylcholine and sodium nitroprusside was examined in vivo, on systemic blood pressure and heart rate and in vitro, on the precontracted isolated mesenteric artery. The in vivo response to both vasodilators was examined in awake rats monitored by an indwelling catheter in the femoral artery. Isolated segments of the third-generation mesenteric artery were examined in vitro with a Mulvany dual myograph after precontraction with noradrenaline. Resultsr In isolated mesenteric arteries obtained from rats chronically treated with L-NAME, the initial relaxant response to acetylcholine was significantly decmased whereas that to sodium nitroprusside was enhanced. A late acetylcholine-induced contractile response was present and abolished by indomethacin. In vivo, the hypotensive action of sodium nitroprusside was also enhanced in the L-NAME-treated rats. Acetylcholine reduced blood pressure in the L-NAME-treated hypertensive animals more than in normotensive controls, but less than in control rats infused intravenously with noradrenaline at a dose increasing their blood pressure to hypertensive levels. Conclusions: The NO-mediated vasodilation induced by acetylcholine is attenuated during chronic NO synthase inhibition, both in vivo and in vitro. The blunted hypotensive response to acetylcholine can be demonstrated only if blood pressure of control rats is acutely increased to hypertensive levels.

The present assay reliably measures ET-1 levels in rat and human plasma. It allows to discriminate between different forms of hypertension with high or low circulating levels of ET-1.