Effects of Chronic ET A -Receptor Blockade in Angiotensin II-Induced Hypertension

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Abstract
Angiotensin II, a constrictor and mitogen of vascular smooth muscle cells, affects the release of endothelium-derived factors such as nitric oxide or endothelin-1. This study investigated the influence of endothelin-1, using the selective endothelin A receptor antagonist LU135252 , on blood pressure and endothelial function in angiotensin II-induced hypertension in the rat. Two weeks of angiotensin II administration (200 ng/kg per minute) increased systolic blood pressure (+35±5 mm Hg; tail-cuff method) compared with placebo ( P <.05). LU135252 alone did not affect systolic pressure but lowered the angiotensin II-induced pressure increase ( P <.05). In isolated aortic rings, endothelium-dependent relaxations to acetylcholine were reduced in the angiotensin II group ( P <.05 versus placebo) and improved by concomitant chronic LU135252 treatment ( P <.05 versus angiotensin II). Blood pressure elevation strongly correlated with impaired endothelium-dependent relaxations to acetylcholine ( r =−.967). LU135252 did not affect endothelium-independent relaxations to sodium nitroprusside, which were diminished after angiotensin II treatment ( P <.05). In quiescent rings, chronic angiotensin II administration enhanced endothelium-dependent contractions to acetylcholine, which were reduced by LU135252 ( P <.05). Impaired contractions to endothelin-1 and norepinephrine in the angiotensin II group were normalized after treatment with LU135252 ( P <.05). Thus, chronic therapy with LU135252 partially prevents angiotensin II-induced hypertension and the alternations of the endothelial function observed in this experimental model.