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

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 antagonistLU135252 , 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 chronicLU135252 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 byLU135252 (P <.05). Impaired contractions to endothelin-1 and norepinephrine in the angiotensin II group were normalized after treatment withLU135252 (P <.05). Thus, chronic therapy withLU135252 partially prevents angiotensin II-induced hypertension and the alternations of the endothelial function observed in this experimental model.