Angiotensin II increases tissue endothelin and induces vascular hypertrophy - Reversal by ETA-receptor antagonist

Background In vitro studies on vascular smooth muscle cells suggest that endothelin has a stimulating effect on cellular proliferation. This study was designed to determine the endogenous effect of endothelin on angiotensin II-induced hypertrophy of small arteries in vivo. Methods and Results Two weeks of angiotensin II administration (200 ng.kg(-1).min(-1)) increased media thickness, media/lumen ratio, and cross-sectional area of basilar and small mesenteric arteries, confirming the proliferative properties of angiotensin II. The tissue levels of endothelin-l were elevated in mesenteric arteries after angiotensin II administration. The administration of the selective and specific ETA-receptor antagonist LU135252 (50 mg.kg(-1).d(-1)) in combination with angiotensin II prevented the changes of vascular geometry and partially reduced the increase in blood pressure induced by angiotensin II. Indeed, part of the effect on the vascular structure of the endothelin-receptor antagonist seemed pressure-independent. Conclusions Our results therefore demonstrate that angiotensin II increases the production of endothelin in the blood vessel wall that, via ETA receptors, mediates changes in vascular structure of the cerebral and mesenteric circulation. Endothelin antagonists may therefore be of value to reduce blood pressure and to prevent vascular structural changes in conditions of increased activity of the renin-angiotensin system.