Prevention of the cardiovascular and renal effects of angiotensin II by endothelin blockade.

Angiotensin II (Ang II) stimulates the release and gene expression of endothelin-1 in isolated vascular smooth muscle cells. In 47 Sprague-Dawley rats, we assessed the influence of concomitant treatment by the mixed ET(A)/ET(B) endothelin receptor antagonist bosentan (30 mg/kg per day, gavage) on the effect of a 10-day infusion of Ang II (200 ng/kg per minute, SC, osmotic pump) on arterial pressure, renal hemodynamics (microsphere method), albuminuria, cardiac weight, and carotid structure. Ang II increased systolic arterial pressure (SAP) by 49+/-7 mm Hg. Although bosentan alone did not affect SAP, the development of Ang II-induced hypertension was entirely prevented by the endothelin antagonist. In addition, the reduction in renal blood flow induced by Ang II (4.9+/-0.3 versus 7.4+/-0.2 mL x min-1 x g-1 in control rats) was prevented by concomitant administration of bosentan (8.8+/-0.8 mL x min-1 x g-1). The marked increase in albuminuria observed in rats infused with Ang II (2524+/-961 versus 91+/-6 microg/24 h in control rats) was prevented by bosentan. Similarly, bosentan abolished the increase in heart weight index (from 2.96+/-0.03 to 3.41+/-0.08 mg/g body weight) and carotid media thickness (from 73+/-14 to 108+/-6 microm) induced by Ang II infusion. Of interest, the dipsogenic action of Ang II was not influenced by bosentan. In conclusion, endogenous endothelin contributes to the cardiovascular and renal effects of Ang II.