LOSARTAN BUT NOT VERAPAMIL INHIBITS ANGIOTENSIN-II-INDUCED TISSUE ENDOTHELIN-1 INCREASE - ROLE OF BLOOD-PRESSURE AND ENDOTHELIAL FUNCTION

Endothelin partially mediates angiotensin (Ang) II-induced vascular ch anges in vivo. This study investigated the effects of the angiotensin type I receptor antagonist losartan and the calcium channel blocker ve rapamil on vascular reactivity and tissue endothelin-1 levels in aorta s of Wistar-Kyoto rats treated for 2 weeks with Ang II (200 ng.kg(-)1. min(-1)). Ang II increased systolic blood pressure (39+/-4 mm Hg, P<0. 05). Concomitant treatment with losartan abolished the Ang II-induced pressure increase (P<0.05), whereas verapamil reduced it only partiall y (P<0.05). In the aortas of rats with Ang II-induced hypertension, ti ssue endothelin-1 content was increased threefold and contractions to endothelin-1 were impaired (P<0.05). Interestingly, these alterations were normalized by losartan (P<0.05) but not by verapamil, Hence, ther e was a strong, negative correlation between contractions to endotheli n-1 and tissue endothelin-1 content (r=-0.733, P<0.0001). In contrast, both antihypertensive drugs normalized impaired endothelium-dependent relaxations to acetylcholine and reduced the sensitivity of vascular smooth muscle to sodium nitroprusside compared with Ang II-treated rat s (P<0.05). Ang II-induced hypertension enhanced endothelium-dependent contractions to acetylcholine, and these were normalized by either dr ug. In conclusion, these findings suggest that long-term treatment wit h Ang II modulates endothelin-1 protein expression in the rat aorta. A lthough both antihypertensive agents lowered blood pressure and normal ized endothelial function, only losartan prevented the increase in tis sue endothelin-1 content, suggesting that angiotensin type I receptor antagonists but not calcium antagonists modulate tissue endothelin-1 i n vivo.