From Cardiovascular Research, Institute of Physiology, University of
Zürich, and the Division of Cardiology, University Hospital, Zürich,
and the Division of Cardiology and Department of Clinical Research, University
Hospital, Bern (S.S.), Switzerland.
Correspondence to Thomas F. Lüscher, MD, FACC, FESC, Professor and Head of Cardiology, University Hospital, CH-8091 Zürich, Switzerland. E-mail 100771.1237{at}compuserve.com
Abstract—Endothelin partially
mediates angiotensin (Ang) II–induced vascular changes in
vivo. This study investigated the effects of the
angiotensin type 1 receptor antagonist
losartan and the calcium channel blocker verapamil
on vascular reactivity and tissue endothelin-1 levels in aortas 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
partially (P<0.05). In the aortas of rats with Ang
II–induced hypertension, tissue 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, there was a strong, negative correlation
between contractions to endothelin-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 rats
(P<0.05). Ang II–induced hypertension enhanced
endothelium-dependent contractions to acetylcholine,
and these were normalized by either drug. In conclusion, these findings
suggest that long-term treatment with Ang II modulates endothelin-1
protein expression in the rat aorta. Although both antihypertensive
agents lowered blood pressure and normalized
endothelial function, only losartan prevented
the increase in tissue endothelin-1 content, suggesting that
angiotensin type 1 receptor antagonists but not
calcium antagonists modulate tissue endothelin-1 in vivo.
© 1998 American Heart Association, Inc.
Scientific Contributions
Losartan but Not Verapamil Inhibits Angiotensin II–Induced Tissue Endothelin-1 Increase
Role of Blood Pressure and Endothelial Function
Key Words: angiotensin II • endothelin • endothelium • losartan • verapamil • aorta
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