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 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 x kg(-1) x 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.
d'Uscio
L V
LV
Cardiovascular Research, Institute of Physiology, University of Zürich, University Hospital, Zürich, Switzerland.
Shaw
S
S
Barton
M
M
Lüscher
T F
TF
D000804:Angiotensin II; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000737:chemistry / Q000187:drug effects; D001794:Blood Pressure / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000032:analysis / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000187:drug effects; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D017466:Receptors, Endothelin / Q000187:drug effects; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology*
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D017466:Receptors, Endothelin; D014665:Vasodilator Agents; D000804:Angiotensin II; D009599:Nitroprusside; D014700:Verapamil; D019808:Losartan