Endothelin receptor blockade does not affect blood pressure or angiotensin II levels in CYP1A1-Ren-2 transgenic rats with acutely induced hypertension.
We found previously that selective blockade of endothelin ETA receptors is superior to nonselective ET(A)/ET(B) in attenuating hypertension and survival rate in Ren-2 transgenic rats (TGR). In the present pilot study, we were interested in whether similar effects will be found in TGR with inducible malignant hypertension (iTGR; official strain name Cyp1A1-Ren-2rats), which were derived from the original Ren-2 transgenic rat strain. Studies were performed in three-month old male iTGR. Treatment with either bosentan, a non-selective ET(A)/ET(B), or with atrasentan, a selective ET(A) receptor blocker, was started on day 2 of the experiment. Feeding with indole-3-carbinole (13C; 03% in rat chow), a natural xenobiotic which activates the Cyplal promoter of the mouse Ren-2 gene, began on day 3 and lasted for 4 days until day 6. Systolic BP, body weight, plasma ANG II and tissue ANG II and ET-1 concentrations were determined daily. Severe hypertension developed as early as 1 day after beginning of 13C feeding which was accompanied by a significant reduction in body weight and by increases in plasma and tissue ANG II and left ventricle ET-1 concentrations. Atrasentan or bosentan had no effects on the rise in BP or plasma and tissue ANG II concentrations but prevented the rise in heart ventricle ET-1 concentration. Our data show that blockade of the ET system does not prevent or attenuate the rapid development of severe hypertension in iTGR; a long-term protective effect of ET blockade on cardiac (and renal) damage, however, cannot be excluded and awaits further investigations.
Vanourková
Zdenka
Z
Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Kramer
Herbert J
HJ
Erbanová
Michaela
M
Bäcker
Angela
A
Cervenka
Ludek
L
Husková
Zuzana
Z
Chábová
Vera Certíková
VC
Tesar
Vladimír
V
Dvorák
Pavel
P
Malý
Jan
J
Vanecková
Ivana
I
D000804:Angiotensin II / Q000097:blood / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects*; D000077300:Bosentan; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000235:genetics*; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D006352:Heart Ventricles / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy*; D007211:Indoles / Q000009:adverse effects; D007668:Kidney / Q000378:metabolism; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007211:Indoles; D011759:Pyrrolidines; C535029:Ren2 protein, rat; D013449:Sulfonamides; D000804:Angiotensin II; C016517:indole-3-carbinol; D019363:Cytochrome P-450 CYP1A1; D012083:Renin; D000077300:Bosentan; D000077868:Atrasentan