Endothelin receptor blockade does not affect blood pressure or angiotensin II levels in CYP1A1-Ren-2 transgenic rats with acutely induced hypertension
Abstract
We found previously that selective blockade of endothelin ETA receptors is superior to nonselective ETA/ETB 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 ETA/ETB, or with atrasentan. a selective ETA receptor blocker, was started on day 2 of the experiment.
Feeding with indole-3-carbinole (13C; 0.3% in rat chow), a natural xenobiotic which activates the Cyp1a1 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 EN 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.