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.