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Article history:Received 9 September 2008Received in revised form 8 December 2008Accepted 21 January 2009Keywords:HypertensionInducibleEndothelin receptorsCyp1A1-Ren-2 rats 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, wewere interested inwhether similar effects will be found inTGR 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. Feedingwith indole-3-carbinole (I3C; 0.3% in rat chow), a natural xenobiotic which activates the Cyp1a1 promoter ofthe mouse Ren-2 gene, began on day 3 and lasted for 4 days until day 6. Systolic BP, body weight, plasma ANGII and tissue ANG II and ET-1 concentrations were determined daily. Severe hypertension developed as earlyas 1 dayafter beginning of I3C feeding which was accompanied bya significant reduction in body weight andby increases in plasma and tissue ANG II and left ventricle ET-1 concentrations. Atrasentan or bosentan hadno effects on the rise in BP or plasma and tissue ANG II concentrations but prevented the rise in heartventricle ET-1 concentration. Our data show that blockade of the ETsystem does not prevent or attenuate therapid 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.© 2009 Elsevier Inc. All rights reserved.

Objective The present study was performed to characterize the autoregulatory efficiency of renal blood flow and glomerular filtration rate and the pressure-natriuresis relationship in transgenic rats with inducible angiotensin II (ANG II)-dependent hypertension (Cyp1a1-Ren-2 rats). Methods The renin gene was induced in Cyp1a1-Ren-2 rats through dietary administration of the natural xenobiotic indole-3-carbinol (I3C, 0.3%) for 12 and 24 h, respectively. Noninduced rats served as controls. Anesthetized rats were prepared for renal function studies and an aortic clamp was placed above the junction of the left renal artery to regulate the level of renal arterial pressure. Plasma renin activity, ANG II and aldosterone levels were measured at the end of the experiment by radioimmunoassay. Results Administration of I3C resulted in progressive increases in plasma renin activity and plasma and kidney ANG II levels; however, it did not significantly alter aldosterone levels as compared with those in noninduced rats. I3C induction for 12 h did not cause significant changes in blood pressure as compared with those in noninduced rats. I3C induction for 24 h elicited a significant rise in blood pressure. Twelve-hour I3C induction caused an impairment of the autoregulatory efficiency of renal blood flow and glomerular filtration rate and of the pressure-natriuresis relationship as compared with that in noninduced rats. In addition, 24 h I3C induction of the renin gene resulted in a marked reduction in renal blood flow and glomerular filtration rate and a further impairment of the pressure-natriuresis mechanism as compared with that in noninduced rats. Conclusion Our findings indicate that an impairment of the pressure-natriuresis mechanism precedes the development of ANG II-dependent hypertension in Cyp1a1-Ren-2 transgenic rats.

The present study was performed to examine in two-kidney, one-clip (2K1C) Goldblatt hypertensive mice: first, the relative contribution of angiotensin II receptor subtypes 1A (AT(1A)) and 1B (AT(1B)); second, the role of angiotensin II type 2 (AT(2)) receptors in the development of hypertension in wild-type (AT(1A)+/+) and AT(1A) receptor knockout (AT(1A)-/-) mice; and third, the role of increased nitric oxide synthase activity in counteracting the hypertensinogenic action of angiotensin II in this model.AT(1A)+/+ and AT(1A)-/- mice underwent clipping of one renal artery and were infused with either saline vehicle or selective AT(2) receptor agonist CGP-42112A (CGP). Blood pressure was monitored by radiotelemetry. Blood pressure responses to the nitric oxide synthase inhibitor nitro-L-arginine-methyl-ester were evaluated.AT(1A)+/+ mice responded to clipping by a rise in blood pressure that was not modified by CGP infusion. Clip placement caused a slight increase in blood pressure in AT(1A)-/- mice that remained significantly lower than in AT(1A)+/+ mice. Acute nitric oxide synthase inhibition caused greater increase in blood pressure in 2K1C/AT(1A)+/+ than in AT(1A)+/+ mice.The present data support the critical role of AT(1A) receptors in the development of 2K1C hypertension, whereas AT(1B) receptors play only a minor role in blood pressure regulation in this model of angiotensin II-dependent hypertension. Activation of AT(2) receptors does not play an antagonistic role in the AT(1) receptor-mediated hypertensinogenic actions of angiotensin II in this model. Finally, enhanced nitric oxide synthase activity plays a protective role by counteracting the vasoconstrictor influences of angiotensin II in 2K1C hypertensive mice.

Objective We evaluated the effects of salt restriction and of increasing dietary salt loading on blood pressure and the renin-angiotensin system in transgenic rats with inducible hypertension. Methods Hypertension was induced in Cyp1a1-Ren-2 rats through dietary administration of the natural xenobiotic indole-3-carbinol (0.3%), which activates the renin gene. Rats were fed either a normal-salt diet (0.6% NaCl), three different high-salt diets (2, 4 and 8% NaCl) or a low-salt diet (