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Enhanced tubuloglomerular feedback in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

¹Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana; and ²Centre for Cardiovascular Science, University of Edinburgh Medical School, Edinburgh, Scotland

Submitted 21 December 2004 ; accepted in final form 13 July 2005

The present study was performed to evaluate tubuloglomerular feedback responses in transgenic rats [TGR(Cypa1a1Ren2)] with inducible malignant hypertension and to determine the degree to which feedback responsiveness is modulated by ANG II in these rats. Male Cyp1a1-Ren2 rats were fed a normal diet containing the aryl hydrocarbon indole-3-carbinol (I3C; 0.3%), for 5–6 days to stimulate expression of the Cyp1a1-Ren2 transgene and, thereby, to induce malignant hypertension. Stop-flow pressure (SFP) feedback responses to a late proximal perfusion rate of 40 nl/min were assessed in pentobarbital sodium-anesthetized rats during control conditions and after administration of the AT₁ receptor antagonist candesartan (0.1 mg/kg iv). Rats induced with I3C (n = 6) exhibited elevated mean arterial pressure and increased maximal SFP feedback responses compared with noninduced rats (n = 4; 163 ± 4 vs. 130 ± 2 mmHg, P < 0.01 and 16.3 ± 1.4 vs. 11.7 ± 0.5 mmHg, P < 0.05, respectively). Systemic candesartan decreased arterial pressure (to 98 ± 7 and to 101 ± 5 mmHg, respectively, P < 0.001) and attenuated SFP feedback responses (to 2.0 ± 0.4 and to 3.3 ± 0.9 mmHg, respectively, P < 0.01) in both hypertensive and normotensive rats. In additional experiments, peritubular capillary infusion of 10^–3 M candesartan did not alter arterial pressure but attenuated feedback responses in both hypertensive (19.3 ± 1.4 to 8.8 ± 0.9 mmHg, P < 0.01, n = 9) and normotensive Cyp1a1-Ren2 rats (9.0 ± 0.8 to 4.7 ± 0.6 mmHg, P < 0.01, n = 7). The present findings indicate that Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension exhibit augmented tubuloglomerular feedback responses. The data also show that AT₁ receptor activation by ANG II contributes to the enhanced feedback responsiveness in Cyp1a1-Ren2 rats with malignant hypertension.

renal micropuncture; kidney; renal hemodynamics; AT₁ receptors; blood pressure

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