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1 Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
2 Centre for Cardiovascular Science, University of Edinburgh Medical School, Edinburgh, Scotland, United Kingdom
* To whom correspondence should be addressed. E-mail: kdmitch{at}tulane.edu.
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 angiotensin II (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-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 non-induced 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 mmHg and to 3.3±0.9 mmHg, respectively, P<0.01) in both hypertensive and normotensive rats. In additional experiments, peritubular capillary infusion of 10-3M 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 IIdependent 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.
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