Enhanced tubuloglomerular feedback in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension.
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 AT(1) 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 AT(1) receptor activation by ANG II contributes to the enhanced feedback responsiveness in Cyp1a1-Ren2 rats with malignant hypertension.
Mitchell
Kenneth D
KD
Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. kdmitch@tulane.edu
Mullins
John J
JJ
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D005246:Feedback / Q000502:physiology; D005919:Glomerular Filtration Rate; D006974:Hypertension, Malignant / Q000139:chemically induced / Q000503:physiopathology*; D007211:Indoles; D007678:Kidney Glomerulus / Q000503:physiopathology*; D007684:Kidney Tubules / Q000503:physiopathology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects; D012079:Renal Circulation; D012083:Renin / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology
D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007211:Indoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; C016517:indole-3-carbinol; D019363:Cytochrome P-450 CYP1A1; D012083:Renin; C081643:candesartan