scholarly journals Direct Inhibition with Aliskiren Normalizes Blood Pressure in Cyp1a1‐Ren2 Transgenic Rats with Inducible ANG II‐Dependent Malignant Hypertension

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
Catherine G Howard ◽  
Kenneth D Mitchell
Keyword(s):  
Blood Pressure ◽  
Malignant Hypertension ◽  
Ang Ii ◽  
Direct Inhibition ◽  
Transgenic Rats

scholarly journals 20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Lenka Sedláková ◽  
Soňa Kikerlová ◽  
Zuzana Husková ◽  
Lenka Červenková ◽  
Věra Čertíková Chábová ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cytochrome P450 ◽  
Cardiac Injury ◽  
Malignant Hypertension ◽  
Ang Ii ◽  
Hydroxyeicosatetraenoic Acid ◽  
Hypertensive Rats ◽  
Transgenic Rats ◽  
Renin Gene ◽  
Marked Suppression

We hypothesized that vascular actions of 20-hydroxyeicosatetraenoic acid (20-HETE), the product of cytochrome P450 (CYP450)-dependent ω-hydroxylase, potentiate prohypertensive actions of angiotensin II (ANG II) in Cyp1a1-Ren-2 transgenic rats, a model of ANG II-dependent malignant hypertension. Therefore, we evaluated the antihypertensive effectiveness of 20-HETE receptor antagonist (AAA) in this model. Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. Treatment with AAA was started either simultaneously with induction of hypertension or 10 days later, during established hypertension. Systolic blood pressure (SBP) was monitored by radiotelemetry, indices of renal and cardiac injury, and kidney ANG II levels were determined. In I3C-induced hypertensive rats, early AAA treatment reduced SBP elevation (to 161 ± 3 compared with 199 ± 3 mmHg in untreated I3C-induced rats), reduced albuminuria, glomerulosclerosis index, and cardiac hypertrophy (P<0.05 in all cases). Untreated I3C-induced rats showed augmented kidney ANG II (405 ± 14 compared with 52 ± 3 fmol/g in non-induced rats, P<0.05) which was markedly lowered by AAA treatment (72 ± 6 fmol/g). Remarkably, in TGR with established hypertension, AAA also decreased SBP (from 187 ± 4 to 158 ± 4 mmHg, P<0.05) and exhibited organoprotective effects in addition to marked suppression of kidney ANG II levels. In conclusion, 20-HETE antagonist attenuated the development and largely reversed the established ANG II-dependent malignant hypertension, likely via suppression of intrarenal ANG II levels. This suggests that intrarenal ANG II activation by 20-HETE is important in the pathophysiology of this hypertension form.

Alterations in Blood Pressure and Heart Rate Variabililty in Transgenic Rats with Low Brain Angiotensinogen

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 727-727
Author(s):  
Ovidiu Baltatu ◽  
Ben J Janssen ◽  
Ralph Plehm ◽  
Detlev Ganten ◽  
Michael Bader
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Baroreflex Sensitivity ◽  
Circadian Variation ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Short Term ◽  
Baroreflex Control ◽  
Sd Rats ◽  
The Brain

P191 The brain renin-angiotensin system (RAS) system may play a functional role in the long-term and short-term control of blood pressure (BPV) and heart rate variability (HRV). To study this we recorded in transgenic rats TGR(ASrAOGEN) with low brain angiotensinogen levels the 24-h variation of BP and HR during basal and hypertensive conditions, induced by a low-dose s.c. infusion of angiotensin II (Ang II, 100 ng/kg/min) for 7 days. Cardiovascular parameters were monitored by telemetry. Short-term BPV and HRV were evaluated by spectral analysis and as a measure of baroreflex sensitivity the transfer gain between the pressure and heart rate variations was calculated. During the Ang II infusion, in SD but not TGR(ASrAOGEN) rats, the 24-h rhythm of BP was inverted (5.8 ± 2 vs. -0.4 ± 1.8 mm Hg/group of day-night differences of BP, p< 0.05, respectively). In contrast, in both the SD and TGR(ASrAOGEN) rats, the 24-h HR rhythms remained unaltered and paralleled those of locomotor activity. The increase of systolic BP was significantly reduced in TGR(ASrAOGEN) in comparison to SD rats as previously described, while the HR was not altered in TGR(ASrAOGEN) nor in SD rats. The spectral index of baroreflex sensitivity (FFT gain between 0.3-0.6 Hz) was significantly higher in TGR(ASrAOGEN) than SD rats during control (0.71 ± 0.1 vs. 0.35 ± 0.06, p<0.05), but not during Ang II infusion (0.6 ± 0.07 vs. 0.4 ± 0.1, p>0.05). These results demonstrate that the brain RAS plays an important role in mediating the effects of Ang II on the circadian variation of BP. Furthermore these data are consistent with the view that the brain RAS modulates baroreflex control of HR in rats, with AII having an inhibitory role.

Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

2007 ◽  
Vol 292 (6) ◽  
pp. F1858-F1866 ◽  
Author(s):  
Miguel L. Graciano ◽  
Cynthia R. Mouton ◽  
Matthew E. Patterson ◽  
Dale M. Seth ◽  
John J. Mullins ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Morphological Changes ◽  
Periodic Acid ◽  
Cell Number ◽  
Malignant Hypertension ◽  
Nuclear Antigen ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Periodic Acid Schiff ◽  
Proliferating Cell

Transgenic rats with inducible ANG II-dependent malignant hypertension [TGR(Cyp1a1Ren2)] were generated by inserting the mouse Ren2 renin gene into the genome of the rat. The present study was performed to assess renal morphological changes occurring during the development of ANG II-dependent malignant hypertension in these rats. Male Cyp1a1-Ren2 rats ( n = 10) were fed normal rat food containing indole-3-carbinol (I3C; 0.3%) for 10 days to induce malignant hypertension. Rats induced with I3C had higher mean arterial pressures (173 ± 9 vs. 112 ± 11 mmHg, P < 0.01) than noninduced normotensive rats ( n = 9). Glomerular damage was evaluated by determination of the glomerulosclerosis index (GSI) in tissue sections stained with periodic acid-Schiff. Kidneys of hypertensive rats had a higher GSI than normotensive rats (21.3 ± 5.6 vs. 3.5 ± 1.31 units). Quantitative analysis of macrophage ED-1-positive cells and proliferating cell nuclear antigen using immunohistochemistry demonstrated increased macrophage numbers in the renal interstitium (106.4 ± 11.4 vs. 58.7 ± 5.0 cells/mm2) and increased proliferating cell number in cortical tubules (37.8 ± 5.7 vs. 24.2 ± 2.1 cells/mm2), renal cortical vessels (2.2 ± 0.5 vs. 0.13 ± 0.07 cells/vessel), and the cortical interstitium (33.6 ± 5.7 vs. 4.2 ± 1.4 cells/mm2) of hypertensive rat kidneys. These findings demonstrate that the renal pathological changes that occur during the development of malignant hypertension in Cyp1a1-Ren2 rats are characterized by inflammation and cellular proliferation in cortical vessels and tubulointerstitium.

scholarly journals Renal functional responses to selective intrarenal renin inhibition in Cyp1a1-Ren2 transgenic rats with ANG II-dependent malignant hypertension

2012 ◽  
Vol 302 (1) ◽  
pp. F52-F59 ◽  
Author(s):  
Catherine G. Howard ◽  
Kenneth D. Mitchell
Keyword(s):  
De Novo ◽  
Collecting Duct ◽  
Renal Plasma Flow ◽  
Renin Angiotensin System ◽  
Malignant Hypertension ◽  
Ang Ii ◽  
Functional Responses ◽  
Transgenic Rats ◽  
Excretory Function ◽  
Renin Inhibition

Angiotensin (ANG) II-dependent hypertension is characterized by increases in intrarenal ANG II levels, derangement in renal hemodynamics, and augmented tubular sodium reabsorptive capability. Increased nephron expression of renin-angiotensin system components, such as angiotensinogen by proximal tubule cells and renin by collecting duct principal cells, has been associated with an augmented ability of the kidney to form ANG II in hypertensive states. However, the contribution of de novo intrarenal ANG II production to the development and maintenance of ANG II-dependent hypertension remains unclear. The present study was performed to determine the effects of selective intrarenal renin inhibition on whole kidney hemodynamics and renal excretory function in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension in the absence of the confounding influence of associated reductions in mean arterial pressure (MAP). Male Cyp1a1-Ren2 transgenic rats were induced to develop malignant hypertension, anesthetized, and surgically prepared for intrarenal administration of the direct renin inhibitor aliskiren (0.01 mg/kg). Following acute aliskiren treatment, urine flow and sodium excretion increased (10.5 ± 1.1 to 15.9 ± 1.9 μl/min, P < 0.001; 550 ± 160 to 1,370 ± 320 neq/min, P < 0.001, respectively) and ANG II excretion decreased (120 ± 30 to 63 ± 17 fmol/h, P < 0.05). There were no significant changes in MAP, glomerular filtration rate, estimated renal plasma flow, plasma ANG II levels, or protein excretion. The present findings demonstrate that selective renal renin inhibition elicits diuretic and natriuretic responses in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension. Elevated intraluminal ANG II levels likely act to augment tubular reabsorptive function and, thereby, contribute to the elevated blood pressure in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension.

scholarly journals Enhancement of renin and prorenin receptor in collecting duct of Cyp1a1-Ren2 rats may contribute to development and progression of malignant hypertension

2011 ◽  
Vol 300 (2) ◽  
pp. F581-F588 ◽  
Author(s):  
Minolfa C. Prieto ◽  
Dustyn E. Williams ◽  
Liu Liu ◽  
Kimberly L. Kavanagh ◽  
John J. Mullins ◽  
...  
Keyword(s):  
Gene Expression ◽  
Collecting Duct ◽  
Normal Diet ◽  
Malignant Hypertension ◽  
Soluble Form ◽  
Transgenic Rat ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Protein Levels ◽  
Prorenin Receptor

To determine whether in the transgenic rat model [TGR(Cyp1a1Ren2)] with inducible ANG II-dependent malignant hypertension changes in the activation of intrarenal renin-angiotensin system may contribute to the pathogenesis of hypertension, we examined the gene expression of angiotensinogen (AGT) in renal cortical tissues and renin and prorenin receptor [(P)RR] in the collecting duct (CD) of the kidneys from Cyp1a1Ren2 rats ( n = 6) fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days and noninduced rats maintained on a normal diet (0.6% NaCl diet; n = 6). Rats induced with I3C developed malignant hypertension and exhibited alterations in the expression of renin and (P)RR expressed by the CD cells. In the renal medullary tissues of the Cyp1a1Ren2 transgenic rats with malignant hypertension, renin protein levels in CD cells were associated with maintained renin content and lack of suppression of the endogenous Ren1c gene expression. Furthermore, these tissues exhibited increased levels of (P)RR transcript, as well as of the protein levels of the soluble form of this receptor, the s(P)RR. Intriguingly, although previous findings demonstrated that urinary AGT excretion is augmented in Cyp1a1Ren2 transgenic rats with malignant hypertension, in the present study we did not find changes in the gene expression of AGT in renal cortical tissues of these rats. The data suggest that upregulation of renin and the s(P)RR in the CD, especially in the renal medullary tissues of Cyp1a1Ren2 transgenic rats with malignant hypertension, along with the previously demonstrated increased availability of AGT in the urine of these rats, may constitute a leading mechanism to explain elevated formation of kidney ANG II levels in this model of ANG II-dependent hypertension.

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