This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Siragy, H. M. Articles by Carey, R. M. Search for Related Content PubMed PubMed Citation Articles by Siragy, H. M. Articles by Carey, R. M. Related Collections ACE/Angiotension receptors Other hypertension Hypertension - basic studies Other Treatment Endothelium/vascular type/nitric oxide

(Hypertension. 2000;35:1074.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Angiotensin Type 2 Receptor Mediates Valsartan-Induced Hypotension in Conscious Rats

Helmy M. Siragy; Marc de Gasparo; Robert M. Carey

From the Department of Medicine (H.M.S., R.M.C.), University of Virginia Health System, Charlottesville, and Novartis Pharma (M.d.G.), Basel, Switzerland.

Correspondence to Helmy M. Siragy, MD, Department of Internal Medicine, Box 482, University of Virginia Health System, Charlottesville, VA 22908. E-mail hms7a{at}virginia.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract—Inhibition of the renin-angiotensin system is associated with vasodilation and reduction in blood pressure. We hypothesized that angiotensin type 1 (AT₁) receptor (AT₁R) blockade is associated with increased production of renal nitric oxide (NO) mediated by release of bradykinin (BK). By use of a microdialysis technique, changes in renal interstitial fluid (RIF) BK, NO end products nitrite and nitrate (NOX), and cGMP were monitored in response to intravenous infusion of the AT₁R blocker valsartan (10 mg/kg), the angiotensin type 2 (AT₂) receptor (AT₂R) blocker PD123319 (50 µg · kg^-1 · min^-1), and the BK B₂ receptor blocker icatibant (10 µg · kg^-1 · min^-1) in conscious rats (n=10) during low sodium intake. RIF BK, NOX, and cGMP significantly increased during valsartan treatment, whereas AT₂R blockade caused a significant decrease in these autacoids. During icatibant infusion, RIF NOX and cGMP decreased by 64% and 40%, respectively, whereas BK increased. Combined administration of valsartan and icatibant, of valsartan and PD123319, or of valsartan, PD123319, and icatibant prevented the increase in RIF cGMP and NOX in response to valsartan alone. These data demonstrate that AT₁R blockade with valsartan is associated with release of renal BK, which in turn mediates NO production. The results suggest that increased angiotensin II, in response to sodium restriction and valsartan infusion, stimulates AT₂R, which mediates a BK and NO cascade.

Key Words: receptors, angiotensin II • bradykinin • nitric oxide • cyclic GMP • valsartan

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
All components of the renin-angiotensin system are present within the kidney.¹ Angiotensin II (Ang II) is the most active component of this system. The tissue production of Ang II in proximity to its receptors on the target cells constitutes a paracrine function for this hormone. Ang II plays a major role in regulating body fluid and electrolyte homeostasis and blood pressure. The majority of the effects of Ang II are mediated by stimulation of the angiotensin type-1 (AT₁) receptor. Inhibition of the AT₁ receptor results in increased renin secretion,² resulting in a subsequent increase in Ang II production, a decrease in blood pressure, diuresis, and natriuresis.³ The interaction between Ang II and other vasoactive peptides contributes to the preservation of these functions. One of the important peptides that is produced in the kidney is bradykinin (BK). Mainly by inducing diuresis and natriuresis, BK has been shown to regulate renal function⁴ in a manner opposite that induced by Ang II.

In the present study, we evaluated the effect of AT₁ receptor blockade on renal production of BK and its mediators, nitric oxide (NO) and cGMP. We hypothesized that AT₁ receptor blockade is associated with increased production of renal interstitial fluid (RIF) BK. We used a novel microdialysis technique to monitor changes in RIF BK, the NO end products nitrite and nitrate (NOX), and cGMP during AT₁, angiotensin type-2 (AT₂), or BK B₂ receptor blockade.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Renal Microdialysis Technique
To determine the levels of renal RIF BK, NOX, and cGMP, we constructed a microdialysis probe as described previously.^{5 6} The dialysis membrane was obtained from Hospal. In vitro recoveries of cold and radiolabeled BK or cGMP by the dialysis probes were 55% and 78%, respectively, for BK⁷ and 59% and 70%, respectively, for cGMP.^{5 6 7} Negligible amounts of these peptides stick to the polyethylene tubes of the dialysis probes, as demonstrated by recovery of >99.8% of these substances in the perfusate.^{5 6 7}

Animal Preparation
The experiments, which were approved by the University of Virginia Animal Research Committee, were conducted in 4-week-old Sprague-Dawley rats (Harlan Teklad, Madison, Wis). The rats were placed under general anesthesia with ketamine (80 mg/kg IM) and xylazine (8 mg/kg IM), and the right and left kidneys were exposed by a midline abdominal incision. To obtain a vascular access, a heparinized polyethylene tube was inserted into the right jugular vein. This tube was flushed daily with 10% heparin in 5% dextrose in water and capped with a small piece of copper wire. The exterior end of this tube was secured in place by suturing it to the skin at the exit site and was covered with a stainless-steel spring (to prevent the rats from damaging it). Rats were housed under controlled conditions (temperature 21±1°C, humidity 60±10%, and light 8 to 20 hours). Experiments were started at the same time each day (8 AM) to prevent any diurnal variation of the measured plasma renin activity (PRA) or systolic blood pressure (SBP). For in vivo determinations of RIF BK, NOX, and cGMP, the microdialysis probes were placed in the cortex^{5 6} of both kidneys while the rats were under general anesthesia. All RIF measurements were made on experimental day 7 after implanting the probes. For collection of RIF, the inflow tube of the dialysis probe was connected to a gas-tight syringe filled with lactated Ringer’s solution and perfused at 3 µL/min. The effluent was collected from the outflow tube of the dialysis probe for 30-minute sample periods.

Analytical Methods
Urinary sodium concentrations were measured by using a NOVA Biomedical analyzer. PRA was measured by radioimmunoassay.⁸ SBP was measured at 30-minute intervals in the tail, and recorded values were averaged for each study period.⁷ RIF BK levels were measured by ELISA.⁷ The sensitivity of this assay is 1 pg/mL and is 100% specific for BK. It does not react with any other peptides. RIF NOX and cGMP levels in dialysate samples were measured by using an enzyme immunoassay kit.⁶ The sensitivity is 2.5 µmol/L and 0.11 pmol/mL for NOX and cGMP, respectively, and the specificity is 100% for both. The intra-assay and interassay cross-reactivities with other cyclic nucleotides were <0.01%.

Effects of AT₁, AT₂, and BK B₂ Receptor Blockade Individually or Combined
Animals (n=10) were placed in metabolic cages. Each animal served as its own control, and different treatments were carried out in the same group of animals. One day before surgery, while rats were consuming a normal sodium diet (0.28% NaCl), baseline body weight, PRA, and SBP were measured, and a 24-hour urine sample was collected for calculation of urinary volume and sodium excretion (U_NaV). After surgery, the animals were placed on a low sodium diet (0.04% NaCl) for 10 days (experimental days 1 to 6). On experimental day 6, body weight, PRA, SBP, and a 24-hour urine collection were obtained. On experimental days 7 to 10, SBP, RIF BK, NOX, and cGMP were monitored during right jugular vein administration (20 µL/min for 30 minutes), in random order, of 5% dextrose in water vehicle (20 µL/min); valsartan, a nonpeptide Ang II antagonist at the AT₁ receptor (10 mg/kg); PD123319 (PD), an AT₂ receptor antagonist (50 µg · kg^-1 · min^-1); icatibant, a potent and specific BK B₂ receptor antagonist (10 µg · kg^-1 · min^-1)⁹ ; or combined administration of these treatments.

Statistical Analysis
Comparisons among pharmacological agents and controls were examined by ANOVA, including a repeated measure term, by use of the general linear models procedure of the Statistical Analysis System. Multiple comparisons of individual pairs of effect means were conducted by using the least squares method of pooled variance. Data are expressed as mean±SE. Statistical significance was identified at P<0.05.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Changes in PRA, 24-Hour Urinary Volume, U_NaV, and Blood Pressure Responses to Low Sodium Intake
PRA during normal sodium intake was 1.6±1 ng · mL^-1 · h^-1 and increased to 13.8±3.1 ng · mL^-1 · h^-1 (P<0.0001) by day 6 of low sodium intake. In contrast, 24-hour urinary volume and U_NaV decreased significantly from 22.3±2.0 mL/d and 1150±30 µmol/d to 3.1±0.8 mL/d and 173±8 µmol/d (P<0.0001), respectively, in response to low sodium intake. SBP was 118±4 mm Hg during normal sodium intake and did not change in response to low sodium intake.

RIF BK, NOX, and cGMP Response to Low Sodium Intake
During normal sodium intake, RIF BK, NOX, and cGMP recoveries were 53±12 pg/min, 0.1±0.02 µmol/min, and 0.12±0.02 µmol/min, respectively. By day 6 of low sodium intake, there were significant increases (Figure 1) in recovery of RIF BK, NOX, and cGMP to 360±20 pg/min, 0.28±0.01 µmol/min, and 0.9±0.01 µmol/min (P<0.0001), respectively.

View larger version (14K): [in this window] [in a new window]   Figure 1. RIF BK, NOX, and cGMP increased in response to low sodium intake. Values are mean±SE (n=10). *P<0.0001 vs normal.

Changes in SBP in Response to AT₁ and BK B₂ Receptor Blockade During Low Sodium Intake
There were no changes in SBP in response to vehicle (5% dextrose) administration. Administration of valsartan (the AT₁ receptor blocker) caused a significant decrease in SBP (Figure 2) from 119±3 to 110±2 mm Hg (P<0.05). In contrast, icatibant (the BK B₂ receptor antagonist) increased SBP from 118±2 to 124±3 mm Hg (P<0.05). There was no change in SBP during PD administration. Combined administration of valsartan and icatibant, of valsartan and PD, or of valsartan, PD, and icatibant completely prevented (to similar levels) the decrease in SBP that was observed with valsartan alone (Figure 2).

View larger version (18K): [in this window] [in a new window]   Figure 2. Effect of Ang II and BK receptor blockade on systolic blood pressure (BP). Valsartan (V) significantly (*P<0.05 vs vehicle) reduced BP, whereas icatibant (I) increased BP. Combined blockade of the AT1 and BK receptors (V+I) totally prevented the decrease in BP induced by valsartan. Blockade of the AT2 receptor with PD alone did not affect BP, but PD blocked the BP reduction in response to valsartan. TC indicates time control (vehicle administration). The solid bars represent data obtained in the group treated with 5% dextrose in water (vehicle), whereas the open bars are the results for the treated groups. Values are mean±SE (n=10).

Changes in RIF BK, NOX, and cGMP in Response to AT₁ and BK B₂ Receptor Blockade
There were no changes in RIF BK, NOX, and cGMP during time-control vehicle administration. RIF BK, NOX, and cGMP increased (P<0.001) during valsartan treatment (Figure 3). Similarly, RIF BK increased during icatibant treatment or combined valsartan and icatibant treatment (P<0.001). However, in contrast to valsartan, icatibant decreased RIF NOX and cGMP by 64%(P<0.0001) and 40% (P<0.001), respectively (Figure 3). PD alone or combined with valsartan decreased RIF BK, NOX, and cGMP to those levels observed during normal sodium intake (P<0.0001). Combined administration of valsartan and icatibant or of valsartan, PD, and icatibant prevented the increase in RIF cGMP and NOX. Similarly, combined treatment with valsartan, PD, and icatibant reduced RIF BK (P<0.0001) to levels similar to those observed during treatment with PD alone or PD and valsartan.

View larger version (25K): [in this window] [in a new window]   Figure 3. Changes in RIF BK, NOX, and cGMP. Valsartan (V) increased BK, NOX, and cGMP (*P<0.001 vs vehicle), whereas icatibant (I) increased BK but decreased NOX and cGMP (*P<0.001 vs vehicle). AT2 receptor blocker (PD) alone or combined with valsartan decreased BK, NOX, and cGMP to levels observed during normal sodium intake (**P<0.0001 vs vehicle). Values are mean±SE (n+10). Solid and open bars are similar to those in Figure 2.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study demonstrates that AT₁ receptor blockade is associated with an increase in renal tissue levels of BK, NO, and cGMP. Our results suggest that the vasodilator response to AT₁ receptor blockade is mediated, at least in part, by the concomitant increase in tissue BK, which is stimulated via the AT₂ receptor. Further vasodilator action is obtained via BK stimulation of NO in this pathway. The observed levels of RIF BK, NOX, and cGMP are not due to changes in renal hemodynamics induced by the use of various drugs, according to our previous studies,^{6 7} which have demonstrated the following: (1) Losartan, a renal vasodilator agent, and Ang II, a renal vasoconstrictor hormone, increase RIF BK. (2) Ang II increases RIF cGMP, whereas N^G-nitro-L-arginine methyl ester, an NO synthase inhibitor and a renal vasoconstrictor, decreases RIF cGMP. These data demonstrate that changes in recovered RIF substances are specific to each treatment regardless of the general effects of treatments on renal hemodynamics.

Sodium depletion is associated with an increase in RIF Ang II and BK concentrations.^{10 11} It is likely that the increase in RIF BK is secondary to the increase in RIF Ang II levels. This thesis is strengthened by the observations that exogenous Ang II increases RIF BK during normal sodium intake.⁷ BK increases NO production,¹² which activates soluble guanylyl cyclase, releasing cGMP into the RIF. This response is mediated at the BK B₂ receptor, because it can be blocked by icatibant, a specific B₂ receptor antagonist. In the present and previous studies,^{6 7} the RIF BK, NOX, and cGMP levels during time-control studies were stable and did not change from day to day. However, we should caution that these studies were not designed to determine the absolute levels of recovered substances.

The AT₁ receptor blocker valsartan and the AT₂ receptor blocker PD were used to evaluate whether the AT₁ or AT₂ receptor was involved in the process of increasing renal BK levels. RIF BK increased during sodium depletion. RIF BK levels further increased during valsartan treatment and decreased during PD administration. These responses suggest that the AT₂ receptor is responsible for the increase in RIF BK and that during sodium depletion, BK formation is tonically stimulated by Ang II at the AT₂ receptor. In the presence of AT₁ receptor blockade at the level of renal juxtaglomerular cells, increased circulating Ang II¹³ enhances BK production through stimulation of the unblocked AT₂ receptor.

Our previous studies⁵ demonstrated that under conditions of increased Ang II levels, AT₂ receptor stimulation is associated with an increase in RIF cGMP, the production of which is mediated by AT₂ receptor stimulation of NO.⁶ In the present study, AT₂ receptor stimulation of BK production offers clarification of the mechanisms leading to NO release. Whether the changes in RIF BK stimulated by Ang II contribute to the regulation of renal hemodynamic and excretory function awaits further investigation.

In the present study, it was technically impossible to measure U_NaV or renal blood flow in conscious rats during the different experimental manipulations. However, changes in blood pressure suggest that the hypotensive effect of AT₁ receptor blockade is at least partially mediated by BK release through stimulation of the AT₂ receptor. In addition, present knowledge suggests that the renal kallikrein-kinin system is involved in the regulation of sodium and water excretion and may participate in blood pressure control.¹⁴ BK is known to release NO from vascular endothelial, renal interstitial, or epithelial cells.¹² At least a portion of the renal effects of kinins appears to be mediated by NO, because inhibition of NO synthesis reduces the renal vasodilator response to BK.¹⁵

Previously, we have shown that AT₂ receptor stimulation mediates NO release.⁶ Furthermore, acute administration of icatibant reduced NO to levels similar to those observed during AT₂ receptor blockade.⁷ The present study clearly indicates that partial renal NO production is mediated by the AT₂ receptor via increased production of BK. AT₁ receptor blockade shifts Ang II toward stimulation of the unblocked AT₂ receptor to release BK. Consequently, AT₂ receptor blockade reduces renal BK and NO.

The mechanism whereby AT₂ receptor stimulation releases BK is unclear. However, our data suggest that the increase in kinin production under such conditions counteracts the vasoconstrictor mechanisms activated in response to increased Ang II. The observed increase in blood pressure during icatibant treatment confirms the role of bradykinin in blood pressure regulation.¹⁶ In the present study, BK B₂ receptor blockade completely prevented the blood pressure–reducing effects of valsartan. The specific contribution of AT₂ receptor–mediated BK to the hypotensive effects of valsartan is supported by the fact that combined valsartan and PD prevented the valsartan hypotensive response to the same magnitude produced by combined valsartan and icatibant. Combined administration of valsartan, PD, and icatibant did not have any potentiation or synergistic effects on blood pressure or RIF BK; this finding suggests that PD and icatibant are influencing the same pathway. These data support our previous finding that BK partially mediates the hypotensive effects of AT₁ receptor blockade.⁷ Additionally, our results are supported by a recent finding that in mice overexpressing the AT₂ receptor, the AT₂ receptor–mediated vasodilation was caused by the effect of BK, leading to activation of endothelial NO/cGMP.¹⁷ Combined administration of valsartan and PD caused a greater decrease in renal tissue levels of NO and cGMP than did combined treatment with valsartan and icatibant. These results suggest that the AT₂ receptor can directly stimulate NO in addition to its effect through kinin release. Thus, AT₂ receptor–mediated BK release and the subsequent generation of NO via BK B₂ receptor stimulation directly contribute to the blood pressure–lowering effects of valsartan. Because RIF cGMP levels parallel changes of RIF NOX during AT₁, AT₂, and BK B₂ receptor blockade, it is likely that cGMP may be important in vasodilator signal transduction.

In conclusion, AT₁ receptor blockade with valsartan is associated with hypotension and increased production of renal BK, NO, and cGMP. AT₂ receptor blockade with PD inhibited both the hypotension and renal autacoid responses to valsartan, confirming that during AT₁ receptor blockade, there is concomitant stimulation of the AT₂ receptor. The increase in renal NO and cGMP during AT₂ receptor stimulation is mediated by BK because BK B₂ receptor blockade inhibited this response.

	Acknowledgments

 
This study was supported by grants HL-47669 and HL-57503 (H.M.S.) and HL-49575 (R.M.C.) from the National Institutes of Health. H.M.S. was the recipient of Research Career Development Award K04-HL-03006 from the National Institutes of Health.

Received August 13, 1999; first decision October 13, 1999; accepted January 3, 2000.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Navar GL, Imig ID, Zou L, Wang CT. Intrarenal production of angiotensin II. Semin Nephrol. 1997;17:412–422.[Medline] [Order article via Infotrieve]
2. Campbell DJ. Endogenous angiotensin II levels and the mechanism of action of angiotensin converting enzyme inhibitors and angiotensin receptor type 1 antagonists. Clin Exp Pharmacol Physiol Suppl.. 1996;3:S125–S131.[Medline] [Order article via Infotrieve]
3. Fricker AF, Nussberger J, Meilenbrock S, Brunner HR, Burnier M. Effect of indomethacin on the renal response to angiotensin II receptor blockade in healthy subjects. Kidney Int. 1998;54:2089–2097.
4. Siragy HM. Evidence that intrarenal bradykinin plays a role in regulation of renal function. Am J Physiol. 1993;265:E648–E654.[Abstract/Free Full Text]
5. Siragy HM, Carey RM. The subtype-2 (AT₂) angiotensin receptor regulates renal cyclic guanosine 3', 5'-monophosphate and AT₁ receptor-mediated prostaglandin E₂. J Clin Invest. 1996;97:1978–1982.[Medline] [Order article via Infotrieve]
6. Siragy HM, Carey RM. The subtype-2 (AT₂) angiotensin receptor mediates renal production of nitric oxide in conscious rats. J Clin Invest. 1997;100:264–269.[Medline] [Order article via Infotrieve]
7. Siragy HM, Carey RM. Protective role of the angiotensin AT₂ receptor in a renal wrap hypertension model. Hypertension. 1999;33:1237–1242.[Abstract/Free Full Text]
8. Sealy JE, Laragh JH. How to do a plasma renin assay. Cardiovasc Med. 1980;20:947–957.
9. Wirth K, Hock FJ, Albus U, Linz W, Albermann HG, Anagnostopoulos H, Henke ST, Breipohl G, König W, Knolle J, Schölkens BA. HOE 140, a new potent and long acting bradykinin antagonist: in vivo studies. Br J Pharmacol. 1991;102:774–777.[Medline] [Order article via Infotrieve]
10. Siragy HM, Howell NL, Ragsdale NV, Carey RM. Renal interstitial fluid angiotensin modulation by anesthesia, epinephrine, sodium depletion, and renin inhibition. Hypertension. 1995;25:1021–1024.[Abstract/Free Full Text]
11. Siragy HM, Ibrahim MM, Jaffa AA, Mayfield R, Margolius HS. Rat renal interstitial bradykinin, prostaglandin E₂, and cyclic guanosine 3',5'-monophosphate: effects of altered sodium intake. Hypertension. 1994;23:1068–1070.[Abstract/Free Full Text]
12. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333:664–666.[Medline] [Order article via Infotrieve]
13. Bunkenburg B, Schnell C, Baum HP, Cumin F, Wood JM. Prolonged angiotensin II antagonism in spontaneously hypertensive rats: hemodynamic and biochemical consequences. Hypertension. 1991;18:278–288.[Abstract/Free Full Text]
14. Carretero OA, Scicli AG. The renal kallikrein-kinin system. Am J Physiol. 1980;238:F247–F255.
15. Fulton D, McGiff JC, Quilley J. Contribution of NO and cytochrome P450 to the vasodilator effect of bradykinin in the rat kidney. Br J Pharmacol. 1992;107:722–725.[Medline] [Order article via Infotrieve]
16. Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin receptor blockade on the response to angiotensin converting enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med. 1998;339:1285–1292.[Abstract/Free Full Text]
17. Yoshiaki Tsutsumi, Hiroaki Matsubara, Hiroya Masaki, Hiroki Kurihara, Satoshi Murasawa, Shinji Takai, Mizuo Miyazaki, Yoshihisa Nozawa, Ryoji Ozono, Keigo Nakagawa, et al. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest. 1999;104:925–935.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				J. P Collister and D. B Nahey Changing dietary sodium alters the chronic cardiovascular effects of losartan in rats Journal of Renin-Angiotensin-Aldosterone System, March 1, 2008; 9(1): 10 - 16. [Abstract] [PDF]

				F. Palm, S. G. Connors, M. Mendonca, W. J. Welch, and C. S. Wilcox Angiotensin II Type 2 Receptors and Nitric Oxide Sustain Oxygenation in the Clipped Kidney of Early Goldblatt Hypertensive Rats Hypertension, February 1, 2008; 51(2): 345 - 351. [Abstract] [Full Text] [PDF]

				D. C. Isbell, S. Voros, Z. Yang, J. M. DiMaria, S. S. Berr, B. A. French, F. H. Epstein, S. P. Bishop, H. Wang, R. J. Roy, et al. Interaction between bradykinin subtype 2 and angiotensin II type 2 receptors during post-MI left ventricular remodeling Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3372 - H3378. [Abstract] [Full Text] [PDF]

				E. Messadi-Laribi, V. Griol-Charhbili, A. Pizard, M.-P. Vincent, D. Heudes, P. Meneton, F. Alhenc-Gelas, and C. Richer Tissue Kallikrein Is Involved in the Cardioprotective Effect of AT1-Receptor Blockade in Acute Myocardial Ischemia J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 210 - 216. [Abstract] [Full Text] [PDF]

				H. M. Siragy, T. Inagami, and R. M. Carey NO and cGMP mediate angiotensin AT2 receptor-induced renal renin inhibition in young rats Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1461 - R1467. [Abstract] [Full Text] [PDF]

				M. A. F. de Godoy and S. Rattan Translocation of AT1- and AT2-Receptors by Higher Concentrations of Angiotensin II in the Smooth Muscle Cells of Rat Internal Anal Sphincter J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1088 - 1095. [Abstract] [Full Text] [PDF]

				N. W. Rajapakse, G. A. Eppel, R. E. Widdop, and R. G. Evans ANG II type 2 receptors and neural control of intrarenal blood flow Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2006; 291(6): R1669 - R1676. [Abstract] [Full Text] [PDF]

				P. M. Abadir, A. Periasamy, R. M. Carey, and H. M. Siragy Angiotensin II Type 2 Receptor-Bradykinin B2 Receptor Functional Heterodimerization Hypertension, August 1, 2006; 48(2): 316 - 322. [Abstract] [Full Text] [PDF]

				L. M. Duke, R. G. Evans, and R. E Widdop AT2 receptors contribute to acute blood pressure-lowering and vasodilator effects of AT1 receptor antagonism in conscious normotensive but not hypertensive rats Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2289 - H2297. [Abstract] [Full Text] [PDF]

				P. E. Walters, T. A. Gaspari, and R. E. Widdop Angiotensin-(1-7) Acts as a Vasodepressor Agent Via Angiotensin II Type 2 Receptors in Conscious Rats Hypertension, May 1, 2005; 45(5): 960 - 966. [Abstract] [Full Text] [PDF]

				K. Alfakih, R. A. Lawrance, A. Maqbool, K. Walters, S. G. Ball, A. J. Balmforth, and A. S. Hall The clinical significance of a common, functional, X-linked angiotensin II type 2-receptor gene polymorphism (-1332 G/A) in a cohort of 509 families with premature coronary artery disease Eur. Heart J., March 2, 2005; 26(6): 584 - 589. [Abstract] [Full Text] [PDF]

				D. You, L. Loufrani, C. Baron, B. I. Levy, R. E. Widdop, and D. Henrion High Blood Pressure Reduction Reverses Angiotensin II Type 2 Receptor-Mediated Vasoconstriction Into Vasodilation in Spontaneously Hypertensive Rats Circulation, March 1, 2005; 111(8): 1006 - 1011. [Abstract] [Full Text] [PDF]

				H. M. Siragy, C. Xue, P. Abadir, and R. M. Carey Angiotensin Subtype-2 Receptors Inhibit Renin Biosynthesis and Angiotensin II Formation Hypertension, January 1, 2005; 45(1): 133 - 137. [Abstract] [Full Text] [PDF]

				C. M. Bove, Z. Yang, W. D. Gilson, F. H. Epstein, B. A. French, S. S. Berr, S. P. Bishop, H. Matsubara, R. M. Carey, and C. M. Kramer Nitric Oxide Mediates Benefits of Angiotensin II Type 2 Receptor Overexpression During Post-Infarct Remodeling Hypertension, March 1, 2004; 43(3): 680 - 685. [Abstract] [Full Text] [PDF]

				P. M. Abadir, R. M. Carey, and H. M. Siragy Angiotensin AT2 Receptors Directly Stimulate Renal Nitric Oxide in Bradykinin B2-Receptor-Null Mice Hypertension, October 1, 2003; 42(4): 600 - 604. [Abstract] [Full Text] [PDF]

				C. M. B. Helou, M. Imbert-Teboul, A. Doucet, R. Rajerison, C. Chollet, F. Alhenc-Gelas, and J. Marchetti Angiotensin receptor subtypes in thin and muscular juxtamedullary efferent arterioles of rat kidney Am J Physiol Renal Physiol, September 1, 2003; 285(3): F507 - F514. [Abstract] [Full Text] [PDF]

				B. K Irons and A. Kumar Valsartan-Induced Angioedema Ann. Pharmacother., July 1, 2003; 37(7): 1024 - 1027. [Abstract] [Full Text] [PDF]

				R. M. Carey and H. M. Siragy Newly Recognized Components of the Renin-Angiotensin System: Potential Roles in Cardiovascular and Renal Regulation Endocr. Rev., June 1, 2003; 24(3): 261 - 271. [Abstract] [Full Text] [PDF]

				A. Nap, J. C Balt, M. Pfaffendorf, and P. A van Zwieten No involvement of the AT2-receptor in angiotensin II-enhanced sympathetic transmission in vitro Journal of Renin-Angiotensin-Aldosterone System, June 1, 2003; 4(2): 100 - 105. [Abstract] [PDF]

				J. P. Collister and M. D. Hendel Role of the Subfornical Organ in the Chronic Hypotensive Response to Losartan in Normal Rats Hypertension, March 1, 2003; 41(3): 576 - 582. [Abstract] [Full Text] [PDF]

				S. Nakamura, D. B. Averill, M. C. Chappell, D. I. Diz, K. B. Brosnihan, and C. M. Ferrario Angiotensin receptors contribute to blood pressure homeostasis in salt-depleted SHR Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R164 - R173. [Abstract] [Full Text] [PDF]

				R. E. Widdop, K. Matrougui, B. I. Levy, and D. Henrion AT2 Receptor-Mediated Relaxation Is Preserved After Long-Term AT1 Receptor Blockade Hypertension, October 1, 2002; 40(4): 516 - 520. [Abstract] [Full Text] [PDF]

				J. C Balt, M.-J. Mathy, A. Nap, M. Pfaffendorf, and P. A van Zwieten Involvement of the AT2-receptor in angiotensin II-induced facilitation of sympathetic neurotransmission Journal of Renin-Angiotensin-Aldosterone System, September 1, 2002; 3(3): 181 - 187. [Abstract] [PDF]

				S. Phoon and L. G. Howes Forearm vasodilator response to angiotensin II in elderly women receiving candesartan: role of AT2- receptors Journal of Renin-Angiotensin-Aldosterone System, March 1, 2002; 3(1): 36 - 39. [Abstract] [PDF]

				L. Wu, M. Iwai, H. Nakagami, R. Chen, J. Suzuki, M. Akishita, M. de Gasparo, and M. Horiuchi Effect of Angiotensin II Type 1 Receptor Blockade on Cardiac Remodeling in Angiotensin II Type 2 Receptor Null Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 49 - 54. [Abstract] [Full Text] [PDF]

				C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2337 - H2365. [Abstract] [Full Text] [PDF]

				R. M. Carey, N. L. Howell, X.-H. Jin, and H. M. Siragy Angiotensin Type 2 Receptor-Mediated Hypotension in Angiotensin Type-1 Receptor-Blocked Rats Hypertension, December 1, 2001; 38(6): 1272 - 1277. [Abstract] [Full Text] [PDF]

				L. Wu, M. Iwai, H. Nakagami, Z. Li, R. Chen, J. Suzuki, M. Akishita, M. de Gasparo, and M. Horiuchi Roles of Angiotensin II Type 2 Receptor Stimulation Associated With Selective Angiotensin II Type 1 Receptor Blockade With Valsartan in the Improvement of Inflammation-Induced Vascular Injury Circulation, November 27, 2001; 104(22): 2716 - 2721. [Abstract] [Full Text] [PDF]

				H. M. Siragy, M. de Gasparo, M. El-Kersh, and R. M. Carey Angiotensin-Converting Enzyme Inhibition Potentiates Angiotensin II Type 1 Receptor Effects on Renal Bradykinin and cGMP Hypertension, August 1, 2001; 38(2): 183 - 186. [Abstract] [Full Text] [PDF]

				J. Varagic, D. Susic, and E. D. Frohlich Coronary Hemodynamic and Ventricular Responses to Angiotensin Type 1 Receptor Inhibition in SHR : Interaction With Angiotensin Type 2 Receptors Hypertension, June 1, 2001; 37(6): 1399 - 1403. [Abstract] [Full Text] [PDF]

				A. F. Moore, N. T. Heiderstadt, E. Huang, N. L. Howell, Z.-Q. Wang, H. M. Siragy, and R. M. Carey Selective Inhibition of the Renal Angiotensin Type 2 Receptor Increases Blood Pressure in Conscious Rats Hypertension, May 1, 2001; 37(5): 1285 - 1291. [Abstract] [Full Text] [PDF]

				P. S Sever and C. Limmie Chang Discordant responses to two classes of drugs acting on the renin-angiotensin system Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1): 25 - 30. [Abstract] [PDF]

				Z. J. Cheng, T. Vaskonen, I. Tikkanen, K. Nurminen, H. Ruskoaho, H. Vapaatalo, D. Muller, J.-K. Park, F. C. Luft, and E. M. A. Mervaala Endothelial Dysfunction and Salt-Sensitive Hypertension in Spontaneously Diabetic Goto-Kakizaki Rats Hypertension, February 1, 2001; 37(2): 433 - 439. [Abstract] [Full Text] [PDF]