Renal actions of the selective angiotensin AT2 receptor ligands CGP 42112B and PD 123319 in the sodium-depleted rat

Macari, David; Bottari, Serge P.; Whitebread, Steven; Gasparo, Marc de; Levens, Nigel

doi:10.1016/0014-2999(93)90665-5

Cited by 81 publications

(81 citation statements)

References 16 publications

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“…[7][8][9] However, the results of pharmacological studies in the anaesthetised cat and rat and in the sodium-depleted rat do not support a role for AT 2 -receptors. [10][11][12][13][14] In an attempt to characterise acute haemodynamic responses to Ang II and to define the role of AT 1 -and AT 2 -receptors and the autonomic nervous system in mediating pressor responses to Ang II in the mouse (a species in which less is known), the effects of candesartan and of PD 123319, AT 1 -and AT 2 -receptor antagonists, respectively, and of autonomic blocking agents on increases in systemic arterial pressure and total peripheral resistance in response to Ang II were investigated in anaesthetised CD1 mice.…”

Section: Introductionmentioning

confidence: 99%

Analysis of responses to angiotensin II in the mouse

Bivalacqua

Champion

Hyman

et al. 2001

J Renin Angiotensin Aldosterone Syst

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Responses to angiotensin II (Ang II) were investigated in anaesthetised CD1 mice. Injections of Ang II caused dose-related increases in systemic arterial pressure that were antagonised by candesartan. Responses to Ang II were not altered by PD 123319. At the lowest dose studied (20 µg/kg i.v.), the inhibitory effects of candesartan were competitive, whereas at the highest dose (100 µg/kg i.v.), the dose-response curve for Ang II was shifted to the right in a non-parallel manner. The inhibitory effects of candesartan were selective and were similar in animals pretreated with enalaprilat to reduce endogenous Ang II production. Pressor responses to Ang II were not altered by propranolol, phentolamine or atropine, but were enhanced by hexamethonium. Increases in total peripheral resistance were inhibited by the AT 1 -receptor antagonist (ARB) but were not altered by AT 2 -receptor, alpha-or beta-receptor antagonists. These results suggest that pressor responses to Ang II are mediated by AT 1 -receptors, are buffered by the baroreceptors, are not modulated by effects on AT 2 -receptors, and that activation of the sympathetic nervous system plays little role in mediating rapid haemodynamic responses to the peptide in anaesthetised mice. IntroductionAngiotensin II (Ang II) plays an important role in regulating arterial pressure, sodium, and water balance.1 Ang II binds with high affinity to AT 1 -and AT 2 -receptors.2-4 Ang II-induced increases in systemic arterial pressure and the release of aldosterone are mediated by AT 1 -receptors, whereas less is known about the role of the AT 2 -receptor in the regulation of cardiovascular function.2-4 AT 1 -receptors are widely distributed, and AT 1 -antagonists are effective in the treatment of hypertension and congestive heart failure.5 AT 2 -receptors are highly expressed in the foetus and are downregulated with time, suggesting that they are involved in growth and development.

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Section: Introductionmentioning

confidence: 99%

Analysis of responses to angiotensin II in the mouse

Bivalacqua

Champion

Hyman

et al. 2001

J Renin Angiotensin Aldosterone Syst

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“…Furthermore, bradykinin receptor participates in Ang 1-7 effect (15,30). Infusion of AT2R antagonist; PD123319 at 1, 10, and 100 mg/kg/ min does not significantly affect either blood pressure or any parameter of renal hemodynamics measured (21). The dose of PD123319 in our study was 1 mg/kg/h, therefore, it was assumed that decrease in MAP, RPP, and RVR was not related to the PD123319.…”

Section: Discussionmentioning

confidence: 62%

Role of Mas receptor antagonist (A779) in renal hemodynamics in condition of blocked angiotensin II receptors in rats

Mansoori

Oryan

Nematbakhsh

2016

Acta Physiologica Hungarica

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The vasodilatory effect of angiotensin 1–7 (Ang 1-7) is exerted in the vascular bed via Mas receptor (MasR) gender dependently. However, the crosstalk between MasR and angiotensin II (Ang II) types 1 and 2 receptors (AT1R and AT2R) may change some actions of Ang 1-7 in renal circulation. In this study by blocking AT1R and AT2R, the role of MasR in kidney hemodynamics was described. In anaesthetized male and female Wistar rats, the effects of saline as vehicle and MasR blockade (A779) were tested on mean arterial pressure (MAP), renal perfusion pressure (RPP), renal blood flow (RBF), and renal vascular resistance (RVR) when both AT1R and AT2R were blocked by losartan and PD123319, respectively. In male rats, when AT1R and AT2R were blocked, there was a tendency for the increase in RBF/wet kidney tissue weight (RBF/KW) to be elevated by A779 as compared with the vehicle (P=0.08), and this was not the case in female rats. The impact of MasR on renal hemodynamics appears not to be sexual dimorphism either when Ang II receptors were blocked. It seems that co-blockade of all AT1R, AT2R, and MasR may alter RBF/ KW in male more than in female rats. These findings support a crosstalk between MasR and Ang II receptors in renal circulation.

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“…32,33 There was no inhibition of AII binding to the renal membrane fraction by the AT 2 blocker until concentrations were reached at which the AT 2 blocker has been reported to bind to the AT 1 receptor. 22,29,34 The lack of detectable inhibition of AII binding to renal membranes by the AT 2 blocker (at 0.1-10 μM) occurred in both normal and irradiated animals, suggesting that the efficacy of the AT 2 blocker in radiation nephropathy was not due to radiation-induced upregulation of AT 2 receptors. The possibility that radiation-induced renal failure could lead to upregulation of AT 2 receptors, as it does in other forms of renal failure, 35 was not directly tested as the AT 2 blocker was used in these studies before frank radiation injury had occurred.…”

Section: Discussionmentioning

confidence: 96%

Role of the angiotensin II type-2 receptor in radiation nephropathy

Cohen

Fish

Sharma

et al. 2007

Translational Research

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Experimental studies have shown that blockade of the angiotensin II type-1 (AT 1 ) receptor is effective in the mitigation and treatment of radiation-induced chronic renal failure. We have shown that blockade of the angiotensin II type-2 (AT 2 ) receptor with PD-123319 also had a modest, but reproducible, beneficial effect in experimental radiation nephropathy, and that it might also augment the efficacy of an AT 1 blocker (L-158,809). Those studies could not exclude the possibility that the effects of AT 2 blockade were non-specific. The current studies confirm the efficacy of AT 2 blockade for mitigation of experimental radiation nephropathy, but paradoxically find no detectable level of AT 2 receptor binding in renal membranes. However, a bioassay showed that the circulating levels of the AT 2 blocker were orders-of-magnitude too low to block AT 1 receptors. We conclude that the effect of AT 2 blockade in radiation nephropathy cannot be explained by binding to the AT 1 receptor, and that the efficacy of the AT 1 blockade in the same model cannot be explained by unopposed overstimulation of the AT 2 receptor.Radiation-induced chronic renal failure is well-documented in subjects undergoing total body irradiation (TBI) for hematopoietic stem cell transplants, 1,2 and in subjects receiving radiolabeled biologicals for cancer therapy. 3,4 We and others have shown the benefit of blockade of the renin-angiotensin system in experimental 5-7 and clinical 8,9 radiation nephropathy. In a rat model of radiation nephropathy, the use of angiotensin II (AII) blockade, 5,6 or reciprocally the use of AII infusion, 10 have shown that the renin-angiotensin system is particularly important between one and three months after irradiation. Further, the efficacy of an AII type-1 (AT 1 ) receptor blocker strongly suggests that the mechanism of injury is via the AT 1 receptor. 5,9 It has been suggested that the benefit of the AT 1 receptor blockade might be via over-stimulation of the unblocked angiotensin II type-2 (AT 2 ) receptor. 11 This hypothesis implied that blockade of the AT 2 receptor would negate or even reverse the effects of AT 1 blockade. Initial studies in our model have shown that AT 2 blockade has a modest, but reproducible, beneficial effect in experimental radiation nephropathy. 12,13 A similar benefit of AT 2 blockade was found by Cao et al 14 in the remnant kidney model. However, these studies could not exclude the possibility that the effects of AT 2 blockade were non-specific, possibly via binding to the AT 1 receptor. We undertook studies to confirm the efficacy of AT 2 receptor blockade in experimental radiation nephropathy, and to elucidate the pharmacologic basis for this effect.Address for correspondence: Eric P. Cohen, Department of Medicine, Medical College of Wisconsin, 9200 W. Wisconsin Ave., Milwaukee, WI 53226, ecohen@mcw.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early ver...

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Renal actions of the selective angiotensin AT2 receptor ligands CGP 42112B and PD 123319 in the sodium-depleted rat

Cited by 81 publications

References 16 publications

Analysis of responses to angiotensin II in the mouse

Analysis of responses to angiotensin II in the mouse

Role of Mas receptor antagonist (A779) in renal hemodynamics in condition of blocked angiotensin II receptors in rats

Role of the angiotensin II type-2 receptor in radiation nephropathy

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