Angiotensin II Type 2 Receptor–Mediated and Nitric Oxide–Dependent Renal Vasodilator Response to Compound 21 Unmasked by Angiotensin-Converting Enzyme Inhibition in Spontaneously Hypertensive Rats In Vivo

Brouwers, Sofie; Smolders, Ilse Julia; Massie, Ann; Dupont, Alain

doi:10.1161/hypertensionaha.112.00762

Cited by 34 publications

(23 citation statements)

References 38 publications

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“…This suggests that upregulation of renal vascular AT2R in hypertension is associated with a countervailing function opposing the increased AT1R-mediated tonic renal vasoconstriction. 9 Thus, the counter-regulatory function of AT1R and AT2R may occur in the vasculature of hypertensive rodents, as described previously in humans also. 10 This implies the need of AT1R blockade to obtain the therapeutic benefit of AT2R stimulation in the vasculature of hypertensive subjects and indirectly supports the existence of a cross-talk between Ang II receptor subtypes.…”

Section: Hypertensionsupporting

confidence: 52%

Impact of the Direct Angiotensin II Type 2 Receptor Stimulation on Renal Function

Savoia¹,

Volpe²

2014

Hypertension

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Section: Hypertensionsupporting

confidence: 52%

Impact of the Direct Angiotensin II Type 2 Receptor Stimulation on Renal Function

Savoia¹,

Volpe²

2014

Hypertension

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“…However, when given in combination with the AT 1 R antagonist, candesartan, C21 lowered arterial pressure in SHRs, 10 which fits with this hypothesis. The possibility also exists that high levels of endogenous AngII may result in significant AT 2 R stimulation and thus limit an additional vasodilator effect of C21 administration, as suggested recently by Brouwers et al 11 Similar to the present study, this group did not identify any significant effect of intravenous bolus doses of C21 on RBF in male SHRs, 11 which may reflect the presence of anesthesia, unlike other studies, 10 although AT 2 Rmediated vasodilatation occurred in anesthetized female SHRs in the current study. Interestingly, during combined angiotensin-converting-enzyme inhibition with captopril to inhibit the endogenous production of AngII, Brouwers et al 11 reported that C21 induced dose-dependent renal vasodilatation in male SHRs in the absence of any change in arterial pressure, thus supporting their proposition that the inhibition of endogenous AngII is required in male SHRs for AT 2 R-mediated vasodilatory responses to be manifest.…”

Section: Discussionmentioning

confidence: 96%

Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

et al. 2014

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378T he development and progression of hypertension differs between men and women. Before menopause, arterial pressure is lower in women than in men of similar age. 1 However, after menopause, this cardioprotection in women is lost, and a higher proportion of women than men have hypertension after the age of 65 years.1 Similar differences in arterial pressure control have been observed in other mammalian species, including spontaneously hypertensive rats (SHRs). 2,3These sex-related differences in the development of hypertension have been strongly linked to sexual dimorphism in the renin-angiotensin system (RAS), which plays a pivotal role in the long-term regulation of arterial pressure. 3,4 Classically, angiotensin II (AngII) acts via the angiotensin type 1 receptor (AT 1 R) to cause vasoconstriction and sodium retention. Activation of the pressor RAS is a key mediator in the development of hypertension, and drugs that target this system are mainstays of current antihypertensive therapy. More recently, a depressor arm of the RAS has been recognized, which counterbalances the actions of AngII at AT 1 R. AngII together with other biologically active angiotensin peptides, including angiotensin (1-7) and angiotensin III, interact with angiotensin type 2 receptor (AT 2 R) to evoke vasodilatation and natriuresis. Overwhelming evidence suggests that the depressor RAS is upregulated in women by estrogen, and this contributes to sexual dimorphism in arterial pressure control.3,4 It is, therefore, plausible that enhancement of the depressor RAS, and in particular the AT 2 R, may represent a novel therapeutic target in the treatment of hypertension, particularly in women.Our recent data from normotensive rats support the notion that AT 2 R plays an integral, yet sexually dimorphic, functional Abstract-Accumulating evidence suggests that the protective pathways of the renin-angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT 2 R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT 2 R stimulation to modulate renal function in hypertension, we examined the influence of the AT 2 R agonist, compound 21 (100-300 ng/kg per minute), on renal function in 18-to 19-weekold anesthetized male and female spontaneously hypertensive rats. AT 2 R stimulation significantly increased renal blood flow in female hypertensive rats (P Treatment <0.001), without influencing arterial pressure. For example, at 300 ng/kg per minute of compound 21, renal blood flow increased by 14.3±1.8% from baseline. Furthermore, at 300 ng/kg per minute of compound 21, a significant increase in urinary sodium excretion was observed in female hypertensive rats (+180±59% from baseline; P<0.05 versus vehicle-treated rats). This was seen in the absence of any major change in glomerular filtration rate, indicating that the natriuretic effects of AT 2 R stimulation were likely the result of altered renal tubular function. Conversely, we did not observe any sign...

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“…- C21 may have an impact on BP, depending upon whether blood pressure measurements are made in conscious or anaesthetised rats, because there are at least two examples of AT2R-mediated reductions in blood pressure in anaesthetised rats of strains/models (SHR, obese Zucker rats), in which in the conscious state blood pressure was not affected by AT2R-stimulation [13,16], while under anaesthesia it was [5,26]. …”

Section: Effects Of Systemic At2r Stimulation On Blood Pressure Controlmentioning

confidence: 99%

Angiotensin type 2 receptors: blood pressure regulation and end organ damage

Sumners

Kloet

Krause

et al. 2015

Current Opinion in Pharmacology

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In most situations, the angiotensin AT2-receptor (AT2R) mediates physiological actions opposing those mediated by the AT1-receptor (AT1R), including a vasorelaxant effect. Nevertheless, experimental evidence vastly supports that systemic application of AT2R-agonists is blood pressure neutral. However, stimulation of AT2R locally within the brain or the kidney apparently elicits a systemic blood pressure lowering effect. A systemic effect of AT2R stimulation on blood pressure can also be achieved, when the prevailing effect of continuous background AT1R-stimulation is attenuated by low-dose AT1R blockade. Despite a lack of effect on blood pressure, AT2R stimulation still protects from hypertensive end-organ damage. Current data and evidence therefore suggest that AT2R agonists will not be suitable as future anti-hypertensive drugs, but that they may well be useful for end-organ protection in combination with established anti-hypertensives.

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Angiotensin II Type 2 Receptor–Mediated and Nitric Oxide–Dependent Renal Vasodilator Response to Compound 21 Unmasked by Angiotensin-Converting Enzyme Inhibition in Spontaneously Hypertensive Rats In Vivo

Cited by 34 publications

References 38 publications

Impact of the Direct Angiotensin II Type 2 Receptor Stimulation on Renal Function

Impact of the Direct Angiotensin II Type 2 Receptor Stimulation on Renal Function

Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

Angiotensin type 2 receptors: blood pressure regulation and end organ damage

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