AT2 receptors: beneficial counter-regulatory role in cardiovascular and renal function

Padia, Shetal H.; Carey, Robert M.

doi:10.1007/s00424-012-1146-3

Cited by 115 publications

(108 citation statements)

References 77 publications

(114 reference statements)

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“…This includes resistance vessels from the renal, mesenteric, uterine, adrenal, coronary, and peripheral circulations, as well as large capacitance vessels such as the aorta. 7 This observation of a sex-specific renal vascular response to C21 in the present study is consistent with our previous observations in rodents that AT 2 R plays a greater functional role in female than in male renal vasculature, providing protection against the vasoconstrictor effects of AngII. 5,6,8 Furthermore, our data support the notion that differences in the renal response to C21 between male and female SHRs is attributable to sex differences in renal AT 2 R expression.…”

Section: Discussionsupporting

confidence: 93%

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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Section: Discussionsupporting

confidence: 93%

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

et al. 2014

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“…9 In healthy adults the AT 2 receptor expression is low and mainly found in renal, cardiovascular, and brain tissues. 7,8 Notably, during certain pathological conditions, such as myocardial infarction, vascular injury, brain ischemia, renal failure, and cutaneous wounds, the AT 2 receptor expression is significantly up-regulated. 7,8 Recently, several studies conducted in experimental disease models have revealed that the selective potent AT 2 receptor agonist 1 acts as an anti-inflammatory agent and exerts pronounced tissue protective effects in particular in cardiovascular and renal disease.…”

Section: Abstract: At 2 Receptor Nonpeptide Ligands Agonist Antagomentioning

confidence: 99%

“…7,8 For example, receptor activation stimulates neurite outgrowth in neuronal cells, which is one of the first steps in neuronal differentiation.…”

mentioning

confidence: 99%

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands

Wallinder

Sköld

Botros

et al. 2014

ACS Med. Chem. Lett.

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Migration of the methylene imidazole side chain in the first reported selective drug-like AT 2 receptor agonist C21/M024 (1) delivered the AT 2 receptor antagonist C38/M132 (2). We now report that the AT 2 receptor antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein. KEYWORDS:AT 2 receptor, nonpeptide ligands, agonist, antagonist, C21/M024, C38/M132 T he sartans (angiotensin II receptor blockers, ABRs) have been on the market as antihypertensives for more than two decades and act as selective antagonists at the angiotensin II AT 1 receptor. More recently, the angiotensin AT 2 receptor has emerged as a new target for drug intervention.1−3 In 2004, the first selective and drug-like AT 2 receptor agonist C21/ M024 (1) was disclosed, 4 and thereafter, a series of structural analogues with agonistic properties have been reported. 5,6 The activation of the AT 2 receptor is known to render a large number of diverse biological responses. 7,8 For example, receptor activation stimulates neurite outgrowth in neuronal cells, which is one of the first steps in neuronal differentiation. 9In healthy adults the AT 2 receptor expression is low and mainly found in renal, cardiovascular, and brain tissues. 7,8 Notably, during certain pathological conditions, such as myocardial infarction, vascular injury, brain ischemia, renal failure, and cutaneous wounds, the AT 2 receptor expression is significantly up-regulated. 7,8 Recently, several studies conducted in experimental disease models have revealed that the selective potent AT 2 receptor agonist 1 acts as an anti-inflammatory agent and exerts pronounced tissue protective effects in particular in cardiovascular and renal disease. Hence, the compound has had a large impact on the view of the AT 2 receptor as a drug target.1,9−14 In addition, the AT 2 receptor is a promising drug target for antagonists. Thus, the AT 2 receptor antagonist EMA401 has demonstrated convincing efficacy data in patients suffering from neuropathic pain (postherpetic neuralgia) in a phase II study. 3 We discovered that migration of the methylene imidazole substituent of 1 from the para to the meta substitution pattern delivered a selective AT 2 receptor antagonist, compound C38/M132 (2) (Figure 1). 15,16 Thus, a minor structural alteration resulted in the interconversion of a selective AT 2 receptor agonist to a selective AT 2 receptor antagonist.Herein, we report the synthesis and biological evaluation of four AT 2 receptor ligands, the biphenyl derivatives, and regioisomers, 3, 4, 5, and 6 (Figure 2), and that the relative position of the imidazole and isobutyl substituent determines the functional outcome.The

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“…This could in turn lower the blood pressure. [46][47][48] With regard to kidney AT2 receptor activation, it has been shown to suppress renin biosynthesis. Because renin plasma levels were not significantly affected by the present protocol, it seems unlikely that peripheral renal AT2 receptors were activated in the present setting.…”

Section: 10mentioning

confidence: 99%

Intranasal Angiotensin II in Humans Reduces Blood Pressure When Angiotensin II Type 1 Receptors Are Blocked

et al. 2014

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T he peptide hormone angiotensin II (ANGII) displays a wide range of regulatory actions on blood pressure. Besides its systemic effects on the blood vessels and different organ systems, local ANGII is crucially involved in the central nervous regulation of blood pressure.1-6 ANGII receptors, mainly type 1 receptors (AT1) and also type 2 receptors (AT2), are expressed in several cerebral nuclei where they mediate effects of locally produced ANGII.7-10 Inhibition of central nervous ANGII synthesis reversed hypertension in spontaneously hypertensive rats. 11The differentiation of central nervous and peripheral actions of ANGII is important for understanding blood pressure homeostasis and the development of essential hypertension in humans. Peripheral ANGII increases blood pressure but cannot surpass the blood-brain barrier, except via the circumventricular organs (area postrema, organum vasculosum laminae terminalis).12,13 These structures express a magnitude of AT1 receptors and seem to serve as an interface gating effects of circulating ANGII to brain stem and hypothalamic nuclei (ie, nucleus tractus solitarius, supraoptic nucleus, and paraventricular nuclei). Such humoral ANGII input is known to increase tonic blood pressure levels by an upward resetting of the sympathetic baroreceptor reflex activity 2,14-17 and may also activate intrinsic hypothalamic neurohypophysial fiber pathways, inducing the release of vasopressin. 3,[18][19][20] When ANGII is directly injected into the nucleus tractus solitarius, the baroreceptor reflex is suppressed via activation of AT1 receptors. After intracerebral administration, however, pressor effects of ANGII were revealed to be variable and even contradictory depending on dose and location of the injection, therefore suggesting differential effects on blood pressure regulation. 3,4,9,10,19,[21][22][23][24] The intranasal administration of small peptide molecules represents an established approach to bypass the bloodbrain barrier in humans and to achieve direct central nervous effects. [25][26][27][28][29] These studies demonstrate that peptide molecules such as ANGII directly enter the cerebrospinal fluid after their intranasal administration without previous uptake to the blood but instead via diffusion along neuronal clefts in the nasal mucosa. Importantly, because of the relatively great amounts of substance administered to achieve central nervous effects of the peptide, it cannot be prevented that, rather than directly accessing the cerebrospinal fluid compartment, some portion of the substance spills over into the circulation. Peptide that enters the circulation might then mask direct central nervous effects after intranasal peptide administration. Thus, a viable approach to unravel direct brain effects of intranasal peptide administration is to combine this treatment with a peripherally acting receptor blocker of the peptide.Abstract-Intranasal administration of angiotensin II (ANGII) affects blood pressure in a mode different from intravenously administered ANGII via a d...

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AT2 receptors: beneficial counter-regulatory role in cardiovascular and renal function

Cited by 115 publications

References 77 publications

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

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

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands

Intranasal Angiotensin II in Humans Reduces Blood Pressure When Angiotensin II Type 1 Receptors Are Blocked

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AT2 receptors: beneficial counter-regulatory role in cardiovascular and renal function

Cited by 115 publications

References 77 publications

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

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

Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands

Intranasal Angiotensin II in Humans Reduces Blood Pressure When Angiotensin II Type 1 Receptors Are Blocked

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Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands