Evidence for functional expression of vascular angiotensin II type 2 receptors in patients with insulin resistance

Brillante, D.; O’Sullivan, Anthony J; Johnstone, Martina T; Howes, L. G.

doi:10.1111/j.1463-1326.2006.00678.x

Cited by 19 publications

(13 citation statements)

References 25 publications

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“…However, in the present study we show an interaction between AngII and BKB2R, possibly via AT2R activated by infused AngII, in young, AT1R-blocked healthy individuals, i.e., just in a condition associated with the lowest level of AT2R expression (Jones et al, 2008). On the other hand, in animal studies (Tsutsumi et al, 1999;Jones et al, 2008;Yayama and Okamoto, 2008), upregulation of AT2R may result from aging, vascular disease, and chronic AT1R blockade and in human clinical conditions as well, such as diabetes or insulin resistance (Savoia et al, 2007;Brillante et al, 2008;Jones et al, 2008). Thus, participation of BKB2R in the control of BP and UNaV under AT1R blockade, as shown by the limits of our model, may pertain to long-term conditions of elevated AngII, upregulated AT2R, and stimulated BK-NO-cAMP cascade, such as in ARB-treated patients.…”

Section: Discussionsupporting

confidence: 49%

Contribution of Bradykinin B2 Receptors to the Inhibition by Valsartan of Systemic and Renal Effects of Exogenous Angiotensin II in Salt-Repleted Humans

Musiari²,

Iori³

et al. 2010

J Pharmacol Exp Ther

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To investigate whether bradykinin (BK) participates in the inhibition of renal effects of exogenous angiotensin II (AngII) by AngII type 1 receptor (AT1R) blockade, eight salt-repleted volunteers underwent four p-aminohippurate-and inulin-based renal studies of AngII infusion at increasing rates of 0.625, 1.25, and 2.5 ng⅐kg⅐min Ϫ1 for 30 min. Studies 1 and 2 were preceded by 3 days of placebo, whereas studies 3 and 4 used 240 to 320 mg⅐day Ϫ1 valsartan. Bradykinin B2-type receptor (BKB2R) antagonist icatibant (50 g⅐kg Ϫ1 ) was coinfused in studies 2 and 4. Mean blood pressure (MBP), glomerular filtration rate (GFR), renal blood flow (RBF), and renal sodium excretion (UNaV) were measured. In study 1, MBP rose by 12.8%, UNaV decreased by 68%, and GFR and RBF also fell (p Ͻ 0.001 for all). In study 2, GFR and RBF fell as in study 1, but the rise in MBP and the fall in UNaV were accentuated [ϩ20.0%, analysis of variance (ANOVA), p Ͻ 0.02 versus study 1 and Ϫ80.0%, p Ͻ 0.05, respectively]. In study 3, AngII had no effects, and in study 4, renal hemodynamics remained unaffected, but MBP still rose and UNaV fell (ANOVA, p Ͻ 0.02 and 0.005 versus study 3, respectively). Icatibant accentuated AngII-induced changes in MBP and UNaV. Previous AT1R blockade prevented any systemic and renal effects of AngII, but significant changes in MBP and UNaV still followed AngII plus icatibant even after AT1R blockade. BK, through BKB2Rs, participates in the inhibitory action of AT1R blockers toward actions of exogenous AngII on MBP and UNaV in healthy humans.

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Section: Discussionsupporting

confidence: 49%

Contribution of Bradykinin B2 Receptors to the Inhibition by Valsartan of Systemic and Renal Effects of Exogenous Angiotensin II in Salt-Repleted Humans

Musiari²,

Iori³

et al. 2010

J Pharmacol Exp Ther

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“…Distinct contributions by both AT 1 and AT 2 receptor subtypes have been demonstrated in hypertensive rats that exhibited AT 1 -mediated changes in blood pressure but AT 2 -mediated SMC hypertrophy (9). Similar observations have been made in normotensive Sprague-Dawley rats, leading to speculation that the activation of both AT 1 and AT 2 receptors is necessary for the trophic and proliferative effects of ANG II (2).…”

mentioning

confidence: 53%

“…As a consequence, many studies of SMCs have not included an analysis of the AT 2 receptor and fewer details of its biological functions have thus been elucidated (25). Although adult aorta express a small but significant population of AT 2 receptors (5), AT 2 receptor expression is also influenced by cardiovascular disease states such as diabetes (1), hypertension (25), and heart failure (9).…”

mentioning

confidence: 99%

“…In this investigation, primary cultures of porcine SMCs derived from explants of coronary artery were used to determine more precisely the relationship between specific AT 1 and AT 2 receptor subtypes and the cellular processes coupled to cell growth. Both AT 1 and AT 2 receptor subtypes were found to contribute to the mitogenic actions of ANG II on vascular SMCs.…”

mentioning

confidence: 99%

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Both AT₁and AT₂receptors mediate proliferation and migration of porcine vascular smooth muscle cells

Louis

Saward

Zahradka

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Louis S, Saward L, Zahradka P. Both AT1 and AT2 receptors mediate proliferation and migration of porcine vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 301: H746 -H756, 2011. First published May 27, 2011 doi:10.1152/ajpheart.00431.2010.-Angiotensin receptor antagonists have shown clinical promise in modulating vascular disease, in part by limiting smooth muscle cell proliferation and migration. The majority of studies examining the contribution of these receptors have been undertaken in cells derived from rat aorta, which primarily express the ANG II type 1 (AT1) receptor. This investigation studied the relative contribution of AT1 and ANG II type 2 (AT2) receptors to the mitogenic program of porcine smooth muscle cells. Smooth muscle cells were derived from porcine coronary artery explants. The presence of both AT1 and AT2 receptors was demonstrated through ligand binding and RT-PCR analysis. Biochemical and cellular markers of proliferation were monitored in the presence of selective receptor antagonists. Smooth muscle cell migration was measured using both wound healing and Boyden chamber migration assays. Visualization of the AT1 and AT2 receptors in growing and quiescent porcine smooth muscle cells with epifluorescence microscopy demonstrated that their subcellular distribution varied with growth state. An examination with several growth assays revealed that both AT1-specific losartan and AT2-specific PD-123319 receptor antagonists inhibited ANG II-stimulated RNA and DNA synthesis, PCNA expression, and hyperplasia. ANG II induced both directional and nondirectional cell migration. AT1 receptor antagonist treatment significantly decreased ANG II-induced directional migration only, whereas AT2 receptor antagonist treatment significantly reduced both modes of migration. Interestingly, the focal adhesion kinase inhibitor PF-573228 also blocked migration but not proliferation. Furthermore, focal adhesion kinase activation in response to ANG II was prevented only by PD-123319, indicating that this activation is downstream of the AT2 receptor. The observed role of the AT2 receptor in ANG II-induced migration was confirmed with smooth muscle cells depleted of the AT2 receptor with short hairpin RNA treatment.focal adhesion kinase; angiotensin II types 1 and 2 receptors; losartan; PD-123319; PF-573228 EXCESSIVE SMOOTH MUSCLE CELL (SMC) growth has been implicated in the development and progression of cardiovascular diseases such as atherosclerosis and hypertension. A critical mediator of these disease processes is angiotensin II (ANG II), a biologically active peptide with a broad range of physiological effects on the cardiovascular system (8). The actions of ANG II are mediated by at least two different ANG II receptors, ANG II types 1 (AT 1 ) and 2 (AT 2 ) receptors; however, the AT 1 receptor is typically regarded as the primary mediator of the vascular response to ANG II. As a consequence, many studies of SMCs have not included an analysis of the AT 2 receptor and fewer details of its biological f...

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“…52 No signifi cant hemodynamic or arterial stiffness changes were demonstrated after PD123319 infusion, compared with placebo infusion. 53 In contrast, our study on individuals with HOMA-IR Ͼ 2 (a measure of insulin resistance) and age-and sex-matched NCs given the same dose of intravenous PD123319 (10 micrograms/min for 3 minutes), produced a signifi cantly greater increase in RI, or small to medium sized arterial stiffness with a concurrent rise in systemic vascular resistance index in INSR subjects 54 while no change occurred in normal controls (NCs). Interestingly, baseline RI levels were lower in the subjects with early INSR consistent with the hypothesis that increased activity of both AT2 and NO medicated mechanisms lead to a reduction in RI in early INSR.…”

mentioning

confidence: 70%

Arterial stiffness in insulin resistance: The role of nitric oxide and angiotensin II receptors

Brillante

O’Sullivan²,

Howes³

2008

VHRM

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Abstract:The insulin resistance syndrome (INSR) is associated with increased cardiovascular risk, and affects up to 25% of the Australian population aged Ͼ20 years. Increased arterial stiffness has been proposed as a common pathway by which INSR leads to increased cardiovascular risk. We have reviewed the role of nitric oxide (NO) and angiotensin II receptors in the modulation of arterial stiffness in the setting of insulin resistance. There is emerging evidence that early stages of INSR may be characterized by increased basal nitric oxide activity and increased activity of non-NO vasodilators such as endothelial derived hyperpolarization factor (EDHF) which is manifest by reduced arterial stiffness. Depletion of NO or ineffectiveness of NO mediated vasodilator mechanisms associated with the progression of INSR to type 2 diabetes may result in increased arterial stiffness, which predicts the development of cardiovascular disease. Thus in the early stages of INSR, increased NO and EDHF activity may represent compensatory mechanisms to early vascular damage. The renin-angiotensin system is activated in diseased vascular beds, with up regulation of the two known angiotensin II receptors: the angiotensin II type 1 receptor (AT1R) and the angiotensin II type 2 receptor (AT2R). Increased AT1R mediated activity in the vasculature is central to the development of increased arterial stiffness and is enhanced in INSR states. AT2R activity is increased in early in INSR and may contribute to the apparent increase in basal NO activity. AT1R blockade may therefore be valuable treatment for early INSR as antagonism of AT1 receptors would allow angiotensin II to act unopposed at AT2 receptors.

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Evidence for functional expression of vascular angiotensin II type 2 receptors in patients with insulin resistance

Abstract: The results suggest the functional expression of AT2 receptors in small vessels that determine the inflection of the digital volume pulse wave in patients with INSR, possibly as an indicator of early vascular damage.

Cited by 19 publications

References 25 publications

Contribution of Bradykinin B2 Receptors to the Inhibition by Valsartan of Systemic and Renal Effects of Exogenous Angiotensin II in Salt-Repleted Humans

Contribution of Bradykinin B2 Receptors to the Inhibition by Valsartan of Systemic and Renal Effects of Exogenous Angiotensin II in Salt-Repleted Humans

Both AT₁and AT₂receptors mediate proliferation and migration of porcine vascular smooth muscle cells

Arterial stiffness in insulin resistance: The role of nitric oxide and angiotensin II receptors

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Evidence for functional expression of vascular angiotensin II type 2 receptors in patients with insulin resistance

Abstract: The results suggest the functional expression of AT2 receptors in small vessels that determine the inflection of the digital volume pulse wave in patients with INSR, possibly as an indicator of early vascular damage.

Cited by 19 publications

References 25 publications

Contribution of Bradykinin B2 Receptors to the Inhibition by Valsartan of Systemic and Renal Effects of Exogenous Angiotensin II in Salt-Repleted Humans

Contribution of Bradykinin B2 Receptors to the Inhibition by Valsartan of Systemic and Renal Effects of Exogenous Angiotensin II in Salt-Repleted Humans

Both AT1and AT2receptors mediate proliferation and migration of porcine vascular smooth muscle cells

Arterial stiffness in insulin resistance: The role of nitric oxide and angiotensin II receptors

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Both AT₁and AT₂receptors mediate proliferation and migration of porcine vascular smooth muscle cells