AT<sub>2</sub> antagonist‐sensitive potentiation of angiotensin II‐induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature

Muller, Catherine; Endlich, Karlhans; Helwig, Jean-Jacques

doi:10.1038/sj.bjp.0701906

Cited by 23 publications

(25 citation statements)

References 38 publications

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“…Alternatively, an intact endothelium may be a prerequisite for the full expression of the pressor actions of Ang II. 27,28 Whether endothelial mediators like endothelin-1 or vasoconstrictor prostanoids might contribute to the pressor response to Ang II 29,30 requires further study.…”

Section: Discussionmentioning

confidence: 99%

Renin Uptake by the Endothelium Mediates Vascular Angiotensin Formation

et al. 2001

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Abstract-We investigated the role of the vascular endothelium in the local production of angiotensin. Angiotensin release from isolated rat hindquarters perfused with an artificial medium was measured by high-performance liquid chromatography and radioimmunoassay. Perfused hindquarters with endothelium released angiotensin I spontaneously, indicating ongoing renin-angiotensinogen reaction. Endothelium denudation (by a detergent, validated by electron microscopy and by the absence of a vasodilator response to acetylcholine) reduced angiotensin I release by Ͼ90%, whereas bilateral nephrectomy 24 hours before perfusion abolished the release completely. Infusion of renin into perfused hindquarters induced sustained local angiotensin I release in the presence of an intact endothelium but not after endothelium denudation. The conversion of angiotensin I to angiotensin II was abrogated by endothelium denudation, whereas the disappearance of angiotensin II was unchanged. Endothelium denudation diminished the pressor response to angiotensin II but abolished the response to renin and angiotensin I. Expression of renin messenger RNA, investigated by reverse-transcription polymerase chain reaction using 4 different primer combinations, was not detected in up to 5 g vascular RNA, whereas a renin signal was readily detected with 5 ng kidney RNA.

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Section: Discussionmentioning

confidence: 99%

Renin Uptake by the Endothelium Mediates Vascular Angiotensin Formation

et al. 2001

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“…31 However, many other reports support the vasodilator actions of the AT 2 receptor. 27,28,[32][33][34][35][36][37][38][39][40][41] Antisense oligonucleotide technology is a highly specific method of demonstrating the physiological action of a protein if an appropriate reduction in expression is observed. [42][43][44][45][46][47][48][49] In the present study, we were able to achieve an Ϸ40% reduction in AT 2 receptor protein in response to AS-ODN and no change in response to S-ODN.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of the Renal Angiotensin Type 2 Receptor Increases Blood Pressure in Conscious Rats

et al. 2001

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Abstract-The angiotensin II type 2 (AT 2 ) receptor is present in rat kidney; however, its function is not well understood.The purpose of this study was to evaluate the role of the AT 2 receptor in blood pressure (BP) regulation. The effects of selective inhibition of the renal AT 2 receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) were examined in conscious uninephrectomized rats. Oligodeoxynucleotides (AS-ODN or scrambled [S-ODN]) were infused directly into the renal interstitial space by using an osmotic pump at 1 L/h for 7 days. Texas red-labeled AS-ODN was distributed in renal tubules in the infused but not the contralateral kidney of normal rats. Continuous renal interstitial infusion of the AS-ODN, but not S-ODN, caused a significant (PϽ0.01) increase in BP 1 to 5 days after the initiation of the infusion. AS-ODN-treated rats experienced an increase in systolic BP from 109Ϯ4 to 130Ϯ4 mm Hg (nϭ8, PϽ0.01), whereas S-ODN-treated (nϭ8) and vehicle-treated (nϭ8) rats did not show any significant change in BP. On day 5 of the oligodeoxynucleotide infusion, AS-ODN-treated rats exhibited a greater pressor response to systemic angiotensin II infusion (30 ng/kg per hour) than did S-ODN-treated rats (PϽ0.01). Renal interstitial fluid cGMP decreased from 11.9Ϯ0.8 to 3.6Ϯ0.5 pmol/mL (PϽ0.001), and bradykinin decreased from 0.05Ϯ0.05 to 0.18Ϯ0.03 ng/mL (PϽ0.001) in response to AS-ODN, but they were not significantly changed in response to S-ODN. Key Words: blood pressure Ⅲ receptors, angiotensin II Ⅲ hypertension, experimental Ⅲ kidney Ⅲ rats A ngiotensin II (Ang II) is a vasoactive peptide that plays an important role in blood pressure (BP) regulation. Ang II exerts its physiological effects by interacting with 1 of 2 major Ang II receptors, AT 1 or AT 2 . The cDNAs that encode the AT 1 and AT 2 receptors have been cloned, and their cell-signaling pathways have been defined. Ang II has equal affinity for AT 1 and AT 2 receptors. The 2 receptors share a sequence homology of Ϸ34%, and their cDNAs are 91% identical in their nucleotide sequences within their coding regions but only 60% identical in their untranslated regions. Each receptor subtype has distinctive functional properties and cell-signaling mechanisms. 1 The vast majority of the known functions of Ang II result from its interaction with the AT 1 receptor, which mediates renal afferent and efferent arteriolar vasoconstriction, decreases glomerular filtration rate and renal plasma flow, and stimulates sodium and fluid reabsorption in the proximal tubules as well as cell growth and differentiation. [2][3][4][5] The AT 1 receptor has been localized to the brain, peripheral blood vessels, adrenal gland, heart, and kidney. 1,5 Relatively little is known about the AT 2 receptor compared with the AT 1 receptor. 6 AT 2 receptor mRNA has been localized to the rat adrenal gland, heart, and brain, and the receptor protein has been identified by immunohistochemistry and Western blot in rat kidney and heart. 7-11 AT 2 receptor expression is also known...

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“…33 In contrast, in the in situ perfused kidney, AT 2 R blockade decreases Ang II-dependent vasoconstriction when NO synthesis is inhibited. 34 From these in vivo or in situ perfused organs experiments, it can be deduced that AT 2 Rs play a weak role in the control of systemic blood pressure under normal physiological conditions. However, the AT 2 R likely plays a role in the local control of blood flow in several organs.…”

Section: Experimental Evidence Obtained In Vivo or In Situmentioning

confidence: 99%

“…13 In the kidney, AT 2 R-dependent contraction is proposed to involve CyP450 metabolites such as 20-HETE. 34,64 Mediators Involved in the AT 2 R-Mediated Dilation Although the aorta is not, per se, involved in the local control of blood flow, it is the most commonly used experimental model in the study of receptor function. Ang II increases cGMP content in the aorta from rabbits and rats.…”

Section: Mediators Involved In the At 2 R-mediated Contractionmentioning

confidence: 99%

Physiological and Pathophysiological Functions of the AT ₂ Subtype Receptor of Angiotensin II

2001

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Abstract-Angiotensin II exerts a potent role in the control of hemodynamic and renal homeostasis. Angiotensin II is also a local and biologically active mediator involved in both endothelial and smooth muscle cell function acting on 2 receptor subtypes: type 1 (AT 1 R) and type 2 (AT 2 R). Whereas the key role of AT 2 R in the development of the embryo has been extensively studied, the role of AT 2 R in the adult remains more questionable, especially in humans. In vitro studies in cultured cells and in isolated segments of aorta have shown that AT 2 R stimulation could lead to the production of vasoactive substances, among which NO is certainly the most cited, suggesting that acute AT 2 R stimulation will produce vasodilation. However, in different organs or in small arteries isolated from different type of tissues, other vasoactive substances may also mediate AT 2 R-dependent dilation. Sometimes, such as in large renal arteries, AT 2 R stimulation may lead to vasoconstriction, although it is not always seen. In isolated arteries submitted to physiological conditions of pressure and flow, AT 2 R stimulation may also have a role in shear stress-induced dilation through a endothelial production of NO. Thus, when acutely stimulated, the most probable response expected from AT 2 R stimulation will be a vasodilation. Therefore, in the perspective of a chronic AT 1 R blockade in patients, overstimulation of AT 2 R might be beneficial, given their potential vasodilator effect. Concerning the possible role of AT 2 R in cardiovascular remodeling, the situation is more controversial. In vitro AT 2 R stimulation clearly inhibits cardiac and vascular smooth muscle growth and proliferation, stimulates apoptosis, and promotes extra cellular matrix synthesis. In vivo, the situation might be less beneficial if not deleterious; indeed, if chronic AT 2 R overstimulation would lead to cardiovascular hypertrophy and fibrosis, then the long-term consequences of chronic AT 1 R blockade, and thus AT 2 R overstimulation, require more in-depth analysis. (Hypertension. 2001;38: 1150-1157.)

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AT₂ antagonist‐sensitive potentiation of angiotensin II‐induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature

Cited by 23 publications

References 38 publications

Renin Uptake by the Endothelium Mediates Vascular Angiotensin Formation

Renin Uptake by the Endothelium Mediates Vascular Angiotensin Formation

Selective Inhibition of the Renal Angiotensin Type 2 Receptor Increases Blood Pressure in Conscious Rats

Physiological and Pathophysiological Functions of the AT ₂ Subtype Receptor of Angiotensin II

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AT2 antagonist‐sensitive potentiation of angiotensin II‐induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature

Cited by 23 publications

References 38 publications

Renin Uptake by the Endothelium Mediates Vascular Angiotensin Formation

Renin Uptake by the Endothelium Mediates Vascular Angiotensin Formation

Selective Inhibition of the Renal Angiotensin Type 2 Receptor Increases Blood Pressure in Conscious Rats

Physiological and Pathophysiological Functions of the AT 2 Subtype Receptor of Angiotensin II

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AT₂ antagonist‐sensitive potentiation of angiotensin II‐induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature

Physiological and Pathophysiological Functions of the AT ₂ Subtype Receptor of Angiotensin II