AT2 receptor-mediated relaxation is preserved after long-term AT1 receptor blockade
Identifieur interne : 00B842 ( Main/Exploration ); précédent : 00B841; suivant : 00B843AT2 receptor-mediated relaxation is preserved after long-term AT1 receptor blockade
Auteurs : Robert E. Widdop [Australie] ; Khalid Matrougui [France] ; Bernard I. Levy [France] ; Daniel Henrion [France]Source :
- Hypertension : (Dallas, Tex. 1979) [ 0194-911X ] ; 2002.
Descripteurs français
- Pascal (Inist)
- Angiotensine II, Récepteur angiotensine AT2, Long terme, Relation concentration activité, Cilexétil, Traitement, Candésartan, Chimiothérapie, Efficacité traitement, Vasodilatation, Exploration, Artère, Mésentère, Rat, Animal, Hémodynamique, Activité biologique, Mécanisme action, Peptide, Benzimidazole dérivé, Biphényle dérivé.
English descriptors
- KwdEn :
- AT2 angiotensin receptor, Activity concentration relation, Angiotensin II, Animal, Artery, Benzimidazole derivatives, Biological activity, Biphenyl derivatives, Candesartan, Chemotherapy, Cilexetil, Exploration, Hemodynamics, Long term, Mechanism of action, Mesentery, Peptides, Rat, Treatment, Treatment efficiency, Vasodilation.
Abstract
Angiotensin II type 2 receptor (AT2R) stimulation may cause vasodilation per se and may contribute to the antihypertensive effect produced by Angiotensin II type 1 receptor (AT1R) antagonists, given that AT1R blockade increases endogenous levels of Ang II, suggesting a physiological role for the unblocked AT2R. Thus, we first directly assessed whether or not there is desensitization to AT2R-mediated vasorelaxation because this is an important consideration, given the raised Ang II levels and the marked desensitization that is known to occur after AT1R stimulation. Second, we examined if AT2R-mediated vasorelaxation is preserved after long-term treatment with the AT1R antagonist candesartan cilexetil. Consecutive concentration-response curves to AT2R stimulation, with either Ang II (with AT1R blockade) or the selective agonist CGP42112, were studied in rat isolated mesenteric resistance arteries mounted in an arteriograph. AT2R stimulation with Ang II induced a concentration-dependent relaxation without desensitization. Similarly, CGP42112 evoked highly reproducible relaxation, which, like Ang II, was abolished by the AT2R antagonist PD123319. By contrast, AT1R-mediated contraction exhibited marked desensitization. In rats treated with candesartan cilexetil (2 mg/kg per day for 2 weeks), AT1R-mediated contraction was abolished, whereas AT2R-mediated relaxation evoked by either Ang II or CGP42112 was highly reproducible, PD123319-sensitive, and of a magnitude similar to that observed in naïve animals. Therefore, this study has provided unequivocal evidence for the reproducible nature of AT2R-mediated vasorelaxation during short-term and long-term AT1R blockade. Such preservation of AT2R function is a prerequisite for the consideration of physiological role(s) of AT2R during AT1R blockade.
Affiliations:
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Widdop</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmacology, Monash University</s1><s2>Melbourne, Victoria</s2><s3>AUS</s3><sZ>1 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Melbourne, Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Matrougui, Khalid" sort="Matrougui, Khalid" uniqKey="Matrougui K" first="Khalid" last="Matrougui">Khalid Matrougui</name><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>INSERM U541, IFR Circulation-Paris-Nord Paris VII University</s1><s2>Paris</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Levy, Bernard I" sort="Levy, Bernard I" uniqKey="Levy B" first="Bernard I." last="Levy">Bernard I. Levy</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Department of Physiology, AP-HP-Hôpital Lariboisière</s1><s2>Paris</s2><s3>FRA</s3><sZ>3 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Henrion, Daniel" sort="Henrion, Daniel" uniqKey="Henrion D" first="Daniel" last="Henrion">Daniel Henrion</name><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>INSERM U541, IFR Circulation-Paris-Nord Paris VII University</s1><s2>Paris</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author></analytic><series><title level="j" type="main">Hypertension : (Dallas, Tex. 1979)</title><title level="j" type="abbreviated">Hypertension : (Dallas Tex., 1979)</title><idno type="ISSN">0194-911X</idno><imprint><date when="2002">2002</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Hypertension : (Dallas, Tex. 1979)</title><title level="j" type="abbreviated">Hypertension : (Dallas Tex., 1979)</title><idno type="ISSN">0194-911X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>AT2 angiotensin receptor</term><term>Activity concentration relation</term><term>Angiotensin II</term><term>Animal</term><term>Artery</term><term>Benzimidazole derivatives</term><term>Biological activity</term><term>Biphenyl derivatives</term><term>Candesartan</term><term>Chemotherapy</term><term>Cilexetil</term><term>Exploration</term><term>Hemodynamics</term><term>Long term</term><term>Mechanism of action</term><term>Mesentery</term><term>Peptides</term><term>Rat</term><term>Treatment</term><term>Treatment efficiency</term><term>Vasodilation</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Angiotensine II</term><term>Récepteur angiotensine AT2</term><term>Long terme</term><term>Relation concentration activité</term><term>Cilexétil</term><term>Traitement</term><term>Candésartan</term><term>Chimiothérapie</term><term>Efficacité traitement</term><term>Vasodilatation</term><term>Exploration</term><term>Artère</term><term>Mésentère</term><term>Rat</term><term>Animal</term><term>Hémodynamique</term><term>Activité biologique</term><term>Mécanisme action</term><term>Peptide</term><term>Benzimidazole dérivé</term><term>Biphényle dérivé</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Angiotensin II type 2 receptor (AT<sub>2</sub>R) stimulation may cause vasodilation per se and may contribute to the antihypertensive effect produced by Angiotensin II type 1 receptor (AT<sub>1</sub>R) antagonists, given that AT<sub>1</sub>R blockade increases endogenous levels of Ang II, suggesting a physiological role for the unblocked AT<sub>2</sub>R. Thus, we first directly assessed whether or not there is desensitization to AT<sub>2</sub>R-mediated vasorelaxation because this is an important consideration, given the raised Ang II levels and the marked desensitization that is known to occur after AT<sub>1</sub>R stimulation. Second, we examined if AT<sub>2</sub>R-mediated vasorelaxation is preserved after long-term treatment with the AT<sub>1</sub>R antagonist candesartan cilexetil. Consecutive concentration-response curves to AT<sub>2</sub>R stimulation, with either Ang II (with AT<sub>1</sub>R blockade) or the selective agonist CGP42112, were studied in rat isolated mesenteric resistance arteries mounted in an arteriograph. AT<sub>2</sub>R stimulation with Ang II induced a concentration-dependent relaxation without desensitization. Similarly, CGP42112 evoked highly reproducible relaxation, which, like Ang II, was abolished by the AT<sub>2</sub>R antagonist PD123319. By contrast, AT<sub>1</sub>R-mediated contraction exhibited marked desensitization. In rats treated with candesartan cilexetil (2 mg/kg per day for 2 weeks), AT<sub>1</sub>R-mediated contraction was abolished, whereas AT<sub>2</sub>R-mediated relaxation evoked by either Ang II or CGP42112 was highly reproducible, PD123319-sensitive, and of a magnitude similar to that observed in naïve animals. Therefore, this study has provided unequivocal evidence for the reproducible nature of AT<sub>2</sub>R-mediated vasorelaxation during short-term and long-term AT<sub>1</sub>R blockade. Such preservation of AT<sub>2</sub>R function is a prerequisite for the consideration of physiological role(s) of AT<sub>2</sub>R during AT<sub>1</sub>R blockade.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li></country><region><li>Île-de-France</li></region><settlement><li>Paris</li></settlement></list><tree><country name="Australie"><noRegion><name sortKey="Widdop, Robert E" sort="Widdop, Robert E" uniqKey="Widdop R" first="Robert E." last="Widdop">Robert E. Widdop</name></noRegion></country><country name="France"><region name="Île-de-France"><name sortKey="Matrougui, Khalid" sort="Matrougui, Khalid" uniqKey="Matrougui K" first="Khalid" last="Matrougui">Khalid Matrougui</name></region><name sortKey="Henrion, Daniel" sort="Henrion, Daniel" uniqKey="Henrion D" first="Daniel" last="Henrion">Daniel Henrion</name><name sortKey="Levy, Bernard I" sort="Levy, Bernard I" uniqKey="Levy B" first="Bernard I." last="Levy">Bernard I. 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