β-Arrestin-Biased Agonist Targeting the Brain AT1R (Angiotensin II Type 1 Receptor) Increases Aversion to Saline and Lowers Blood Pressure in Deoxycorticosterone Acetate-Salt Hypertension
Activation of central AT1Rs (angiotensin type 1 receptors) is required for the increased blood pressure, polydipsia, and salt intake in deoxycorticosterone acetate (DOCA)-salt hypertension. TRV120027 (TRV027) is an AT1R-biased agonist that selectively acts through β-arrestin. We hypothesized that intracerebroventricular administration of TRV027 would ameliorate the effects of DOCA-salt. In a neuronal cell line, TRV027 induced AT1aR internalization through dynamin and clathrin-mediated endocytosis. We next evaluated the effect of chronic intracerebroventricular infusion of TRV027 on fluid intake. We measured the relative intake of water versus various saline solutions using a 2-bottle choice paradigm in mice subjected to DOCA with a concomitant intracerebroventricular infusion of either vehicle, TRV027, or losartan. Sham mice received intracerebroventricular vehicle without DOCA. TRV027 potentiated DOCA-induced water intake in the presence or absence of saline. TRV027 and losartan both increased the aversion for saline-an effect particularly pronounced for highly aversive saline solutions. Intracerebroventricular Ang (angiotensin) II, but not TRV027, increased water and saline intake in the absence of DOCA. In a separate cohort, blood pressure responses to acute intracerebroventricular injection of vehicle, TRV, or losartan were measured by radiotelemetry in mice with established DOCA-salt hypertension. Central administration of intracerebroventricular TRV027 or losartan each caused a significant and similar reduction of blood pressure and heart rate. We conclude that administration of TRV027 a selective β-arrestin biased agonist directly into the brain increases aversion to saline and lowers blood pressure in a model of salt-sensitive hypertension. These data suggest that selective activation of AT1R β-arrestin pathways may be exploitable therapeutically.
| Errataetall: |
CommentIn: Hypertension. 2021 Feb;77(2):432-434. - PMID 33439733 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:77 |
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| Enthalten in: |
Hypertension (Dallas, Tex. : 1979) - 77(2021), 2 vom: 20. Feb., Seite 420-431 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zanaty, Mario [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 10.08.2021 Date Revised 03.08.2022 published: Print-Electronic CommentIn: Hypertension. 2021 Feb;77(2):432-434. - PMID 33439733 Citation Status MEDLINE |
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| doi: |
10.1161/HYPERTENSIONAHA.120.15793 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM318162679 |
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| 100 | 1 | |a Zanaty, Mario |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a β-Arrestin-Biased Agonist Targeting the Brain AT1R (Angiotensin II Type 1 Receptor) Increases Aversion to Saline and Lowers Blood Pressure in Deoxycorticosterone Acetate-Salt Hypertension |
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| 500 | |a Date Revised 03.08.2022 | ||
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| 500 | |a CommentIn: Hypertension. 2021 Feb;77(2):432-434. - PMID 33439733 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Activation of central AT1Rs (angiotensin type 1 receptors) is required for the increased blood pressure, polydipsia, and salt intake in deoxycorticosterone acetate (DOCA)-salt hypertension. TRV120027 (TRV027) is an AT1R-biased agonist that selectively acts through β-arrestin. We hypothesized that intracerebroventricular administration of TRV027 would ameliorate the effects of DOCA-salt. In a neuronal cell line, TRV027 induced AT1aR internalization through dynamin and clathrin-mediated endocytosis. We next evaluated the effect of chronic intracerebroventricular infusion of TRV027 on fluid intake. We measured the relative intake of water versus various saline solutions using a 2-bottle choice paradigm in mice subjected to DOCA with a concomitant intracerebroventricular infusion of either vehicle, TRV027, or losartan. Sham mice received intracerebroventricular vehicle without DOCA. TRV027 potentiated DOCA-induced water intake in the presence or absence of saline. TRV027 and losartan both increased the aversion for saline-an effect particularly pronounced for highly aversive saline solutions. Intracerebroventricular Ang (angiotensin) II, but not TRV027, increased water and saline intake in the absence of DOCA. In a separate cohort, blood pressure responses to acute intracerebroventricular injection of vehicle, TRV, or losartan were measured by radiotelemetry in mice with established DOCA-salt hypertension. Central administration of intracerebroventricular TRV027 or losartan each caused a significant and similar reduction of blood pressure and heart rate. We conclude that administration of TRV027 a selective β-arrestin biased agonist directly into the brain increases aversion to saline and lowers blood pressure in a model of salt-sensitive hypertension. These data suggest that selective activation of AT1R β-arrestin pathways may be exploitable therapeutically | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a angiotensin receptor | |
| 650 | 4 | |a beta-arrestin | |
| 650 | 4 | |a blood pressure | |
| 650 | 4 | |a drinking behavior | |
| 650 | 4 | |a hypertension | |
| 650 | 4 | |a renin-angiotensin system | |
| 650 | 7 | |a Angiotensin II Type 1 Receptor Blockers |2 NLM | |
| 650 | 7 | |a Oligopeptides |2 NLM | |
| 650 | 7 | |a Receptor, Angiotensin, Type 1 |2 NLM | |
| 650 | 7 | |a beta-Arrestins |2 NLM | |
| 650 | 7 | |a Desoxycorticosterone |2 NLM | |
| 650 | 7 | |a 40GP35YQ49 |2 NLM | |
| 650 | 7 | |a Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH |2 NLM | |
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| 650 | 7 | |a Losartan |2 NLM | |
| 650 | 7 | |a JMS50MPO89 |2 NLM | |
| 700 | 1 | |a Seara, Fernando A C |e verfasserin |4 aut | |
| 700 | 1 | |a Nakagawa, Pablo |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Guorui |e verfasserin |4 aut | |
| 700 | 1 | |a Mathieu, Natalia M |e verfasserin |4 aut | |
| 700 | 1 | |a Balapattabi, Kirthikaa |e verfasserin |4 aut | |
| 700 | 1 | |a Karnik, Sadashiva S |e verfasserin |4 aut | |
| 700 | 1 | |a Grobe, Justin L |e verfasserin |4 aut | |
| 700 | 1 | |a Sigmund, Curt D |e verfasserin |4 aut | |
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