Activation of central angiotensin type 2 receptors by compound 21 improves arterial baroreflex sensitivity in rats with heart failure

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Abstract

BACKGROUND: In a previous study we demonstrated that central administration of compound 21 (C21), a nonpeptide AT2R agonist, inhibited sympathetic tone in normal rats. In this study, we hypothesized that C21 exerts a similar effect in rats with coronary ligation-induced heart failure (HF). METHODS: C21 was intracerebroventricularly infused for 7 days by osmotic minipump. Blood pressure (BP) and heart rate (HR) were recorded by radiotelemetry in the conscious state to measure spontaneous arterial baroreflex sensitivity. Urine was collected for measurement of norepinephrine excretion. On the last day of C21 treatment, renal sympathetic nerve activity, BP, and HR were directly recorded under anesthesia, and the induced arterial baroreflex sensitivity was evaluated. Protein expressions of neuronal nitric oxide synthase (nNOS) and angiotensin II type 1 receptor (AT1R) in the subfornical organ, paraventricular nucleus, rostral ventrolateral medulla, and nucleus tractus solitarius were determined by Western blot analysis. RESULTS: C21-treated HF rats displayed significantly less norepinephrine excretion (2,385.6 ± 121.1 vs. 3,677.3 ± 147.6 ng/24 hours; P < 0.05) and lower renal sympathetic nerve activity (50.2 ± 1.9% of max vs. 70.9 ± 8.2% of max; P < 0.05) than vehicle-treated HF rats. C21-treated rats also exhibited improved spontaneous arterial baroreflex sensitivity and induced arterial baroreflex sensitivity. Bolus intracerebroventricular injection of angiotensin II-evoked pressor and sympatho-excitatory responses were attenuated in the C21-treated HF rats, which displayed upregulated nNOS and downregulated AT1R expression in the subfornical organ, paraventricular nucleus, and rostral ventrolateral medulla. CONCLUSIONS: Activation of central angiotensin II type 2 receptor AT2R by C21 suppresses sympathetic outflow in rats with HF by improving baroreflex sensitivity and may provide important benefit in the HF syndrome.

Original languageEnglish (US)
Pages (from-to)1248-1256
Number of pages9
JournalAmerican Journal of Hypertension
Volume27
Issue number10
DOIs
StatePublished - Jan 1 2014

Fingerprint

Angiotensin Type 2 Receptor
Baroreflex
Heart Failure
Subfornical Organ
Nitric Oxide Synthase Type I
Angiotensin Type 1 Receptor
Paraventricular Hypothalamic Nucleus
Norepinephrine
Heart Rate
Blood Pressure
Kidney
Solitary Nucleus
Nitric Oxide Synthase Type II
Angiotensin II
Ligation
Down-Regulation
Anesthesia
Western Blotting
Urine
Injections

Keywords

  • Angiotensin type 2 receptor
  • Baroreflex
  • Blood pressure
  • Chronic heart failure
  • Compound 21
  • Hypertension

ASJC Scopus subject areas

  • Internal Medicine

Cite this

@article{1799e571ec324694aa6fb72d7b3c6a03,
title = "Activation of central angiotensin type 2 receptors by compound 21 improves arterial baroreflex sensitivity in rats with heart failure",
abstract = "BACKGROUND: In a previous study we demonstrated that central administration of compound 21 (C21), a nonpeptide AT2R agonist, inhibited sympathetic tone in normal rats. In this study, we hypothesized that C21 exerts a similar effect in rats with coronary ligation-induced heart failure (HF). METHODS: C21 was intracerebroventricularly infused for 7 days by osmotic minipump. Blood pressure (BP) and heart rate (HR) were recorded by radiotelemetry in the conscious state to measure spontaneous arterial baroreflex sensitivity. Urine was collected for measurement of norepinephrine excretion. On the last day of C21 treatment, renal sympathetic nerve activity, BP, and HR were directly recorded under anesthesia, and the induced arterial baroreflex sensitivity was evaluated. Protein expressions of neuronal nitric oxide synthase (nNOS) and angiotensin II type 1 receptor (AT1R) in the subfornical organ, paraventricular nucleus, rostral ventrolateral medulla, and nucleus tractus solitarius were determined by Western blot analysis. RESULTS: C21-treated HF rats displayed significantly less norepinephrine excretion (2,385.6 ± 121.1 vs. 3,677.3 ± 147.6 ng/24 hours; P < 0.05) and lower renal sympathetic nerve activity (50.2 ± 1.9{\%} of max vs. 70.9 ± 8.2{\%} of max; P < 0.05) than vehicle-treated HF rats. C21-treated rats also exhibited improved spontaneous arterial baroreflex sensitivity and induced arterial baroreflex sensitivity. Bolus intracerebroventricular injection of angiotensin II-evoked pressor and sympatho-excitatory responses were attenuated in the C21-treated HF rats, which displayed upregulated nNOS and downregulated AT1R expression in the subfornical organ, paraventricular nucleus, and rostral ventrolateral medulla. CONCLUSIONS: Activation of central angiotensin II type 2 receptor AT2R by C21 suppresses sympathetic outflow in rats with HF by improving baroreflex sensitivity and may provide important benefit in the HF syndrome.",
keywords = "Angiotensin type 2 receptor, Baroreflex, Blood pressure, Chronic heart failure, Compound 21, Hypertension",
author = "Juan Gao and Zucker, {Irving H} and Lie Gao",
year = "2014",
month = "1",
day = "1",
doi = "10.1093/ajh/hpu044",
language = "English (US)",
volume = "27",
pages = "1248--1256",
journal = "American Journal of Hypertension",
issn = "0895-7061",
publisher = "Oxford University Press",
number = "10",

}

TY - JOUR

T1 - Activation of central angiotensin type 2 receptors by compound 21 improves arterial baroreflex sensitivity in rats with heart failure

AU - Gao, Juan

AU - Zucker, Irving H

AU - Gao, Lie

PY - 2014/1/1

Y1 - 2014/1/1

N2 - BACKGROUND: In a previous study we demonstrated that central administration of compound 21 (C21), a nonpeptide AT2R agonist, inhibited sympathetic tone in normal rats. In this study, we hypothesized that C21 exerts a similar effect in rats with coronary ligation-induced heart failure (HF). METHODS: C21 was intracerebroventricularly infused for 7 days by osmotic minipump. Blood pressure (BP) and heart rate (HR) were recorded by radiotelemetry in the conscious state to measure spontaneous arterial baroreflex sensitivity. Urine was collected for measurement of norepinephrine excretion. On the last day of C21 treatment, renal sympathetic nerve activity, BP, and HR were directly recorded under anesthesia, and the induced arterial baroreflex sensitivity was evaluated. Protein expressions of neuronal nitric oxide synthase (nNOS) and angiotensin II type 1 receptor (AT1R) in the subfornical organ, paraventricular nucleus, rostral ventrolateral medulla, and nucleus tractus solitarius were determined by Western blot analysis. RESULTS: C21-treated HF rats displayed significantly less norepinephrine excretion (2,385.6 ± 121.1 vs. 3,677.3 ± 147.6 ng/24 hours; P < 0.05) and lower renal sympathetic nerve activity (50.2 ± 1.9% of max vs. 70.9 ± 8.2% of max; P < 0.05) than vehicle-treated HF rats. C21-treated rats also exhibited improved spontaneous arterial baroreflex sensitivity and induced arterial baroreflex sensitivity. Bolus intracerebroventricular injection of angiotensin II-evoked pressor and sympatho-excitatory responses were attenuated in the C21-treated HF rats, which displayed upregulated nNOS and downregulated AT1R expression in the subfornical organ, paraventricular nucleus, and rostral ventrolateral medulla. CONCLUSIONS: Activation of central angiotensin II type 2 receptor AT2R by C21 suppresses sympathetic outflow in rats with HF by improving baroreflex sensitivity and may provide important benefit in the HF syndrome.

AB - BACKGROUND: In a previous study we demonstrated that central administration of compound 21 (C21), a nonpeptide AT2R agonist, inhibited sympathetic tone in normal rats. In this study, we hypothesized that C21 exerts a similar effect in rats with coronary ligation-induced heart failure (HF). METHODS: C21 was intracerebroventricularly infused for 7 days by osmotic minipump. Blood pressure (BP) and heart rate (HR) were recorded by radiotelemetry in the conscious state to measure spontaneous arterial baroreflex sensitivity. Urine was collected for measurement of norepinephrine excretion. On the last day of C21 treatment, renal sympathetic nerve activity, BP, and HR were directly recorded under anesthesia, and the induced arterial baroreflex sensitivity was evaluated. Protein expressions of neuronal nitric oxide synthase (nNOS) and angiotensin II type 1 receptor (AT1R) in the subfornical organ, paraventricular nucleus, rostral ventrolateral medulla, and nucleus tractus solitarius were determined by Western blot analysis. RESULTS: C21-treated HF rats displayed significantly less norepinephrine excretion (2,385.6 ± 121.1 vs. 3,677.3 ± 147.6 ng/24 hours; P < 0.05) and lower renal sympathetic nerve activity (50.2 ± 1.9% of max vs. 70.9 ± 8.2% of max; P < 0.05) than vehicle-treated HF rats. C21-treated rats also exhibited improved spontaneous arterial baroreflex sensitivity and induced arterial baroreflex sensitivity. Bolus intracerebroventricular injection of angiotensin II-evoked pressor and sympatho-excitatory responses were attenuated in the C21-treated HF rats, which displayed upregulated nNOS and downregulated AT1R expression in the subfornical organ, paraventricular nucleus, and rostral ventrolateral medulla. CONCLUSIONS: Activation of central angiotensin II type 2 receptor AT2R by C21 suppresses sympathetic outflow in rats with HF by improving baroreflex sensitivity and may provide important benefit in the HF syndrome.

KW - Angiotensin type 2 receptor

KW - Baroreflex

KW - Blood pressure

KW - Chronic heart failure

KW - Compound 21

KW - Hypertension

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