AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure

Guo Qing Zhu, Lie Gao, Yifan Li, Kaushik P Patel, Irving H Zucker, Wei Wang

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73 Citations (Scopus)

Abstract

Previous studies showed that the cardiac sympathetic afferent reflex (CSAR) is enhanced in dogs and rats with chronic heart failure (CHF) and that central ANG II type 1 receptors (AT1R) are involved in this augmented reflex. The aim of this study was to determine whether intracerebroventricular administration and microinjection of antisense oligodeoxynucleotides targeted to AT1R mRNA would attenuate the enhanced CSAR and decrease resting renal sympathetic nerve activity (RSNA) in rats with coronary ligation-induced CHF. The CSAR was elicited by application of bradykinin to the epicardial surface of the left ventricle. Reflex responses to epicardial administration of bradykinin were enhanced in rats with CHF. The response to bradykinin was determined every 50 min after intracerebroventricular administration (lateral ventricle) or microinjection (into paraventricular nucleus) of antisense or scrambled oligonucleotides to AT1R mRNA. AT1R mRNA and protein levels in the paraventricular nucleus were significantly reduced 5 h after administration of antisense. Antisense significantly decreased resting RSNA and normalized the enhanced CSAR responses to bradykinin in rats with CHF. Scrambled oligonucleotides did not alter resting RSNA or the enhanced responses to bradykinin in rats with CHF. No significant effects were found in sham-operated rats after administration of either antisense or scrambled oligonucleotides. These results strongly suggest that central AT1R mRNA antisense reduces expression of AT1R protein and normalizes the augmentation of this excitatory sympathetic reflex and that genetic manipulation of protein expression can be used to normalize the sympathetic enhancement in CHF.

Original languageEnglish (US)
Pages (from-to)H1828-H1835
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume287
Issue number4 56-4
DOIs
StatePublished - Oct 1 2004

Fingerprint

Reflex
Heart Failure
Bradykinin
Messenger RNA
Oligonucleotides
Paraventricular Hypothalamic Nucleus
Microinjections
Kidney
Proteins
Oligodeoxyribonucleotides
Lateral Ventricles
Heart Ventricles
Ligation
Dogs

Keywords

  • Angiotensin II
  • Paraventricular nucleus
  • Renal sympathetic nerve activity

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

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title = "AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure",
abstract = "Previous studies showed that the cardiac sympathetic afferent reflex (CSAR) is enhanced in dogs and rats with chronic heart failure (CHF) and that central ANG II type 1 receptors (AT1R) are involved in this augmented reflex. The aim of this study was to determine whether intracerebroventricular administration and microinjection of antisense oligodeoxynucleotides targeted to AT1R mRNA would attenuate the enhanced CSAR and decrease resting renal sympathetic nerve activity (RSNA) in rats with coronary ligation-induced CHF. The CSAR was elicited by application of bradykinin to the epicardial surface of the left ventricle. Reflex responses to epicardial administration of bradykinin were enhanced in rats with CHF. The response to bradykinin was determined every 50 min after intracerebroventricular administration (lateral ventricle) or microinjection (into paraventricular nucleus) of antisense or scrambled oligonucleotides to AT1R mRNA. AT1R mRNA and protein levels in the paraventricular nucleus were significantly reduced 5 h after administration of antisense. Antisense significantly decreased resting RSNA and normalized the enhanced CSAR responses to bradykinin in rats with CHF. Scrambled oligonucleotides did not alter resting RSNA or the enhanced responses to bradykinin in rats with CHF. No significant effects were found in sham-operated rats after administration of either antisense or scrambled oligonucleotides. These results strongly suggest that central AT1R mRNA antisense reduces expression of AT1R protein and normalizes the augmentation of this excitatory sympathetic reflex and that genetic manipulation of protein expression can be used to normalize the sympathetic enhancement in CHF.",
keywords = "Angiotensin II, Paraventricular nucleus, Renal sympathetic nerve activity",
author = "Zhu, {Guo Qing} and Lie Gao and Yifan Li and Patel, {Kaushik P} and Zucker, {Irving H} and Wei Wang",
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T1 - AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure

AU - Zhu, Guo Qing

AU - Gao, Lie

AU - Li, Yifan

AU - Patel, Kaushik P

AU - Zucker, Irving H

AU - Wang, Wei

PY - 2004/10/1

Y1 - 2004/10/1

N2 - Previous studies showed that the cardiac sympathetic afferent reflex (CSAR) is enhanced in dogs and rats with chronic heart failure (CHF) and that central ANG II type 1 receptors (AT1R) are involved in this augmented reflex. The aim of this study was to determine whether intracerebroventricular administration and microinjection of antisense oligodeoxynucleotides targeted to AT1R mRNA would attenuate the enhanced CSAR and decrease resting renal sympathetic nerve activity (RSNA) in rats with coronary ligation-induced CHF. The CSAR was elicited by application of bradykinin to the epicardial surface of the left ventricle. Reflex responses to epicardial administration of bradykinin were enhanced in rats with CHF. The response to bradykinin was determined every 50 min after intracerebroventricular administration (lateral ventricle) or microinjection (into paraventricular nucleus) of antisense or scrambled oligonucleotides to AT1R mRNA. AT1R mRNA and protein levels in the paraventricular nucleus were significantly reduced 5 h after administration of antisense. Antisense significantly decreased resting RSNA and normalized the enhanced CSAR responses to bradykinin in rats with CHF. Scrambled oligonucleotides did not alter resting RSNA or the enhanced responses to bradykinin in rats with CHF. No significant effects were found in sham-operated rats after administration of either antisense or scrambled oligonucleotides. These results strongly suggest that central AT1R mRNA antisense reduces expression of AT1R protein and normalizes the augmentation of this excitatory sympathetic reflex and that genetic manipulation of protein expression can be used to normalize the sympathetic enhancement in CHF.

AB - Previous studies showed that the cardiac sympathetic afferent reflex (CSAR) is enhanced in dogs and rats with chronic heart failure (CHF) and that central ANG II type 1 receptors (AT1R) are involved in this augmented reflex. The aim of this study was to determine whether intracerebroventricular administration and microinjection of antisense oligodeoxynucleotides targeted to AT1R mRNA would attenuate the enhanced CSAR and decrease resting renal sympathetic nerve activity (RSNA) in rats with coronary ligation-induced CHF. The CSAR was elicited by application of bradykinin to the epicardial surface of the left ventricle. Reflex responses to epicardial administration of bradykinin were enhanced in rats with CHF. The response to bradykinin was determined every 50 min after intracerebroventricular administration (lateral ventricle) or microinjection (into paraventricular nucleus) of antisense or scrambled oligonucleotides to AT1R mRNA. AT1R mRNA and protein levels in the paraventricular nucleus were significantly reduced 5 h after administration of antisense. Antisense significantly decreased resting RSNA and normalized the enhanced CSAR responses to bradykinin in rats with CHF. Scrambled oligonucleotides did not alter resting RSNA or the enhanced responses to bradykinin in rats with CHF. No significant effects were found in sham-operated rats after administration of either antisense or scrambled oligonucleotides. These results strongly suggest that central AT1R mRNA antisense reduces expression of AT1R protein and normalizes the augmentation of this excitatory sympathetic reflex and that genetic manipulation of protein expression can be used to normalize the sympathetic enhancement in CHF.

KW - Angiotensin II

KW - Paraventricular nucleus

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