β3-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility

Paul Varghese, Robert W. Harrison, Robert A. Lofthouse, Dimitrios Georgakopoulos, Dan E. Berkowitz, Joshua Hare

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

The cardiac β-adrenergic pathway potently stimulates myocardial performance, thereby providing a mechanism for myocardial contractile reserve. β-Adrenergic activation also increases cardiac nitric oxide (NO) production, which attenuates positive inotropy, suggesting a possible negative feedback mechanism. Recently, in vitro studies suggest that stimulation of the β3-adrenoceptor results in a negative inotropic effect through NO signaling. In this study, using mice with homozygous β3-adrenoceptor deletion mutations, we tested the hypothesis that the β3-adrenoceptor is responsible for β-adrenergic activation of NO. Although resting indices of myocardial contraction were similar, β-adrenergic-stimulated inotropy was increased in β3(-/-) mice, and similar hyperresponsiveness was seen in mice lacking endothelial NO synthase (NOS3). NOS inhibition augmented isoproterenol-stimulated inotropy in wild-type (WT), but not in β3(-/-) mice. Moreover, isoproterenol increased myocardial cGMP in WT, but not β3(-/-), mice. NOS3 protein abundance was not changed in β3(-/-) mice, and cardiac β3-adrenoceptor mRNA was detected in both NOS3(-/-) and WT mice. These findings indicate that the β3-adrenergic subtype participates in NO-mediated negative feedback over β-adrenergic stimulation.

Original languageEnglish
Pages (from-to)697-703
Number of pages7
JournalJournal of Clinical Investigation
Volume106
Issue number5
StatePublished - Sep 1 2000
Externally publishedYes

Fingerprint

Adrenergic Receptors
Nitric Oxide
Adrenergic Agents
Isoproterenol
Myocardial Contraction
Nitric Oxide Synthase Type III
Sequence Deletion
Messenger RNA
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Varghese, P., Harrison, R. W., Lofthouse, R. A., Georgakopoulos, D., Berkowitz, D. E., & Hare, J. (2000). β3-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility. Journal of Clinical Investigation, 106(5), 697-703.

β3-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility. / Varghese, Paul; Harrison, Robert W.; Lofthouse, Robert A.; Georgakopoulos, Dimitrios; Berkowitz, Dan E.; Hare, Joshua.

In: Journal of Clinical Investigation, Vol. 106, No. 5, 01.09.2000, p. 697-703.

Research output: Contribution to journalArticle

Varghese, P, Harrison, RW, Lofthouse, RA, Georgakopoulos, D, Berkowitz, DE & Hare, J 2000, 'β3-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility', Journal of Clinical Investigation, vol. 106, no. 5, pp. 697-703.
Varghese P, Harrison RW, Lofthouse RA, Georgakopoulos D, Berkowitz DE, Hare J. β3-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility. Journal of Clinical Investigation. 2000 Sep 1;106(5):697-703.
Varghese, Paul ; Harrison, Robert W. ; Lofthouse, Robert A. ; Georgakopoulos, Dimitrios ; Berkowitz, Dan E. ; Hare, Joshua. / β3-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility. In: Journal of Clinical Investigation. 2000 ; Vol. 106, No. 5. pp. 697-703.
@article{66061d90e9304c86a7db82b45b609e11,
title = "β3-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility",
abstract = "The cardiac β-adrenergic pathway potently stimulates myocardial performance, thereby providing a mechanism for myocardial contractile reserve. β-Adrenergic activation also increases cardiac nitric oxide (NO) production, which attenuates positive inotropy, suggesting a possible negative feedback mechanism. Recently, in vitro studies suggest that stimulation of the β3-adrenoceptor results in a negative inotropic effect through NO signaling. In this study, using mice with homozygous β3-adrenoceptor deletion mutations, we tested the hypothesis that the β3-adrenoceptor is responsible for β-adrenergic activation of NO. Although resting indices of myocardial contraction were similar, β-adrenergic-stimulated inotropy was increased in β3(-/-) mice, and similar hyperresponsiveness was seen in mice lacking endothelial NO synthase (NOS3). NOS inhibition augmented isoproterenol-stimulated inotropy in wild-type (WT), but not in β3(-/-) mice. Moreover, isoproterenol increased myocardial cGMP in WT, but not β3(-/-), mice. NOS3 protein abundance was not changed in β3(-/-) mice, and cardiac β3-adrenoceptor mRNA was detected in both NOS3(-/-) and WT mice. These findings indicate that the β3-adrenergic subtype participates in NO-mediated negative feedback over β-adrenergic stimulation.",
author = "Paul Varghese and Harrison, {Robert W.} and Lofthouse, {Robert A.} and Dimitrios Georgakopoulos and Berkowitz, {Dan E.} and Joshua Hare",
year = "2000",
month = "9",
day = "1",
language = "English",
volume = "106",
pages = "697--703",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - β3-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility

AU - Varghese, Paul

AU - Harrison, Robert W.

AU - Lofthouse, Robert A.

AU - Georgakopoulos, Dimitrios

AU - Berkowitz, Dan E.

AU - Hare, Joshua

PY - 2000/9/1

Y1 - 2000/9/1

N2 - The cardiac β-adrenergic pathway potently stimulates myocardial performance, thereby providing a mechanism for myocardial contractile reserve. β-Adrenergic activation also increases cardiac nitric oxide (NO) production, which attenuates positive inotropy, suggesting a possible negative feedback mechanism. Recently, in vitro studies suggest that stimulation of the β3-adrenoceptor results in a negative inotropic effect through NO signaling. In this study, using mice with homozygous β3-adrenoceptor deletion mutations, we tested the hypothesis that the β3-adrenoceptor is responsible for β-adrenergic activation of NO. Although resting indices of myocardial contraction were similar, β-adrenergic-stimulated inotropy was increased in β3(-/-) mice, and similar hyperresponsiveness was seen in mice lacking endothelial NO synthase (NOS3). NOS inhibition augmented isoproterenol-stimulated inotropy in wild-type (WT), but not in β3(-/-) mice. Moreover, isoproterenol increased myocardial cGMP in WT, but not β3(-/-), mice. NOS3 protein abundance was not changed in β3(-/-) mice, and cardiac β3-adrenoceptor mRNA was detected in both NOS3(-/-) and WT mice. These findings indicate that the β3-adrenergic subtype participates in NO-mediated negative feedback over β-adrenergic stimulation.

AB - The cardiac β-adrenergic pathway potently stimulates myocardial performance, thereby providing a mechanism for myocardial contractile reserve. β-Adrenergic activation also increases cardiac nitric oxide (NO) production, which attenuates positive inotropy, suggesting a possible negative feedback mechanism. Recently, in vitro studies suggest that stimulation of the β3-adrenoceptor results in a negative inotropic effect through NO signaling. In this study, using mice with homozygous β3-adrenoceptor deletion mutations, we tested the hypothesis that the β3-adrenoceptor is responsible for β-adrenergic activation of NO. Although resting indices of myocardial contraction were similar, β-adrenergic-stimulated inotropy was increased in β3(-/-) mice, and similar hyperresponsiveness was seen in mice lacking endothelial NO synthase (NOS3). NOS inhibition augmented isoproterenol-stimulated inotropy in wild-type (WT), but not in β3(-/-) mice. Moreover, isoproterenol increased myocardial cGMP in WT, but not β3(-/-), mice. NOS3 protein abundance was not changed in β3(-/-) mice, and cardiac β3-adrenoceptor mRNA was detected in both NOS3(-/-) and WT mice. These findings indicate that the β3-adrenergic subtype participates in NO-mediated negative feedback over β-adrenergic stimulation.

UR - http://www.scopus.com/inward/record.url?scp=0033823132&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033823132&partnerID=8YFLogxK

M3 - Article

VL - 106

SP - 697

EP - 703

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -