Absence of gp130 in dopamine β-hydroxylase-expressing neurons leads to autonomic imbalance and increased reperfusion arrhythmias

Diana C. Parrish, Eric N. Alston, Hermann Rohrer, Sam M. Hermes, Sue Aicher, Paul Nkadi, William Woodward, Jutta Stubbusch, Ryan T. Gardner, Beth Habecker

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Inflammatory cytokines that act through glycoprotein (gp)130 are elevated in the heart after myocardial infarction and in heart failure. These cytokines are potent regulators of neurotransmitter and neuropeptide production in sympathetic neurons but are also important for the survival of cardiac myocytes after damage to the heart. To examine the effect of gp130 cytokines on cardiac nerves, we used gp130DBH-Cre/lox mice, which have a selective deletion of the gp130 cytokine receptor in neurons expressing dopamine β-hydroxylase (DBH). Basal sympathetic parameters, including norepinephrine (NE) content, tyrosine hydroxylase expression, NE transporter expression, and sympathetic innervation density, appeared normal in gp130DBH-Cre/lox compared with wild-type mice. Likewise, basal cardiovascular parameters measured under isoflurane anesthesia were similar in both genotypes, including mean arterial pressure, left ventricular peak systolic pressure, dP/dtmax, and dP/dtmin. However, pharmacological interventions revealed an autonomic imbalance in gp130DBH-Cre/lox mice that was correlated with an increased incidence of premature ventricular complexes after reperfusion. Stimulation of NE release with tyramine and infusion of the β-agonist dobutamine revealed blunted adrenergic transmission that correlated with decreased β-receptor expression in gp130DBH-Cre/lox hearts. Due to the developmental expression of the DBH-Cre transgene in parasympathetic ganglia, gp130 was eliminated. Cholinergic transmission was impaired in gp130DBH-Cre/lox hearts due to decreased parasympathetic drive, but tyrosine hydroxylase immunohistochemistry in the brain stem revealed that catecholaminergic nuclei appeared grossly normal. Thus, the apparently normal basal parameters in gp130DBH-Cre/lox mice mask an autonomic imbalance that includes alterations in sympathetic and parasympathetic transmission.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number3
DOIs
StatePublished - Sep 2009

Fingerprint

Mixed Function Oxygenases
Reperfusion
Cardiac Arrhythmias
Dopamine
Neurons
Tyrosine 3-Monooxygenase
Cytokines
Norepinephrine
Cytokine Receptor gp130
Parasympathetic Ganglia
Norepinephrine Plasma Membrane Transport Proteins
Tyramine
Dobutamine
Ventricular Premature Complexes
Isoflurane
Dopaminergic Neurons
Masks
Neuropeptides
Transgenes
Cardiac Myocytes

Keywords

  • Cardiac
  • Ischemia-reperfusion
  • Parasympathetic
  • Sympathetic

ASJC Scopus subject areas

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

Cite this

Absence of gp130 in dopamine β-hydroxylase-expressing neurons leads to autonomic imbalance and increased reperfusion arrhythmias. / Parrish, Diana C.; Alston, Eric N.; Rohrer, Hermann; Hermes, Sam M.; Aicher, Sue; Nkadi, Paul; Woodward, William; Stubbusch, Jutta; Gardner, Ryan T.; Habecker, Beth.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 297, No. 3, 09.2009.

Research output: Contribution to journalArticle

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abstract = "Inflammatory cytokines that act through glycoprotein (gp)130 are elevated in the heart after myocardial infarction and in heart failure. These cytokines are potent regulators of neurotransmitter and neuropeptide production in sympathetic neurons but are also important for the survival of cardiac myocytes after damage to the heart. To examine the effect of gp130 cytokines on cardiac nerves, we used gp130DBH-Cre/lox mice, which have a selective deletion of the gp130 cytokine receptor in neurons expressing dopamine β-hydroxylase (DBH). Basal sympathetic parameters, including norepinephrine (NE) content, tyrosine hydroxylase expression, NE transporter expression, and sympathetic innervation density, appeared normal in gp130DBH-Cre/lox compared with wild-type mice. Likewise, basal cardiovascular parameters measured under isoflurane anesthesia were similar in both genotypes, including mean arterial pressure, left ventricular peak systolic pressure, dP/dtmax, and dP/dtmin. However, pharmacological interventions revealed an autonomic imbalance in gp130DBH-Cre/lox mice that was correlated with an increased incidence of premature ventricular complexes after reperfusion. Stimulation of NE release with tyramine and infusion of the β-agonist dobutamine revealed blunted adrenergic transmission that correlated with decreased β-receptor expression in gp130DBH-Cre/lox hearts. Due to the developmental expression of the DBH-Cre transgene in parasympathetic ganglia, gp130 was eliminated. Cholinergic transmission was impaired in gp130DBH-Cre/lox hearts due to decreased parasympathetic drive, but tyrosine hydroxylase immunohistochemistry in the brain stem revealed that catecholaminergic nuclei appeared grossly normal. Thus, the apparently normal basal parameters in gp130DBH-Cre/lox mice mask an autonomic imbalance that includes alterations in sympathetic and parasympathetic transmission.",
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AU - Aicher, Sue

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AB - Inflammatory cytokines that act through glycoprotein (gp)130 are elevated in the heart after myocardial infarction and in heart failure. These cytokines are potent regulators of neurotransmitter and neuropeptide production in sympathetic neurons but are also important for the survival of cardiac myocytes after damage to the heart. To examine the effect of gp130 cytokines on cardiac nerves, we used gp130DBH-Cre/lox mice, which have a selective deletion of the gp130 cytokine receptor in neurons expressing dopamine β-hydroxylase (DBH). Basal sympathetic parameters, including norepinephrine (NE) content, tyrosine hydroxylase expression, NE transporter expression, and sympathetic innervation density, appeared normal in gp130DBH-Cre/lox compared with wild-type mice. Likewise, basal cardiovascular parameters measured under isoflurane anesthesia were similar in both genotypes, including mean arterial pressure, left ventricular peak systolic pressure, dP/dtmax, and dP/dtmin. However, pharmacological interventions revealed an autonomic imbalance in gp130DBH-Cre/lox mice that was correlated with an increased incidence of premature ventricular complexes after reperfusion. Stimulation of NE release with tyramine and infusion of the β-agonist dobutamine revealed blunted adrenergic transmission that correlated with decreased β-receptor expression in gp130DBH-Cre/lox hearts. Due to the developmental expression of the DBH-Cre transgene in parasympathetic ganglia, gp130 was eliminated. Cholinergic transmission was impaired in gp130DBH-Cre/lox hearts due to decreased parasympathetic drive, but tyrosine hydroxylase immunohistochemistry in the brain stem revealed that catecholaminergic nuclei appeared grossly normal. Thus, the apparently normal basal parameters in gp130DBH-Cre/lox mice mask an autonomic imbalance that includes alterations in sympathetic and parasympathetic transmission.

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