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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/H960    most recent 00409.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Parrish, D. C. Articles by Habecker, B. A. PubMed PubMed Citation Articles by Parrish, D. C. Articles by Habecker, B. A.

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

¹Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon; ²Department of Neurochemistry, Max-Planck Institute for Brain Research, Frankfurt, Germany; and ³Neuroscience Graduate Program, ⁴Department of Pediatrics, and ⁵Department of Neurology, Oregon Health and Science University, Portland, Oregon

Submitted 4 May 2009 ; accepted in final form 7 July 2009

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 gp130^DBH-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 gp130^DBH-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/dt_max, and dP/dt_min. However, pharmacological interventions revealed an autonomic imbalance in gp130^DBH-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 gp130^DBH-Cre/lox hearts. Due to the developmental expression of the DBH-Cre transgene in parasympathetic ganglia, gp130 was eliminated. Cholinergic transmission was impaired in gp130^DBH-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 gp130^DBH-Cre/lox mice mask an autonomic imbalance that includes alterations in sympathetic and parasympathetic transmission.

cardiac; sympathetic; parasympathetic; ischemia-reperfusion