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

1 Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon; 2 Department of Neurochemistry, Max-Planck Institute for Brain Research, Frankfurt, Germany; and 3 Neuroscience Graduate Program, 4 Department of Pediatrics, and 5 Department 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/d t max , and dP/d t 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 Address for reprint requests and other correspondence: B. A. Habecker, Dept. of Physiology and Pharmacology, Oregon Health and