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

Am J Physiol Heart Circ Physiol. 2009 Jul 10; Parrish DC, Alston EN, Rohrer H, Hermes SM, Aicher SA, Nkadi P, Woodward WR, Stubbusch J, Gardner RT, Habecker BAInflammatory cytokines that act through gp130 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 following 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 beta 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 to 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 autonomic imbalance in gp130(DBH-Cre/lox) mice that was correlated with increased incidence of premature ventricular complexes after reperfusion. Stimulation of NE release with tyramine and infusion of the beta agonist dobutamine revealed blunted adrenergic transmission that correlated with decreased beta 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 brainstem revealed that catecholaminergic nuclei appeared grossly normal. Thus, apparently normal basal parameters in gp130(DBH-Cre/lox) mice mask autonomic imbalance that includes alterations in sympathetic and parasympathetic transmission. Key words: cardiac, sympathetic, parasympathetic, ischemia-reperfusion.