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 language||English (US)|
|Journal||American Journal of Physiology - Heart and Circulatory Physiology|
|State||Published - Sep 1 2009|
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)