Article

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

Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97239, USA.
AJP Heart and Circulatory Physiology (impact factor: 3.71). 08/2009; 297(3):H960-7. DOI:10.1152/ajpheart.00409.2009 pp.H960-7
Source: PubMed

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 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 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 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 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.

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Keywords

adrenergic transmission
 
basal cardiovascular parameters
 
Basal sympathetic parameters
 
beta-agonist dobutamine
 
Cholinergic transmission
 
DBH-Cre transgene
 
gp130 cytokine receptor
 
gp130 cytokines
 
heart failure
 
increased incidence
 
myocardial infarction
 
NE release
 
NE transporter expression
 
neuropeptide production
 
parasympathetic drive
 
parasympathetic transmission
 
sympathetic innervation density
 
sympathetic neurons
 
tyrosine hydroxylase expression
 
tyrosine hydroxylase immunohistochemistry