Submitted on May 4, 2007
Accepted on October 17, 2007
Post-infarct sympathetic hyperactivity differentially stimulates expression of tyrosine hydroxylase and norepinephrine transporter
Diana C. Parrish1, Kurt Gritman1, Donna M Van Winkle2, William R. Woodward3, Michael Bader4, and Beth A. Habecker1*
1 Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, United States
2 Anesthesiology, Portland VA Medical Center, Portland, Oregon, United States
3 Neurology, Oregon Health and Science University, Portland, Oregon, United States
4 Max-Delbruck-Center for Molecular Medicine, Berlin, Germany
* To whom correspondence should be addressed. E-mail: habecker{at}ohsu.edu.
The balance between norepinephrine (NE) synthesis, release, and reuptake is disrupted after acute myocardial infarction resulting in elevated extracellular NE. Stimulation of sympathetic neurons in vitro increases NE synthesis and the synthetic enzyme tyrosine hydroxylase (TH) to a greater extent than it increases NE reuptake and the NE transporter (NET) which removes NE from the extracellular space. We used TGR(ASrAOGEN) transgenic rats, which lack post-infarct sympathetic hyperactivity, to test the hypothesis that increased cardiac sympathetic nerve activity accounts for the imbalance in TH and NET expression in these neurons after myocardial infarction. TH and NET mRNA levels were identical in the stellate ganglia of unoperated TGR(ASrAOGEN) rats compared to Sprague Dawley (SD) controls, but the 3-fold increase in TH and 2-fold increase in NET mRNA seen in the stellate ganglia of SD rats one week after ischemia-reperfusion was absent in TGR(ASrAOGEN) rats. Similarly, the increase in TH and NET protein observed in the base of the SD ventricle was absent in the base of the TGR(ASrAOGEN) ventricle. Neuronal TH content was depleted in the left ventricle of both genotypes while NET was unchanged. Basal heart rate and cardiac function were similar in both genotypes, but TGR(ASrAOGEN) hearts were more sensitive to the beta agonist dobutamine. Tyramine-induced release of endogenous NE generated similar changes in ventricular pressure and contractility in both genotypes, but post-infarct relaxation was enhanced in TGR(ASrAOGEN) hearts. These data support the hypothesis that post-infarct sympathetic hyperactivity is the major stimulus increasing TH and NET expression in cardiac neurons.
