Published Online
on March 29, 2004

A more recent version of this article appeared on May 1, 2004

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Submitted on January 28, 2004
Revised on February 10, 2004

Increased O₂^·- Production and Upregulation of ET_B Receptors by Sympathetic Neurons in DOCA-Salt Hypertensive Rats

Xiaoling Dai; James J. Galligan; Stephanie W. Watts; Gregory D. Fink; and David L. Kreulen^*

From the Departments of Physiology (X.D., D.L.K.), Pharmacology and Toxicology (J.J.G., S.W.W., G.D.F.), and Neuroscience Program (X.D., J.J.G., G.D.F., D.L.K.), Michigan State University, East Lansing.

^* To whom correspondence should be addressed. E-mail: dkreulen{at}msu.edu.

Abstract--Superoxide anion (O₂^·-) production is elevated in the vasculature of hypertensive animals but it is not known if O₂^·- production is also elevated in the sympathetic nervous system. We measured O₂^·- levels in prevertebral sympathetic ganglia of deoxycorticosterone acetate (DOCA)-salt hypertensive rats using the dihydroethidine (DHE) fluorescence method. O₂^·- was elevated in ganglia from DOCA-salt rats compared with normotensive sham rats. Treatment of ganglia with endothelin (ET)-1 (3x10^-8 mol/L) resulted in a 200% increase in fluorescence intensity in neurons, which was attenuated by the ET_B receptor antagonist BQ788 (10^-7 mol/L). ET-1 also increased the O₂^·- induced fluorescence in dissociated sympathetic neurons and PC-12 cells via activation of ET_B receptors, but not ET_A receptors. To evaluate whether elevated ET-1 levels in the ganglia might contribute to the elevated O₂^·- found in ganglia we measured the amount of ET-1 using an ELISA assay. ET-1 levels in sham rat celiac ganglia were 695.6±40.9 picogram per gram; they were not different than ET-1 levels in ganglia from DOCA-salt rats. We then compared ET_B receptor levels in ganglia from sham and DOCA-salt animals. ET_B receptor mRNA levels were 32% higher and ET_B receptor protein levels were 20% higher in celiac ganglia from DOCA-salt rats than from sham rats separately. In conclusion, O₂^·- is elevated in prevertebral sympathetic ganglia in DOCA-salt hypertension, and ET-1 is a potent stimulus for the elevation of O₂^·- levels in sympathetic ganglia, an effect that may be mediated by the upregulation of ET_B receptors.

Key words: endothelin • receptors, endothelin • hypertension • sympathetic nervous system • oxidative stress

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