Increased O 2 ·− Production and Upregulation of ET B Receptors by Sympathetic Neurons in DOCA-Salt Hypertensive Rats

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Abstract
Superoxide anion (O 2 ·− ) production is elevated in the vasculature of hypertensive animals but it is not known if O 2 ·− production is also elevated in the sympathetic nervous system. We measured O 2 ·− levels in prevertebral sympathetic ganglia of deoxycorticosterone acetate (DOCA)-salt hypertensive rats using the dihydroethidine (DHE) fluorescence method. O 2 ·− was elevated in ganglia from DOCA-salt rats compared with normotensive sham rats. Treatment of ganglia with endothelin (ET)-1 (3×10 −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 O 2 ·− 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 O 2 ·− 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, O 2 ·− is elevated in prevertebral sympathetic ganglia in DOCA-salt hypertension, and ET-1 is a potent stimulus for the elevation of O 2 ·− levels in sympathetic ganglia, an effect that may be mediated by the upregulation of ET B receptors.