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Cardiovascular-Kidney Interactions in Health and Disease

Activation of ET_B receptors increases superoxide levels in sympathetic ganglia in vivo

¹Neuroscience Program, ²Departments of Pharmacology & Toxicology, ³Department of Physiology, Michigan State University, East Lansing, Michigan

Submitted 11 July 2005 ; accepted in final form 12 September 2005

Dai and colleagues (Dai X, Galligan JJ, Watts SW, Fink GD, and Kreulen DL. Hypertension 43: 1048–1054, 2004) found that endothelin (ET) stimulated O₂^– production in sympathetic ganglion neurons in vitro by activating ET_B receptors. The objective of the present study was to determine whether activation of ET_B receptors in vivo elevates O₂^– levels in sympathetic ganglia. Because ET_B receptor activation increases blood pressure, we also sought to determine whether alteration in O₂^– levels was a direct effect of ET_B receptor activation on sympathetic ganglia or an indirect consequence of hypertension. Male Sprague-Dawley rats received intravenous infusions of either the specific ET_B receptor agonist sarafotoxin 6c (S6c; 5 pmol·kg^–1·min^–1) or isotonic saline at 0.01 ml/min (control) for 120 min. To measure O₂^– levels, we removed the inferior mesenteric ganglion immediately after infusion and stained it with dihydroethidine (DHE). Mean arterial pressure increased 26.6 ± 1.7 mmHg in the S6c-treated rats and 3.65 ± 6 mmHg in control rats. Measurements of average pixel intensity revealed that the DHE fluorescence in ganglionic neurons and surrounding glial cells were 96.7% and 160% greater in S6c-treated than in control rats, respectively. To evaluate the effect of elevated blood pressure on O₂^– production, a separate group of rats received phenylephrine (PE; 10 µg·kg^–1·min^–1 iv) for 2 h. MAP increased 31 ± 1.2 mmHg in PE-infused rats. The DHE fluorescence intensity in ganglia of PE-infused rats was significantly greater than that of control rats, 137.7% in neurons and 104.6% in glia but significantly lower than in ganglia from S6c rats. We conclude that ET_B receptor activation in vivo significantly enhances O₂^– levels in sympathetic ganglia, due to both pressor effects and direct stimulation of ET_B receptors in ganglion cells.

hypertension; sarafotoxin 6c; sympathetic nervous activity; oxidative stress; reactive oxygen species

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