(ET BR) are expressed in multiple tissues and perform different functions depending on their location. ET BR mediate endothelium-dependent vasodilation, clearance of circulating ET, and diuretic effects; all of these should produce a fall in arterial blood pressure. However, we recently showed that chronic activation of ET BR in rats with the selective agonist sarafotoxin 6c (S6c) causes sustained hypertension. We have proposed that one mechanism of this effect is constriction of capacitance vessels. The current study was performed to determine whether S6c hypertension is caused by increased generation of reactive oxygen species (ROS) and/or activation of the sympathetic nervous system. The model used was continuous 5-day infusion of S6c into male Sprague-Dawley rats. No changes in superoxide anion levels in arteries and veins were found in hypertensive S6c-treated rats. However, superoxide levels were increased in sympathetic ganglia from S6c-treated rats. In addition, superoxide levels in ganglia increased progressively the longer the animals received S6c. Treatment with the antioxidant tempol impaired S6c-induced hypertension and decreased superoxide levels in ganglia. Acute ganglion blockade lowered blood pressure more in S6c-treated rats than in vehicle-treated rats. Although plasma norepinephrine levels were not increased in S6c hypertension, surgical ablation of the celiac ganglion plexus, which provides most of the sympathetic innervation to the splanchnic organs, significantly attenuated hypertension development. The results suggest that S6c-induced hypertension is partially mediated by sympathoexcitation to the splanchnic organs driven by increased oxidative stress in prevertebral sympathetic ganglia. endothelin type B receptor; oxidative stress; neuronal regulation WE RECENTLY REPORTED that chronic activation of endothelin (ET) type B receptors (ET B Rs) using intravenous infusion of the ET B R-selective agonist sarafotoxin 6c (S6c) in rats causes an increase in arterial pressure (S6c-induced hypertension) (16). This was surprising in light of the fact that the two best described physiological responses to ET B R activation, i.e., release of vasodilators from endothelial cells, and increased renal sodium and water excretion, should lead to a fall in arterial pressure (42,48,50). We believe venoconstriction contributes to S6c-induced hypertension, because in vitro S6c has been shown to constrict veins from most vascular regions but to have little effect on most arteries (15,27,41,49).It is likely, however, that other mechanisms contribute to S6c-induced hypertension. Reactive oxygen species (ROS) are a variety of oxygen-containing molecules that are by-products of cellular metabolic processes under physiological condition, including superoxide anion (O 2 Ϫ ), hydrogen peroxide (H 2 O 2 ), and hydroxyl ion (OH⅐). Recently, increasing evidence has shown that ROS can function as cellular signaling molecules (5). Increased ROS levels have been found in blood vessels, kidneys, and other tissues in many ex...