Effective treatment of sepsis remains a significant challenge in intensive care units. During sepsis there is widespread activation of the sympathetic nervous system, which is thought to have both beneficial and detrimental effects. The sympathoexcitation is thought to be partly due to the developing hypotension, but may also be a response to the inflammatory mediators released. Thus, we investigated whether intracarotid infusion of prostaglandin E2 (PGE2) induced similar cardiovascular changes to those caused by intravenous infusion of E. coli in sheep, and whether inhibition of prostaglandin synthesis, with the non-selective cyclooxygenase (COX) inhibitor indomethacin, administered at two and eight hours after the onset of sepsis, reduced sympathetic nerve activity (SNA) and heart rate (HR). Studies were performed in conscious sheep instrumented to measure mean arterial pressure (MAP), HR, cardiac SNA (CSNA) and renal SNA (RSNA). Intracarotid infusion of PGE2 (50 ng/kg/min) increased temperature, CSNA and HR, but not MAP or RSNA. Sepsis, induced by infusion of E. coli, increased CSNA, but caused an initial, transient inhibition of RSNA. At two hours of sepsis, indomethacin (1.25 mg/kg bolus) increased MAP and caused reflex decreases in HR and CSNA. After eight hours of sepsis, indomethacin did not alter MAP, but reduced CSNA and HR, without altering baroreflex control. These findings indicate an important role for prostaglandins in mediating the increase in CSNA and HR during the development of hyperdynamic sepsis, whereas prostaglandins do not have a major role in determining the early changes in RSNA.