Abstract--We tested the hypothesis that neuronal prostacyclin is an autocrine regulator of arterial baroreceptor neuronal activity. In isolated rat aortic nodose baroreceptor neurons, mechanical stimulation depolarized 12 neurons by 13.1±3.4 mV and triggered action potentials in 5 of them, averaging 18.2±9.5 spikes. Current injections depolarized 21 neurons by 29.9±8.0 mV and triggered action potentials averaging 17.0±2.4 spikes. After a period of prolonged neuronal activation with pulses of 1 nA at 20 Hz for 1 minute, the action potential responses to mechanical stimulation and to current injections were first markedly suppressed (0.2±0.2 and 2.1±0.7 spikes, respectively) and then enhanced, reaching levels above control (29.0±8.0 and 21.7±2.6 spikes, respectively) over the subsequent 15 minutes. In contrast, there was no inhibition of the depolarizations caused by mechanical stimulation or current injections. The recovery and enhancement of action potentials, which reached 150±5.4% of control values at 15 minutes (n=13), were abrogated by 10 µmol/L of indomethacin and replaced by sustained inhibition for over 15 minutes. Carbacyclin (10 µmol/L) reversed the inhibition and restored action potential responses. Prostacyclin production by cultured nodose neurons was enhanced by arachidonic acid and electrical field stimulation and inhibited by indomethacin. We conclude that prostacyclin provides an autocrine feedback that restores and enhances the responsiveness of arterial baroreceptor neurons after their inhibition from excessive neuronal activation. We speculate that reduced synthesis of neuronal prostacyclin contributes to the resetting phenomenon and the suppressed activity of arterial baroreceptors in hypertension.