The effects of TRH and its metabolically stable analog NS-3 [(3R,6R)-6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-pro linamide tetrahydrate] on thermoregulation and circulatory control have been investigated. Both NS-3 (1-100 ng/kg ICV) and TRH (0.1-10 micrograms/kg ICV) increased rectal temperature and metabolic rate with a transient cutaneous vasoconstriction in conscious rabbits. They also increased arterial blood pressure, heart rate, respiratory rate, and renal sympathetic nerve activity (RSNA) in urethane-anesthetized rabbits. Ten ng/kg of NS-3 and 10 micrograms/kg of TRH had comparable hyperthermic, pressor, and tachycardic activities, while the relative potency of NS-3 to increase RSNA was greater and that to increase metabolic rate was smaller than the other effects. In conclusion, NS-3 was more potent than TRH in all of the effects measured, but there was a dissociation in the relative potency of NS-3 in the different autonomic effects.