On the basis of the distribution of enkephalins within the central and peripheral nervous systems as well as on responses to their administration, it has been suggested that these peptides participate in the regulation of the circulation. The present series of experiments examined the effects of thiorphan, an inhibitor of enkephalinase A, on cardiovascular responses to intracerebroventricular (i.c.v.) administration of [D-Ala2,Met5]enkephalin (DAME) and its amide and on peripheral interactions with the sympathetic nervous system and vasoactive peptides. Thiorphan (30 micrograms i.c.v.) potentiated the pressor response to i.c.v. DAME and DAMEamide in conscious spontaneously hypertensive rats. Responses to i.c.v. angiotensin I (AI) were unaffected suggesting lack of inhibition of central angiotensin converting enzyme (ACE). Peripheral administration of relatively large doses of thiorphan (30 and 100 mg/kg s.c.) attenuated the pressor response to i.v. AI by 30-40% and enhanced the depressor effect of i.v. bradykinin in anesthetized normotensive rats indicating inhibition of peripheral ACE. Pressor and tachycardic responses to activation of spinal sympathetic outflow were not altered by thiorphan in pithed normotensive rats. Thiorphan itself did not affect baseline blood pressure or heart rate in any of these experiments. In conclusion, inhibition of central enkephalinase A by i.c.v. administration of thiorphan potentiates the pressor response to i.c.v. DAME. The compound inhibits peripheral ACE but has little direct cardiovascular activity in its own right.