STIMULATION OF ACTH CORTISOL BY INTRAVENOUSLY INFUSED SUBSTANCE-P IN NORMAL MEN - INHIBITION BY SODIUM VALPROATE

The effect of synthetic substance P (SP), infused intravenously in doses of 0.5, 1 or 1.5 pmol/kg-1/min-1 over 60 min on ACTH/cortisol secretion was evaluated in 7 healthy men. SP tests and a control test with normal saline were randomly performed at weekly intervals. During tests, SP infusion did not produce untoward side effects or changes in blood pressure. Plasma ACTH and cortisol levels were not modified when normal saline or the lowest dose of SP were infused, whereas they were significantly increased in a dose-dependent fashion when higher amounts of SP were administered. Further studies were performed in another 7 healthy men to test the possible influence of GABAergic neurotransmission on the ACTH/cortisol response to SP. For this purpose, subjects were tested with SP (1.5 pmol/kg-1/min-1) alone and on a different occasion with SP after pretreatment with the GABAergic agent sodium valproate (200 mg 16, 8 and 1 h before the SP test). Again, the administration of SP induced a significant increase in plasma ACTH and cortisol levels. The pretreatment with sodium valproate completely abolished both ACTH and cortisol responses to SP. These data demonstrate for the first time in humans that the systemic infusion of SP stimulates ACTH/cortisol secretion, suggesting the involvement of a GABAergic mechanism in the regulation of the action of SP.