Stimulation of ACTH/Cortisol by Intravenously Infused Substance P in Normal Men: Inhibition by Sodium Valproate

Abstract

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.

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“…This difference might be explained by the different time points at which SP was administered. In contrast to our study, in the studies of Coiro et al on SP-induced ACTH-and cortisol-secretion (Coiro et al 1992a) and SP-induced GH-secretion (Coiro et al 1992b), SP was administered at 9:00 A.M. Nevertheless, our results confirm the finding of Coiro et al (1992a) that SP stimulates cortisol secretion.…”

“…In contrast to our study, in the studies of Coiro et al on SP-induced ACTH-and cortisol-secretion (Coiro et al 1992a) and SP-induced GH-secretion (Coiro et al 1992b), SP was administered at 9:00 A.M. Nevertheless, our results confirm the finding of Coiro et al (1992a) that SP stimulates cortisol secretion. This increment is probably due to a central effect of SP since increased cortisol levels went in parallel with an increase in ACTH secretion in the study of Coiro et al (1992a).…”

“…Nevertheless, our results confirm the finding of Coiro et al (1992a) that SP stimulates cortisol secretion. This increment is probably due to a central effect of SP since increased cortisol levels went in parallel with an increase in ACTH secretion in the study of Coiro et al (1992a). It might be speculated that activation of the HPA axis by SP plays a role in the pathogenesis of the hypercortisolism often seen in depressed patients (Holsboer 1995;Linkowski et al 1987), but this cannot definitively be answered from this study, in which we measured acute effects of SP in healthy subjects.…”

“…, which similarly as in our study caused flushing, but were otherwise well tolerated by the subjects (Schaffalitzky De Muckadell et al 1986). Coiro et al (1992a) used doses between 0.5 and 1.5 pmol/kg Ϫ1 /min Ϫ1 given over 60 min, of which even the infusion of 1 pmol/kg Ϫ1 / min Ϫ1 showed significant biological effects, as demonstrated by a significant rise of ACTH and cortisol levels.…”

“…It has been shown that SP given intravenously increases secretion of ACTH and cortisol in a dose dependent manner (Coiro et al 1992a). This indicates that SP may exhibit centrally mediated neuroendocrine effects in humans.…”