Clinical evidence for a neuromodulator action of endothelin in the hypothalamic-pituitary-adrenal axis in man

In order to investigate whether the ubiquitous signalling peptide endothelin might also act as a neuromodulator in the stimulation of the hypothalamic-pituitary-adrenal axis, 15 patients (4 female, 11 male, aged 35-67 years) with hypopituitarism were investigated and the results were compared to those of 8 healthy male volunteers (aged 24-31 years). Patients and controls received double-blind in random order either 0.1 IE per kg body weight regular insulin (insulin induced hypoglycemia) or 1 ml 0.9% sodium chloride placebo) on 2 separate days. Control subjects only received on an additional day 0.1 IE per kg body weight regular insulin plus glucose 10% (euglycemic hyperinsulinemic glucose clamp). In control subjects hypoglycemia resulted in a significant increase in adrenocorticotropin (ACTH) and cortisol which was preceded by an increase in circulating endothelin levels (p < 0.01 vs placebo and euglycemic clamp) while endothelin, ACTH and cortisol remained unchanged both after placebo and in the euglycemic hyperinsulinemic clamp. In contrast, patients with hypopituitarism showed neither changes in circulating endothelin levels nor a stimulation of the hypothalamic-pituitary-adrenal axis during insulin-induced hypoglycemia. These data demonstrate that 1) endothelin levels are enhanced by metabolic stress 2) the responsiveness of endothelin levels to metabolic stress is linked to the presence of an intact pituitary gland and 3) endothelin might be involved in the stimulation of the hypothalamic-pituitary-adrenal axis.