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 endo thelin might also act as a neuromodulator in the stimulation of the hy pothalamic-pituitary-adrenal axis, 15 patients (4 female, 11 male, age d 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 su bjects only received on an additional day 0.1 IE per kg body weight re gular insulin plus glucose 10% (euglycemic hyperinsulinemic glucose cl amp). In control subjects hypoglycemia resulted in a significant incre ase in adrenocorticotropin (ACTH) and cortisol which was preceded by a n increase in circulating endothelin levels (p < 0.01 vs placebo and e uglycemic clamp) while endothelin, ACTH and cortisol remained unchange d both after placebo and in the euglycemic hyperinsulinemic clamp. In contrast, patients with hypopituitarism showed neither changes in circ ulating endothelin levels nor a stimulation of the hypothalamic-pituit ary-adrenal axis during insulin-induced hypoglycemia. These data demon strate that 1) endothelin levels are enhanced by metabolic stress 2) t he responsiveness of endothelin levels to metabolic stress is linked t o the presence of an intact pituitary gland and 3) endothelin might be involved in the stimulation of the hypothalamic-pituitary-adrenal axi s.