THE INTEGRATIVE CONTROL OF ADRENOCORTICOTROPIN SECRETION - A CRITICALROLE FOR CORTICOTROPIN-RELEASING HORMONE

Perifused equine anterior pituitary cells were used to investigate the relationships between the secretion of ACTH and substances known to e ither stimulate (corticotrophin-releasing hormone (CRH), and arginine vasopressin (AW)) or inhibit (cortisol) ACTH secretion. The experiment s were designed to mimic the hormone milieu present in vivo in the hor se, with cortisol (0 or 100 nmol/l) and CRH (0 or 0.02 nmol/l) perifus ed continuously, and pulses of AVP (10 nmol/l) applied for 5 min at 30 -min intervals. In columns perifused with 0.02 nmol CRH/l there was no significant overall effect of 100 nmol cortisol/l on the ACTH respons es to pulses of AVP, although there was a significant interaction betw een AVP pulse number and cortisol showing that ACTH total area (pmol A CTH proportional to area under response curve) in response to AVP puls es 1 and 2 was significantly (P<0.05) decreased in columns perifused w ith 100 nmol cortisol/l. However ACTH incremental area (pmol ACTH prop ortional to the area above the CRH-induced baseline) was not affected by cortisol at any AVP pulse. This contrasts with the effect of cortis ol in columns perifused with 0 nmol CRH/l, where 100 nmol cortisol/l s ignificantly decreased ACTH total area (P=0.0075) and incremental area (P=0.049) at all AVP pulses compared with the responses in columns re ceiving 0 nmol cortisol/l. There was a fall off in ACTH responsiveness with time during the experiment which, in the presence of 0.02 nmol C RH/l, was significantly (P<0.001) greater with 0 nmol cortisol/l than with 100 nmol cortisol/l and if 6 (rather than 3) pulses of AVP were g iven, whereas with 0 nmol CRH/1 there was no difference in the fall of f with time between columns receiving 0 and 100 nmol cortisol/l. These results show that the control of ACTH secretion is influenced not onl y by independent action of secretagogues such as CRH and AVP, or inhib itors such as cortisol, but by a complex interaction of these factors with one another. CRH may have a role in 'protecting' the ACTH respons e to pulses of AW in the presence of cortisol. It follows that, in viv o, 'background' CRH could allow an increase in ACTH in response to AVP released by a new stress, despite the presence of elevated cortisol.