Inhibition of basal and corticotropin-releasing hormone-stimulated adenylate cyclase activity and cytosolic Ca²⁺ levels by somatostatin in human corticotropin-secreting pituitary adenomas

The effects of CRH and somatostatin (SRIH) on adenylate cyclase (AC) activity, intracellular free calcium concentrations ([Ca²⁺]I) and in vitro ACTH release were investigated in six human ACTH-secreting pituitary adenomas. In all tumors, CRH induced a marked stimulation (from 69-210% at 10 nM), whereas SRIH caused a definite inhibition (from 29-50% at 100 nM) of membrane AC. When added together, CRH and SRIH caused a purely additive effect on AC. In adenomatous corticotrophs CRH (10 nM) caused [Ca²⁺]i to rise from 160 ± 30 nM (mean ± SD) to 410 ± 95 nM. CRH-induced transients were biphasic, with an initial peak predominantly due to redistribution from intracellular Ca²⁺ stores and a secondary phase due to Ca²⁺ influx. The effects of CRH on [Ca²⁺]i were totally independent of the stimulation of AC. In fact, cAMP-elevating agents other than CRH did not modify [Ca²⁺]i. SRIH (100 nM) decreased resting [Ca²⁺]i (̃20-40%) as well as [Ca²⁺]i rises induced by CRH, arginine vasopressin, or high K⁺. The effect of SRIH on [Ca²⁺]i was maintained in presence of high cAMP levels, while was totally abolished after pertussis toxin pretreatment. CRH (10 nM) stimulated ACTH release (from 22.5 ± 3.5 to 45.0 ± 8.5 pmol/L) by an extent similar to that elicited by calcium ionophore and forskolin. By contrast, SRIH (0.1 γM) inhibited both basal and CRH-stimulated ACTH release. In conclusion, in human adenomatous corticotrophs SRIH exerts an inhibitory action by reducing both AC activity and, independently, [Ca²⁺]i. In this way, SRIH can efficiently counteract the stimulatory action of CRH that in these cells involves activation of both cAMP and Ca²⁺ pathways.