[Endothelin 3 (ET3) stimulates the hypothalamic-pituitary-adrenal axis mainly by corticotropin-releasing-hormone...

Endothelin 3 (ET3) is a member of the novel vasoconstrictive peptide family, identified in the porcine central nervous system. The effect of ET3 on the hypothalamic-pituitary-adrenal axis in male rats was examined in vivo and in vitro. Intravenous bolus injection of 1000pmol/kg of ET3 in free moving rats caused significant increases in plasma ACTH and corticosterone levels, almost equivalent to those of 100pmol/kg of rat corticotropin-releasing hormone (rCRH). Since an iv bolus injection of ET3 1000pmol/kg did not cause significant changes in the blood pressure of anesthetized rats or the locomotor activity of free moving rats, it seems unlikely that ET3 1000pmol/kg acted as a nonspecific stressor. When ET3 (10(-11) greater than 10(-7)M) was added to cultured anterior pituitary cells, neither direct stimulation of ACTH release nor potentiation of rCRH action was noted. Although it has been shown that ET3 administered systemically probably does not cross the brain-blood-barrier, circulating ET3 may reach the brain tissues through regions lacking the tight barrier, circumventricular structures. The next studies included pretreatment of antagonists or blockers of ACTH stimulating hormones to elucidate the mechanisms of ET3 induced ACTH release. The action of ET3 was virtually abolished by pretreatment of CRH-antagonist alpha helical CRH (150 micrograms/rat icv). But pretreatment of catecholamine-blocker alpha methyl-tyrosine (100mg/kg iv), arginine vasopressin-antagonist dP-thy(Me)AVP (50 micrograms/rat iv) and prostaglandin-blocker indomethacin (3mg/rat iv) did not inhibit the action of ET3. The results indicate that ET3 may play the role of a neuropeptide and that the stimulation of the CRH-neurons is mainly responsible for activation of ACTH and corticosterone release.