Multiple α1-adrenergic receptor subtypes support synergistic stimulation of vasopressin and oxytocin release by ATP and phenylephrine

Abstract

Simultaneous exposure of explants of the hypothalamo-neurohypophyseal system (HNS) to ATP and the α1-adrenergic receptor (α1-R) agonist, phenylephrine (ATP+PE) induces a synergistic stimulation of vasopressin and oxytocin (VP/OT) release that is sustained for hours ( 23 ). The current studies confirm that the synergism is dependent upon activation of α1-R by demonstrating that an α1-R antagonist prevents the response. The role of the α1A, B, and D-adrenergic receptor subtypes in the synergistic effect of ATP+PE on intracellular calcium ([Ca2+]i) in supraoptic nucleus (SON) neurons and VP/OT release from neural lobe was evaluated. The increase in [Ca2+]i induced by PE in SON predominantly reflects release from intracellular stores and is mediated by activation of the α1A adrenergic receptor subtype. The α1A subtype is also required for the sustained elevation in [Ca2+]i induced by ATP+PE. In contrast, although synergistic stimulation of VP/OT release was eliminated by removal of PE and was blunted by benoxathian, an α1-R antagonist that is not subtype selective, no single α1-R subtype selective antagonist prevented sustained stimulation of VP/OT release by ATP+PE. Thus, sustained activation of α1-R is essential for the synergistic VP and OT response to ATP+PE, but multiple α1-R subtypes can support the response. Redundancy amongst the α1-R subunits in supporting this response is consistent with the predicted importance of the response for sustaining the elevated VP release required to prevent cardiovascular collapse during hemorrhage and sepsis.