Amyloid β peptides mediate physiological remodelling of the acute O2 sensitivity of adrenomedullary chromaffin cells following chronic hypoxia

Objective: The non-neurogenic response of the neonatal adrenal medulla is vital in cardiovascular and respiratory development and to the survival of newborns exposed to hypoxic stress. Here, we examined the acute hypoxic response of immortalised rat adrenomedullary chromaffin cells following exposure to chronic hypoxia (CH; 6% O-2 for 24 h). Methods: Ca2+ and W channel currents were recorded using by whole-cell patch-clamp. Results: Following incubation in CH, the acute 0, sensitivity of K+ current in immortalised adrenomedullary chromaffin (MAH) cells was enhanced due to a selective increase in the density of an O-2-sensitive Ca2+-dependent K+ current, secondary to ROS-mediated augmentation of voltage-gated Ca2+ currents. The effect of CH on Ca2+ currents was not additive to exogenous Abeta(1-40) and was blocked by the gamma-secretase inhibitors gamma-X and gamma-VI, demonstrating a role for amyloid beta peptide (AbetaP) production. Ca2+ current enhancement was abolished in the presence of the transcription inhibitor actinomycin D but unaffected by the vactiolar H+ ATPase inhibitor bafilomycin A1. Conclusion: AbetaP production and transcriptional regulation during CH regulated the properties of a peripheral chemosensory cell, defining a role for these enigmatic peptides in the signalling pathway of a physiological response to CH in the developing cardiovascular system. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.