J Physiol. 2007 Aug 16; [Epub ahead of print]

Increased Secretory Capacity of Mouse Adrenal Chromaffin Cells By Intermittent Hypoxia: Involvement of Protein Kinase C.

Episodic or intermittent hypoxia (IH) occurs in patients suffering from sleep apnoea and is due to obstruction to breathing. IH is thought to activate a stress response in the sympathetic nervous system. The elevated sympathetic activity increases catecholamine release from the adrenal medullary chromaffin cells that leads to elevated serum catecholamine levels. If left untreated, IH leads to pathologies such as hypertension, vascular disease and diabetes. However, the mechanism by which elevated catecholamine output occurs remains unclear. For example, it is not known whether the increased catecholamine release from chromaffin cells is simply a function of increased sympathetic input, or an inherent alteration in the secretion function of the chromaffin cells themselves, or both. Previous work showed an enhanced transmitter release from clonal neuroendocrine PC-12 cells in response to hypoxic culture conditions and that this increase was sensitive to general protein kinase blockers. In the current study we exposed mice to multiple hypoxic conditions. We then measured the exocytic capacity from chromaffin cells in situ in perforated patch electrical capacitance recordings. Data from these experiments indicate that exposure to intermittent hypoxia results in an increase in the number of catecholamine-containing secretory granules available for release. Furthermore, we report that this effect is specific to intermittent hypoxia and is not triggered by continuous hypoxic conditions. Lastly, we provide a cellular mechanism for the intermittent hypoxia-mediated secretory facilitation that involves a reactive oxygen species-dependent increase in the level of active protein kinase C, leading to the enhanced availability of secretory granules.

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