Catecholamine synthesis and secretion by adrenal chromaffin cells are reduced in deer mice native to high altitude

Hypoxia at high altitude can constrain aerobic metabolism and elicit physiological responses that are detrimental to health and fitness. Responses of the sympathoadrenal system are vital for coping with acute hypoxia but can become maladaptive with prolonged activation in chronic hypoxia. We examined how adrenal function is altered in high-altitude populations of deer mice (Peromyscus maniculatus), which have evolved to overcome chronic hypoxia in their native environment. High- and low-altitude populations were each born and raised in common laboratory conditions and then acclimated to normoxia or chronic hypoxia during adulthood. High-altitude mice exhibited lower plasma epinephrine concentrations than low-altitude mice in both normoxia and hypoxia. Primary cultures of chromaffin cells were used to examine the cellular mechanisms underlying differences in epinephrine secretion from the adrenal medulla. Chromaffin cells from high-altitude mice did not mount a diminished Ca²⁺ response to nicotinic stimulation, but cellular catecholamine stores were much lower in high-altitude mice than in low-altitude mice. Histological analyses of the adrenal gland showed that high-altitude mice did not have smaller adrenal medullae. Therefore, reductions in chromaffin cell catecholamine stores were the primary mechanism for lower secretion rates and circulating concentrations of catecholamines in high-altitude mice, which may help avoid sympathoadrenal overactivity in chronic hypoxia. Further exploratory analysis found that high-altitude mice have a larger adrenal cortex and higher plasma concentrations of corticosterone, which could reflect changes in stress responsiveness or metabolic regulation. Therefore, multiple evolved changes in the physiology of the adrenal gland may contribute to high-altitude adaptation in deer mice.NEW & NOTEWORTHY Prolonged activation of the sympathoadrenal system can become maladaptive in chronic hypoxia, but few previous studies have examined adrenal function in high-altitude natives. Comparing high-altitude versus low-altitude populations of mice, we show that high-altitude mice synthesize and store fewer catecholamines in adrenal chromaffin cells and thus have lower secretion rates and circulating concentrations of catecholamines in hypoxia.