Iron and chemical control of breathing

Iron is a constituent of eukaryotic cells. In a previous study we found that chronic deficiency of iron decreases the acute hypoxic ventilatory response (HVR) along with morphological changes in the carotid body, which supports iron's role in chemoreception. The question arises to what extend this role is specific for the carotid generated hypoxic chemoreflex. We addressed the issue in the current study in which we compared the effects of iron chelation on the HVR (14 and 9% O2 in N2) and hypercapnic ventilatory (5 and 10% CO2 in O2) (HCVR) responses, mediated, in the main, by peripheral and central chemoreceptors, respectively. The experiments were performed in conscious, male, Wistar rats. Ventilation was measured using a whole body rodent plethysmography, before and after 7-day administration of the lipophilic intracellular iron chelator – ciclopirox olamine (CPX; 20mg/kg, ip, daily). We found that CPX dampened the hypoxic, but not hypercapnic responses. The peak HVR was decreased from the basal 1499±116SE and 2142±83ml·min-1kg-1 before to 1079±108 and 1732±149ml·min-1kg-1 at 14 and 9% hypoxia, respectively (P<0.01 for both), after iron chelation. On the other hand, the peak HCVR changed inappreciably from 1608±189SE and 2833±267ml·min-1kg-1 before to 1619±193 and 3053±331ml·min-1kg-1 at 5 and 10% hypercapnia, respectively, after iron chelation. In a separate ultrastructural comparative investigation that followed the functional study we found that iron chelation caused profound degenerative changes in carotid body parenchyma, which were distinctly different from the nearly unaffected brainstem or the superior cervical sympathetic ganglion cells taken as the reference neural tissues. We conclude that iron is a specific regulator of the carotid body chemoreceptive mechanisms.