Hypoxic ventilatory response in limited iron in the rat

The study seeks to determine the role of iron in the ventilatory response to acute hypoxia in anesthetized, spontaneously breathing Wistar rats, using an experimental paradigm of chronic iron chelation. Since the hypoxic ventilatory response is generated by carotid body chemoreceptors, another objective of the study was to assess the hitherto unknown effects of iron chelation on carotid body ultrastructure. Minute ventilation and its tidal and frequency components' responses to acute 9% FiO2 were measured with plethysmography before and after iron chelation with ciclopirox olamine (CPX, 20 mg/kg, i.p.) for 7 days. Transmission electron microscopy was employed to assess the ultrastructure of carotid body tissue. We found that CPX pretreatment significantly decreased both resting and peak hypoxic ventilation in a range of 20-25%. Iron chelation caused degenerative changes in carotid body parenchyma, particularly affecting the chemoreceptor cell ultrastructure, consisting of cytoplasmic vacuolization, formation of lysosomes and multivesicular bodies, and damage to mitochondria. We report herein that inhibition of ventilatory responsiveness in limited iron is explicable by iron's role in maintaining carotid body ultrastructural viability rather than by emulation of hypoxic HIF-1alpha-mediated transduction pathway in chemoreceptor cells suggested by previous in vitro studies.