Prenatal hypoxia impairs the early postnatal development of the carotid chemoafferent pathway

Abstract

Rat carotid bodies (CB) are considered as the main component that initiates the Hypoxic Ventilatory Response (HVR). Most of these chemoafferent fibres project into discrete areas of the medulla oblongata via the petrosal ganglion (PG), mainly in the caudal part of the nucleus Tractus Solitarius (NTS), and, to a lesser extent, in the ventrolateral medulla (VLM) [1]. Both medullary areas contain two major respiratory cell groups: the dorsal respiratory group, in the ventrolateral subset of the solitary tract, and the ventral respiratory group, in the VLM. These two medullary respiratory groups are closely associated with catecholaminergic neurones that belong to, the A2C2 cell group and the A1C1 cell group respectively. There is growing evidence that medullary cate-cholaminergic neurones participate in the chemoreflex response to systemic hypoxia. During the two first weeks of life, the sensitivity of the carotid bodies adapts to the comparatively hypoxic environment of the foetus and then reset to the higher PaO2 of the new-born. This environmental change in oxygen leads to an increase in the carotid body sensitivity, due in part to a decrease in the release of dopamine [2]. The postnatal maturation of the carotid body sensitivity depends on the level of environmental oxygen during the early postnatal period. The aim of the present study is to investigate the effects of prenatal hypoxia (last 15 days of gestation in 10% O2) on the neurochemical and functional development (postnatal day 0, 3, 7, 14, 21 and 68) of the chemoafferent pathway. We thus assessed the development of in vivo tyrosine hydroxylase (TH) activity, the rate-limiting enzyme in the catecholamine synthesis [3], in the CB, PG and the A1C1, A2C2 cell groups. In the same way, TH mRNA was evaluated in the CB, PG structures. Moreover, we evaluated the functional maturity of the chemoreflex pathway by measuring the HVR. We attempted to address four main questions. First, can prenatal hypoxia induce a neurochemical impairment of the CB resetting? Second, could the neurochemical impairment be related to the mRNA level? Third, are central and peripheral structures affected in the same manner? Fourth, are the neuronal impairments reflected at the functional level? Our results show that 1) prenatal hypoxia amplifies the neurochemical resetting of the peripheral chemoreceptors; 2) a part of the neurochemical impairment is explained at the mRNA level; 3) central and peripheral structures exhibit opposite impairment; 4) prenatal hypoxia modifies the HVR pattern. In conclusion, prenatal hypoxic exposure during the two last weeks of gestation impairs the carotid body chemoreflex pathway at the functional, the neurochemical and the molecular level, affecting the CB resetting process.