Ventilatory responses and carotid body function in adult rats perinatally exposed to hyperoxia

Abstract

Hypoxia increases the release of neurotransmitters from chemoreceptor cells of the carotid body (CB) and the activity in the carotid sinus nerve (CSN) sensory fibers, elevating ventilatory drive. According to previous reports, perinatal hyperoxia causes CSN hypotrophy and varied diminishment of CB function and the hypoxic ventilatory response. The present study aimed to characterize the presumptive hyperoxic damage. Hyperoxic rats were born and reared for 28 days in 55%-60% O 2 ; subsequent growth (to 3.5-4.5 months) was in a normal atmosphere. The parenchyma of the carotid body (CB) is formed by chemoreceptor and sustentacular cells organized in clusters surrounded by a dense network of capillaries. Sensory nerve terminals of the carotid sinus nerve (CSN) penetrate the clusters to synapse with chemoreceptor cells (Verna, 1997). Functionally, chemoreceptor cells are activated by hypoxia and hypercapnia, and they respond with an increased release of neurotransmitters that activate the sensory nerve endings of the CSN and produce an increase in the action potential frequency in the CSN. Central projections of the CSN produce a ventilatory response, which facilitates homeostasis of blood O 2 and CO 2 levels. Catecholamines (CA) are the most abundant neurotransmitters present in chemoreceptor cells. Many groups have demonstrated that CA metabolism, including rate of synthesis and release, parallel the level of CB stimulation and action potential frequency in the CSN (Gonzalez et al. , 1994 and references therein). In adult mammals the CB is responsible for the entire hyperventilation evoked by hypoxia and for about 30-50% of the hyperventilation triggered by hypercapnia and acidosis (Cherniack & Altose 1997;Gonzalez et al. 2002a). In the intact animal a decrease in arterial P O 2 from 100 to about 75 mmHg produces only minor changes in the basal level of CSN activity or ventilation. At P O 2 below the apparent threshold of 75 mmHg there is an almost exponential increase in either response. CSN activity and ventilation double at about 50-55 mmHg, and increase by a factor of four near 40 mmHg. In the case of CO 2 the activity in the CSN and the ventilation mediated by the CB increase linearly with the P CO 2 , doubling every 15-20 mmHg (Gonzalez et al. 1994). In neonatal animals, the apparent threshold for the hypoxic response is set at a much lower P O 2 , in the range of 20-25 mmHg, i.e. at P O 2 comparable to that found in utero. At lower P O 2 , the hypoxic response increases with a lower slope than in adults. In response to elevated CO 2 there is a comparable hyposensitivity in newborn animals (Hanson & Kumar 1994;Donnelly, 1997). Functional maturation of the CB during postnatal life occurs in the first few weeks after birth, with some differences among species. In the rat, at four weeks of age the responses are fully developed (Eden & Hanson 1987a;Donnelly & Doyle 1994;Rigual et al. 2000;Donnelly, 1997). Maturation of CB function is greatly affected by the ambient P O 2 in the perinatal period. Thus, if animals ...

Neonatal Environment and Neuroendocrine Programming of the Peripheral Respiratory Control System

“…As we discussed previously, perinatal exposure to excessive or insufficient respiratory stimuli such as chronic changes in ambient O 2 levels produces alterations in the respiratory control system that persist well into adulthood [54,55,[73][74][75]. These studies show that adequate chemosensory guidance during early life is critical to respiratory control development.…”

Long-term effects of the perinatal environment on respiratory control

“…Immediately after a 2-wk exposure to 60% O 2 , single-unit chemoreceptor O 2 responsiveness is reduced, and the conduction time of action potentials between the carotid body and petrosal ganglion is increased (24); some of these effects may be mediated by reduced expression of O 2 -sensitive K ϩ channels (TASK-1, TASK-2, and TASK-5) in the type I cells following perinatal hyperoxia (50). Similarly, Prieto-Lloret et al (81) report that ϳ75% of the CSN fibers and carotid body preparations that respond to increasing extracellular K ϩ fail to respond to hypoxia in adult rats exposed to developmental hyperoxia, suggesting a longlasting loss of O 2 sensitivity in these cells. As a result, adults previously exposed to perinatal hyperoxia exhibit severely attenuated CSN responses to hypoxia (14,33,57,81).…”

“…Similarly, Prieto-Lloret et al (81) report that ϳ75% of the CSN fibers and carotid body preparations that respond to increasing extracellular K ϩ fail to respond to hypoxia in adult rats exposed to developmental hyperoxia, suggesting a longlasting loss of O 2 sensitivity in these cells. As a result, adults previously exposed to perinatal hyperoxia exhibit severely attenuated CSN responses to hypoxia (14,33,57,81).…”

“…Hyperoxia-treated rats develop smaller carotid bodies with fewer O 2 -sensitive (type I) cells and fewer neurons in the carotid sinus nerve (CSN) to carry afferent information to the brain stem (14,29,81). Carotid body hypoplasia appears to result from a failure of the carotid body to grow during the hyperoxic exposure rather than death of existing cells (109, S. E. Piro, E. K. Dmitrieff, and R. W. Bavis, unpublished observations); chemoafferent neuron degeneration may be secondary to the carotid body hypoplasia (29,47).…”

Inhibitory effects of repeated hyperoxia on breathing in newborn mice

“…The use of 100% O 2 instead of room air has been challenged [1] based on studies showing cerebral blood flow reduction [9], generation of oxygen free radicals that cause or worsen brain injury [2,[10][11][12], increased rates of bronchopulmonary dysplasia [13] and retinopathy [14]. In addition, the inhibitory effects of hyperoxia on breathing may compromise oxygenation after O 2 administration, particularly in pre-term humans, who are more susceptible to apnoeas [15].…”