2.3 MARCO CONCEPTUAL
2.3.8 Territorio
Carotid chemoreceptor resetting o f hypoxia sensitivity
There is now substantial evidence documenting the postnatal increase in hypoxia sensitivity o f the carotid body. In this section I will review some o f the literature for chemoreceptor resetting obtained from
direct
nerve recordings in neonatal animals both in vivo and in vitro. I have reviewed this literature in further detail in section 3.1.1 and 3.1.2 as it is pertinent to the experiments in Chapter 3.Indirect
evidence has arisenfrom num erous ventilatory studies in the newborn animal and human infant and is reviewed in section 3.1.3.
W ith the discovery that the chemoreceptors were not involved in the genesis o f FBM, nor were they involved in the inhibition o f FBM, speculation arose as to their function in utero and at the tim e o f birth. B iscoe & Purves (1967) m easured carotid chemoreceptor activity in anaesthetized lambs (n=9) from birth to 5d. They found that discharge was increased w hen breathing 10% O2, and reduced during 100% O2
breathing. They compared in three lambs aged 18hr, 2.5d and 5d the fall in discharge during 100% O2 breathing and the time taken to reach 90% o f the maximal response. All three showed a fall in discharge o f ca. 80% which was o f ca. 16sec duration, and the youngest lamb showed the m ost rapid response. Their observations led them to conclude that hypoxia sensitivity o f the carotid chemoreceptors was mature at birth and they discarded the hypothesis proposed by M iller & Smull (1955) that chemoreceptor reflexes increased in strength postnatally. It is perhaps o f note to consider that the 5d old lamb is still relatively insensitive to hypoxia, so it comes o f little surprise that the fall in discharge during hyperoxia was similar at 18hr and 5d. In this respect it may have been more useful to compare the response to hypoxia with age, but no data was given to investigate this possibility. Further work went on to discount these initial findings.
As previously mentioned, Blanco et al. (1984a) showed in fetuses that chemoreceptor discharge increased when Pa0 2 was reduced below 25mmHg, the cord was occluded or when CO2 equilibrated saline was injected into the lingual artery. In contrast no spontaneous chemoreceptor discharge was recorded on the day o f birth in normoxia, or when the P a 0 2 was lowered. There was however a response to CO2 On the second postnatal day, spontaneous chemoreceptor discharge was recorded and the steady-state P02 response curves for the neonatal lambs were displaced to the left o f the those measured in the adult. This was the first direct evidence from nerve recordings that the large increase in arterial P02 at birth 'silenced' the chemoreceptors. This led further strength to M iller & Smull's (1955) proposal. Their observations o f the respiratory response to hypoxia in new born infants led them to suggest that the hypoxic chemoreflex was weak at the time o f birth and increased postnatally, a process that is now referred to as chemoreceptor 'resetting'.
Further evidence for the process o f postnatal chemoreceptor resetting to hypoxia has been obtained in vivo in the newborn kitten (Marchai, Bairam, Haouzi, Crance, Di Giulio, Vert & L a h iri, 1992a; Carroll, Bamford & Fitzgerald, 1993), and in vitro in the neonatal rat (K holw adw ala & Donnelly, 1992; Pepper, Landauer & Kum ar, 1995). These studies have shown, as did Blanco et al. (1984a), that the chem oreceptor P02
response curve is shifted to the left in younger animals studied around the time o f birth. The increase in hypoxia chemosensitivity associated with resetting can be attributed to a rightward shift o f the curve towards the adult range with increasing postnatal age.
Blanco, H anson & M cCooke (1988) showed that hyperoxia produced by artificial ventilation for a period o f 24-3 Ihrs in fetal lambs in utero initiated the process o f chemoreceptor resetting to hypoxia. After ventilation, fetal lambs w ere delivered by caesarean section and chemoreceptor recordings made from few fibre preparations. Hyperoxic ventilated lambs showed a greater level o f chemoreceptor discharge compared to normoxic ventilated lambs for any given P a 0 2 This demonstrated the importance of an increase in P a 0 2 in resetting o f chemoreceptor sensitivity to hypoxia.
Carotid chemoreceptor resetting o f carhon dioxide sensitivity
Until recently, much less evidence has been available on the postnatal resetting o f chemoreceptor activity to CO2 This was the objective o f my experiments in Chapters
6 and 7, and I have reviewed the literature in these Chapters. Briefly, M archai et al. (1992a) provided prelim inary evidence for reduced carotid chem oreceptor CO2
sensitivity in kittens less than lOd compared to kittens older than 10 days. They described a chem oreceptor CO2 response curve for kittens less than lOd that was displaced to the right o f kittens older than lOd. Responses were only recorded in 100% O2. Carroll et al. (1993) also measured chemoreceptor CO2 responses in kittens aged Iwk, 4wk and 8wks. They measured chemoreceptor responses at three P02 levels and report an increase in the CO2 chemoreceptor response with age. They also comment that the increase in discharge at Iw k and 4wks is due to an upward shift of the CO2
chemoreceptor response curve, and that no multiplicative interaction between CO2 and O2 was observed. Pepper et al. (1995) recorded single fibre chemoreceptor activity in vitro in adult rat and rat pups aged 5-7d. With increasing hypercapnia, the P02 response curve was shifted to the right in the adult but not in the neonate, once again indicating that there was no CO2-O2 interaction in younger animals.
These observations in vitro are in agreement with those made from chem oreceptor recordings in vivo. The problems associated with these experiments are discussed in section 6.1. To address some o f the issues not covered by these experiments I have measured steady state chemoreceptor responses to CO2 at four different P a 0 2 levels over a narrow range o f postnatal ages (see section 6.3).