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An increase in CO(2)/H(+) is a major stimulus for increased ventilation and is sensed by specialized brain stem neurons called central chemosensitive neurons. These neurons appear to be spread among numerous brain stem regions, and neurons from different regions have different levels of chemosensitivity. Early studies implicated changes of pH as playing a role in chemosensitive signaling, most likely by inhibiting a K(+) channel, depolarizing chemosensitive neurons, and thereby increasing their firing rate. Considerable progress has been made over the past decade in understanding the cellular mechanisms of chemosensitive signaling using reduced preparations. Recent evidence has pointed to an important role of changes of intracellular pH in the response of central chemosensitive neurons to increased CO(2)/H(+) levels. The signaling mechanisms for chemosensitivity may also involve changes of extracellular pH, intracellular Ca(2+), gap junctions, oxidative stress, glial cells, bicarbonate, CO(2), and neurotransmitters. The normal target for these signals is generally believed to be a K(+) channel, although it is likely that many K(+) channels as well as Ca(2+) channels are involved as targets of chemosensitive signals. The results of studies of cellular signaling in central chemosensitive neurons are compared with results in other CO(2)- and/or H(+)-sensitive cells, including peripheral chemoreceptors (carotid body glomus cells), invertebrate central chemoreceptors, avian intrapulmonary chemoreceptors, acid-sensitive taste receptor cells on the tongue, and pain-sensitive nociceptors. A multiple factors model is proposed for central chemosensitive neurons in which multiple signals that affect multiple ion channel targets result in the final neuronal response to changes in CO(2)/H(+).
An increase in CO(2)/H(+) is a major stimulus for increased ventilation and is sensed by specialized brain stem neurons called central chemosensitive neurons. These neurons appear to be spread among numerous brain stem regions, and neurons from different regions have different levels of chemosensitivity. Early studies implicated changes of pH as playing a role in chemosensitive signaling, most likely by inhibiting a K(+) channel, depolarizing chemosensitive neurons, and thereby increasing their firing rate. Considerable progress has been made over the past decade in understanding the cellular mechanisms of chemosensitive signaling using reduced preparations. Recent evidence has pointed to an important role of changes of intracellular pH in the response of central chemosensitive neurons to increased CO(2)/H(+) levels. The signaling mechanisms for chemosensitivity may also involve changes of extracellular pH, intracellular Ca(2+), gap junctions, oxidative stress, glial cells, bicarbonate, CO(2), and neurotransmitters. The normal target for these signals is generally believed to be a K(+) channel, although it is likely that many K(+) channels as well as Ca(2+) channels are involved as targets of chemosensitive signals. The results of studies of cellular signaling in central chemosensitive neurons are compared with results in other CO(2)- and/or H(+)-sensitive cells, including peripheral chemoreceptors (carotid body glomus cells), invertebrate central chemoreceptors, avian intrapulmonary chemoreceptors, acid-sensitive taste receptor cells on the tongue, and pain-sensitive nociceptors. A multiple factors model is proposed for central chemosensitive neurons in which multiple signals that affect multiple ion channel targets result in the final neuronal response to changes in CO(2)/H(+).
ABSTRACT:Caffeine is an adenosine receptor antagonist commonly used as a respiratory stimulant to treat neonatal apneas of premature newborn. Neonatal caffeine treatment (NCT) has long-term effects on adenosine receptor expression and distribution; however, the potential effects of NCT on respiratory control development are unknown. To address this issue, rat pups received orally each day from postnatal d 3-12, 15 mg/kg of caffeine (NCT), water (vehicle), or were undisturbed during early life (control). Measurements of resting ventilation, apnea index, and ventilatory response to moderate hypercapnia (FiCO 2 ϭ 0.05) were made using whole-body plethysmography at postnatal d 20 (juvenile) and adulthood. At d 20, resting respiratory variables were not affected by the treatments. Juvenile NCT male rats showed a 22% higher minute ventilation response to hypercapnia than vehicle rats. However, oral gavage alone increased the frequency component of the response by 11%. In adult males, caffeine increased the resting respiratory frequency by 15%. In these animals, the tidal volume response to hypercapnia was increased by 15%, whereas the frequency response was decreased by 20%. In juvenile and adult females, no differences were observed between treatments. In juvenile rats of both sexes, gavage increased the apnea index by at least 200%. These results show that NCT and gavage influence respiratory control during early life and that these effects persist until adulthood. The underlying mechanisms are unclear, but may be related to persistent changes in adenosinergic neurotransmission because neonatal caffeine administration increases A 1 adenosine receptor density in adult rats. (Pediatr Res 59: 519-524, 2006) P eriodic breathing and apnea are common in neonates, especially in preterm infants (1), and caffeine administration is the treatment of choice for apnea of prematurity. The effects of caffeine are mediated by adenosine A 1 and A 2 receptor inactivation to prevent the actions of endogenous adenosine. Although caffeine administration in neonates can last several days, little is known about the potential long-term consequences of this treatment. In rats, NCT, administrated by gavage at dosages comparable to those used therapeutically, has long-term effects on locomotor activity (2) and cognitive capacities (3). These effects have been attributed to persistent changes in adenosinergic neurotransmission because chronic caffeine administration during the neonatal period increases adenosine A 1 receptor density in the CNS of adult rats (4).In the context of respiratory regulation, many studies have investigated the possible consequences of maternal caffeine consumption during pregnancy on ventilatory control in rats; however, little attention has been directed to the persistent repercussion of caffeine treatment administrated after birth in newborn rats. Caffeine administration during gestation can modify respiratory control (5), increase the incidence of apnea in the adult animal (6), or change adenosine receptors expres...
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