O2-sensitive K+ currents in carotid body chemoreceptor cells from normoxic and chronically hypoxic rats and their roles in hypoxic chemotransduction.

Abstract

Carotid body-mediated ventilatory increases in response to acute hypoxia are attenuated in animals reared in an hypoxic environment. Normally, 02-sensitive K+ channels in neurosecretory type I carotid body cells are intimately involved in excitation of the intact organ by hypoxia. We have therefore studied K+ channels and their sensitivity to acute hypoxia The ventilatory responses to acute hypoxia of animals and humans change dramatically from fetal to adult life: in fetal animals, exposure to hypoxia is inhibitory to breathing movements (1), whereas in the adult, hypoxia causes a sustained increase in ventilation (2). Neonatal animals produce an intermediate biphasic response, with ventilation increasing and then falling again during sustained hypoxia (3). This transient increase, along with the sustained increase seen in adults, is a result of stimulation of peripheral chemoreceptors, primarily the carotid body (4, 5). Ventilatory responses to acute hypoxia of neonatal animals born and raised in hypoxic environments are blunted or absent (6), and a similar lack of ventilatory response to hypoxia has also been noted in adult animals exposed to hypoxia chronically (7) and in high-altitude residents (8). It is conceivable that common mechanisms underlie the lack of ventilatory response to hypoxia of chronically hypoxic neonatal animals and high-altitude residents.The carotid bodies of chronically hypoxic animals or humans show dramatic morphological changes following prolonged hypoxia: most notably, type I carotid body cellsThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. undergo hyperplasia and hypertrophy (9, 10). Type I cells are widely accepted as the chemosensory element of the carotid body, and various stimuli including hypoxia stimulate Ca2+-dependent release of neurotransmitters from these cells in a manner that correlates with increased discharge of afferent chemosensory fibers (5, 11). In recent years, several groups have used patchclamp techniques to investigate ion channels in type I cells, and there are several reports describing 02-sensitive K+ channels in these cells (12)(13)(14)(15)(16). These findings have given rise to a proposed mechanism for hypoxic chemotransduction in which inhibition of K+ channels by hypoxia leads to depolarization and increased excitability of type I cells sufficient to activate voltage-gated Ca2+ channels. This leads to Ca2+ influx and triggering of neurosecretion, an essential step in the chemotransductive pathway (5). Here we have compared ionic channels and their modulation by acute hypoxia in type I cells isolated from neonatal rats born and raised in normoxia and hypoxia in order to investigate whether the lack of chemoreceptor-mediated increases in ventilation seen in animals reared under chronically hypoxic conditions can be attributed to altered electrophysiological properties of type I cells. ...

Long-term effects of the perinatal environment on respiratory control

“…This postnatal maturation of the HVR may be triggered by the rapid rise in arterial PO 2 at birth. Consistent with this hypothesis, the HVR is absent or greatly diminished in young rats, cats, and sheep maintained in hypoxia (10 -15% O 2 ) from birth until 0 -24 h before study (5 days to 10 wk of age) (28,42,43,94,113). These effects reflect reduced carotid body responses to hypoxia (42,43,99,113).…”

“…Consistent with this hypothesis, the HVR is absent or greatly diminished in young rats, cats, and sheep maintained in hypoxia (10 -15% O 2 ) from birth until 0 -24 h before study (5 days to 10 wk of age) (28,42,43,94,113). These effects reflect reduced carotid body responses to hypoxia (42,43,99,113). Indeed, the normal postnatal increase in the early phase of the HVR is largely attributable to resetting of carotid body O 2 sensitivity, and this maturation is blocked at the level of the carotid body type I cells when rats are maintained in hypoxia from birth (99).…”

General – Ion Channels

“…Thus in contrast to results obtained in rats born and reared in CH (Wyatt et al 1995), adult type I cells respond to a period of CH with a reduction in the functional expression of Ca2+ -insensitive, voltage-gated K+ channels.…”

“…Ionic channels in type I carotid body cells are believed to play important roles in chemotransduction (Peers & Buckler, 1995). We have previously shown that rats born and reared in chronic hypoxia (CH) show reduced functional expression of Ca?+ -activated K+ (Kca) channels (Wyatt et al 1995), as is the case in immature, normoxically reared rats (Hatton et al 1997). Here, we have investigated the effects of CH on K+ currents in adult rat type I cells.…”

Hypoxia. 4. Hypoxia and ion channel function

“…Recently, detailed molecular biological and electrophysiological studies have shown that T-type (transient) VGCCs are upregulated by CH in the rat pheochromocytoma cell line (PC12), O 2 -responsive cells that release neurotransmitters and possibly in other tissues (48). Interestingly, although the inhibitory effect of hypoxia on whole cell I K was intact after CH, a specific deficiency of K Ca channel activity was noted, leading to loss of depolarization in response to acute hypoxia (253), suggesting that some, but not all, of the O 2 -sensing machinery is impaired by CH.…”