Role of chemoreception in cardiorespiratory acclimatization to, and deacclimatization from, hypoxia.

During sojourn to high altitudes, progressive time-dependent increases occur in ventilation and in sympathetic nerve activity over several days, and these increases persist upon acute restoration of normoxia. We discuss evidence concerning potential mediators of these changes, including the following: 1) correction of alkalinity in cerebrospinal fluid; 2) increased sensitivity of carotid chemoreceptors; and 3) augmented translation of carotid chemoreceptor input (at the level of the central nervous system) into increased respiratory motor output via sensitization of hypoxic sensitive neurons in the central nervous system and/or an interdependence of central chemoreceptor responsiveness on peripheral chemoreceptor sensory input. The pros and cons of chemoreceptor sensitization and cardiorespiratory acclimatization to hypoxia and intermittent hypoxemia are also discussed in terms of their influences on arterial oxygenation, the work of breathing, sympathoexcitation, systemic blood pressure, and exercise performance.

Sleep state dependence of ventilatory long-term facilitation following acute intermittent hypoxia in Lewis rats.

Ventilatory long-term facilitation (vLTF) is a form of respiratory plasticity induced by acute intermittent hypoxia (AIH). Although vLTF has been reported in unanesthetized animals, little is known concerning the effects of vigilance state on vLTF expression. We hypothesized that AIH-induced vLTF is preferentially expressed in sleeping vs.

Upper airway pressure-flow relationships and pharyngeal constrictor EMG activity during prolonged expiration in awake goats.

We undertook the present investigation to establish whether narrowing/closure of the upper airway occurs during spontaneous and provoked respiratory rhythm disturbances and whether pharyngeal constrictor muscle recruitment occurs coincident with upper airway occlusion during prolonged expiratory periods. Upper airway pressure-flow relationships and middle pharyngeal constrictor (mPC) EMG activities were recorded in 11 adult female goats during spontaneous and provoked prolongations in expiratory time (Te). A total of 213 spontaneous prolongations of expiration were recorded.

Sustained hypoxia-induced proliferation of carotid body type I cells in rats.

Sustained hypoxia (SH) has been shown to cause profound morphological and cellular changes in carotid body (CB). However, results regarding whether SH causes CB type I cell proliferation are conflicting. By using bromodeoxyuridine, a uridine analog that is stably incorporated into cells undergoing DNA synthesis, we have found that SH causes the type I cell proliferation in the CB; the proliferation occurs mainly during the first 1-3 days of hypoxic exposure.

Environmental hyperoxia and development of carotid chemoafferent function.

Exposure to hyperoxia in the first few weeks of life causes life-long impairment of carotid chemoreceptor function in rats, e.g., depressed carotid sinus nerve (CSN) and phrenic nerve responses to acute hypoxia.

Respiratory plasticity after perinatal hyperoxia is not prevented by antioxidant supplementation.

Perinatal hyperoxia attenuates the hypoxic ventilatory response in rats by altering development of the carotid body and its chemoafferent neurons. In this study, we tested the hypothesis that hyperoxia elicits this plasticity through the increased production of reactive oxygen species (ROS). Rats were born and raised in 60% O(2) for the first two postnatal weeks while treated with one of two antioxidants: vitamin E (via milk from mothers whose diet was enriched with 1000 IU vitamin E kg(-1)) or a superoxide dismutase mimetic, manganese(III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP; via daily intraperitoneal injection of 5-10 mg kg(-1)); rats were subsequently raised in room air until studied as adults.

Carotid sinus nerve responses and ventilatory acclimatization to hypoxia in adult rats following 2 weeks of postnatal hyperoxia.

Adult rats have decreased carotid body volume and reduced carotid sinus nerve, phrenic nerve, and ventilatory responses to acute hypoxic stimulation after exposure to postnatal hyperoxia (60% O2, PNH) during the first 4 weeks of life. Moreover, sustained hypoxic exposure (12%, 7 days) partially reverses functional impairment of the acute hypoxic phrenic nerve response in these rats. Similarly, 2 weeks of PNH results in the same phenomena as above except that ventilatory responses to acute hypoxia have not been measured in awake rats.

Postnatal growth of the carotid body.

The size of the carotid body (CB) is increased significantly during the postnatal period. Type I cells in the CB are the chemoreceptive element and possess many neuron-like characteristics. In contrast to previous opinions that the number of type I cells is determined before birth, we have found that type I cells continue to proliferate over a period of at least 1 month after birth in rats.

Carotid chemoafferent plasticity in adult rats following developmental hyperoxia.

Developmental hyperoxia impairs carotid chemoreceptor development and induces long-lasting reduction in carotid sinus nerve (CSN) responses to hypoxia in adult rats. Studies were carried out to determine if CSN responses to acute hypoxia would exhibit hypoxia-induced plasticity in adult 3-5-months-old rats previously treated with postnatal hyperoxia (60% O2, PNH) of 1, 2, or 4 weeks duration. CSN responses to acute hypoxia were assessed in adult rats exposed to 1 week of sustained hypoxia (12% O2, SH).

Adult carotid chemoafferent responses to hypoxia after 1, 2, and 4 wk of postnatal hyperoxia.

Exposing newborn rats to postnatal hyperoxia (60% O2) for 1-4 wk attenuates the ventilatory and phrenic nerve responses to acute hypoxia in adult rats. The goal of this research was to increase our understanding of the carotid chemoreceptor afferent neural input in this depressed response with different durations of postnatal hyperoxic exposure. Rats were exposed from a few days before birth to 1, 2, or 4 wk of 60% O2 and studied after 3-5 mo in normoxia.

Level and duration of developmental hyperoxia influence impairment of hypoxic phrenic responses in rats.

Developmental hyperoxia (1-4 wk of 60% O2) causes long-lasting impairment of hypoxic phrenic responses in rats. We hypothesized that shorter or less severe hyperoxic exposures would produce similar changes. Hypoxic phrenic responses were measured in 3- to 5-mo-old, urethane-anesthetized rats exposed to 60% O2 for postnatal day 1 or week 1 or to 30% O2 for postnatal week 1.

Dopaminergic excitation of the goat carotid body is mediated by the serotonin type 3 receptor subtype.

The purpose of the present study was to use chemoafferent recordings from the goat carotid body (CB) to pharmacologically identify the putative low affinity excitatory receptor for dopamine (DA). Close arterial injections of DA (1-50 microg kg(-1)) induced a dose-dependent excitatory burst followed by inhibition of the CB chemoafferent activity. The inhibition is likely DA D(2) receptor-mediated as it was blocked by domperidone (0.

Chronic hypoxia-induced morphological and neurochemical changes in the carotid body.

The carotid body (CB) plays an important role in the control of ventilation. Type I cells in CB are considered to be the chemoreceptive element which detects the levels of PO(2), PCO(2), and [H(+)] in the arterial blood. These cells originate from the neural crest and appear to retain some neuronal properties.

Expression of 5-HT3 receptors in primary sensory neurons of the petrosal ganglion of adult rats.

By using a specific antiserum, expression of the 5-HT3 receptor was examined in the petrosal ganglion (PG) of adult male rats. We found that the 5-HT3 receptors are widely distributed in the PG. This finding was confirmed by RT-PCR detection of the 5-HT3 receptor mRNA in the tissue.

Life-long impairment of hypoxic phrenic responses in rats following 1 month of developmental hyperoxia.

Hypoxic ventilatory and phrenic responses are reduced in adult rats (3-5 months old) exposed to hyperoxia for the first month of life (hyperoxia treated). We previously reported that hypoxic phrenic responses were normal in a small sample of 14- to 15-month-old hyperoxia-treated rats, suggesting slow, spontaneous recovery. Subsequent attempts to identify the mechanism(s) underlying this spontaneous recovery of hypoxic phrenic responses led us to re-evaluate our earlier conclusion.

Induced recovery of hypoxic phrenic responses in adult rats exposed to hyperoxia for the first month of life.

1. Adult rats exposed to hyperoxia for the first month of life have permanently attenuated ventilatory and phrenic nerve responses to hypoxia. We tested the hypothesis that the blunted hypoxic phrenic response in hyperoxia-treated rats (inspired O(2) fraction, F(I,O2) = 0.

Ventilatory effects of alpha2-adrenoceptor blockade in awake goats.

We sought to determine the extent to which alpha2-adrenoceptor (alpha2-AR) pathways exert a tonic influence on respiratory rhythm under normal physiological conditions. The ventilatory effects of alpha2-AR blockade with SKF-86466 were examined in awake adult goats. The antagonist effect of SKF-86466 at alpha(2)-ARs was evident both as a reversal of the ventilatory disturbances produced by the alpha2-AR agonist clonidine (5 microg/kg IV) and as a rightward shift in the potency of the agonist-evoked response after SKF-86466 pretreatment.

Alpha2A-adrenoceptor mediated tachypnea in awake goats.

To further elucidate the role of alpha2-adrenoceptors (alpha2-ARs) in the control of respiratory rhythm we examined the ventilatory effects of guanfacine (a preferentially selective alpha2A-AR agonist) and clonidine (a non-selective alpha2-AR agonist) in awake adult goats. Systemic administration of guanfacine in cumulative doses (20 microg/kg; 140-180 microg/kg total cumulative dose) increased breathing in all animals in a dose-dependent manner. The excitatory effect was entirely mediated by increases in respiratory frequency.

Effect of 8-OH DPAT and ketanserin on the ventilatory acclimatization to hypoxia in awake goats.

We have previously reported that broad-spectrum serotonergic blockade increased the acute hypoxic ventilatory response in awake goats. The purpose of the present study was to examine the putative serotonin (5-HT) receptor subtype(s) that may have contributed to this response. Following the administration of the selective 5-HT(1A)-receptor agonist, 8-hydroxy-(2-di-n-propylamino) tetralin (8-OH DPAT, 0.

Clonidine induces upper airway closure in awake goats.

We examined the effects of the alpha(2)-adrenoceptor (alpha(2)-AR) agonist clonidine on pressure-flow relationships in the upper airway. Inspired and expired airflows, subglottic tracheal pressure (PTR), mask pressure and middle pharyngeal constrictor (MPC) and diaphragm electromyogram (EMG) activities were recorded in awake standing goats. Clonidine-induced central apneas were always associated with continuous tonic activation of the MPC.

Carotid body mechanisms in acclimatization to hypoxia.

Most studies oriented toward examining mechanisms increasing carotid body (CB) sensitivity to hypoxia during ventilatory acclimatization (VAH) have focussed on the role of known neuromodulators of CB function. Two general categories of the neuromodulatory agents studied most extensively could be considered: those thought to be primarily inhibitory to CB function: dopamine, norepinephrine, nitric oxide and those thought to be primarily excitatory: substance P, endothelin. There is evidence that these putative inhibitory agents are up-regulated in the first weeks of chronic hypoxia and that substance P is down-regulated.