This mini-review summarizes the physiological adaptations to and pathophysiological consequences of intermittent hypoxia with special emphasis given to the pathophysiology associated with obstructive sleep apnea. Intermittent hypoxia is an effective stimulus for evoking the respiratory, cardiovascular, and metabolic adaptations normally associated with continuous chronic hypoxia. These adaptations are thought by some to be beneficial in that they may provide protection against disease as well as improve exercise performance in athletes. The long-term consequences of chronic intermittent hypoxia may have detrimental effects, including hypertension, cerebral and coronary vascular problems, developmental and neurocognitive deficits, and neurodegeneration due to the cumulative effects of persistent bouts of hypoxia. Emphasis is placed on reviewing the available data on intermittent hypoxia, making extensions from applicable information from acute and chronic hypoxia studies, and pointing out major gaps in information linking the genomic and cellular responses to intermittent hypoxia with physiological or pathophysiological responses.

This review is a summary of the effects of brain hypoxia on respiration with a particular emphasis on those studies relevant to understanding the cellular basis of these effects. Special attention is given to mechanisms that may be responsible for the respiratory depression that appears to be the primary sequela of brain hypoxia in animal models. Although a variety of potential mechanisms for hypoxic respiratory depression are considered, emphasis is placed on changes in the neuromodulator constituency of the respiratory neuron microenvironment during hypoxia as the primary cause of this phenomenon. Hypoxia is accompanied by a net increase in neuronal inhibition due to both decreased excitatory and increased inhibitory neuromodulator levels. A survey of hypoxia-tolerant cellular systems and organisms suggests that hypoxic respiratory depression may be a manifestation of the depression of cellular metabolism, which appears to be a major adaptation to limited oxygen availability in these systems.

The pre-Bötzinger complex (pre-BötC) has been proposed to be essential for respiratory rhythm generation from work in vitro. Much less, however, is known about its role in the generation and modulation of respiratory rhythm in vivo. Therefore we examined whether chemical stimulation of the in vivo pre-BötC manifests respiratory modulation consistent with a respiratory rhythm generator. In chloralose- or chloralose/urethan-anesthetized, vagotomized cats, we recorded phrenic nerve discharge and arterial blood pressure in response to chemical stimulation of neurons located in the pre-BötC with DL-homocysteic acid (DLH; 10 mM; 21 nl). In 115 of the 122 sites examined in the pre-BötC, unilateral microinjection of DLH produced an increase in phrenic nerve discharge that was characterized by one of the following changes in cycle timing and pattern: 1) a rapid series of high-amplitude, rapid rate of rise, short-duration bursts, 2) tonic excitation (with or without respiratory oscillations), 3) an integration of the first two types of responses (i.e., tonic excitation with high-amplitude, short-duration bursts superimposed), or 4) augmented bursts in the phrenic neurogram (i.e., eupneic breath ending with a high-amplitude, short-duration burst). In 107 of these sites, the phrenic neurogram response was accompanied by an increase or decrease (>/=10 mmHg) in arterial blood pressure. Thus increases in respiratory burst frequency and production of tonic discharge of inspiratory output, both of which have been seen in vitro, as well as modulation of burst pattern can be produced by local perturbations of excitatory amino acid neurotransmission in the pre-BötC in vivo. These findings are consistent with the proposed role of this region as the locus for respiratory rhythm generation.

This mini-review summarizes the present knowledge regarding central oxygen-chemosensitive sites with special emphasis on their function in regulating changes in cardiovascular and respiratory responses. These oxygen-chemosensitive sites are distributed throughout the brain stem from the thalamus to the medulla and may form an oxygen-chemosensitive network. The ultimate effect on respiratory or sympathetic activity presumably depends on the specific neural projections from each of these brain stem oxygen-sensitive regions as well as on the developmental age of the animal. Little is known regarding the cellular mechanisms involved in the chemotransduction process of the central oxygen sensors. The limited information available suggests some conservation of mechanisms used by other oxygen-sensing systems, e.g., carotid body glomus cells and pulmonary vascular smooth muscle cells. However, major gaps exist in our understanding of the specific ion channels and oxygen sensors required for transducing central hypoxia by these central oxygen-sensitive neurons. Adaptation of these central oxygen-sensitive neurons during chronic or intermittent hypoxia likely contributes to responses in both physiological conditions (ascent to high altitude, hypoxic conditioning) and clinical conditions (heart failure, chronic obstructive pulmonary disease, obstructive sleep apnea syndrome, hypoventilation syndromes). This review underscores the lack of knowledge about central oxygen chemosensors and highlights real opportunities for future research.

Recently, we identified a region located in the pre-Bötzinger complex (pre-BötC; the proposed locus of respiratory rhythm generation) in which activation of ionotropic excitatory amino acid receptors using DL-homocysteic acid (DLH) elicits a variety of excitatory responses in the phrenic neurogram, ranging from tonic firing to a rapid series of high-amplitude, rapid rate of rise, short-duration inspiratory bursts that are indistinguishable from gasps produced by severe systemic hypoxia. Therefore we hypothesized that this unique region is chemosensitive to hypoxia. To test this hypothesis, we examined the response to unilateral microinjection of sodium cyanide (NaCN) into the pre-BötC in chloralose- or chloralose/urethan-anesthetized vagotomized, paralyzed, mechanically ventilated cats. In all experiments, sites in the pre-BötC were functionally identified using DLH (10 mM, 21 nl) as we have previously described. All sites were histologically confirmed to be in the pre-BötC after completion of the experiment. Unilateral microinjection of NaCN (1 mM, 21 nl) into the pre-BötC produced excitation of phrenic nerve discharge in 49 of the 81 sites examined. This augmentation of inspiratory output exhibited one of the following changes in cycle timing and/or pattern: 1) a series of high-amplitude, short-duration bursts in the phrenic neurogram (a discharge similar to a gasp), 2) a tonic excitation of phrenic neurogram output, 3) augmented bursts in the phrenic neurogram (i.e., eupneic breath ending with a gasplike burst), or 4) an increase in frequency of phrenic bursts accompanied by small increases or decreases in the amplitude of integrated phrenic nerve discharge. Our findings identify a locus in the brain stem in which focal hypoxia augments respiratory output. We propose that the respiratory rhythm generator in the pre-BötC has intrinsic hypoxic chemosensitivity that may play a role in hypoxia-induced gasping.

ENERGY COSTS vary with an organ's functional needs. The same relationship applies within different regions of the same organ. In vivo regional differences in O t consumption are known within some organs, e.g., white and gray matter of the cerebral cortex, subepicardium, and subendocardium of the left ventricle, and cortex and medulla of the kidney. "3 Only qualitative evidence for these differences exist. We have developed a technique that can quantitatively measure these differences in regional O 2 consumption under different functional conditions. Regional Oj extraction is measured, using our recently developed microspectrophotometric technique, 4 -B and regional blood flow is determined with radioactive microspheres. Regional O 2 consumption is calculated from these data by the Fick principle.This method of determination of regional O, consumption has been applied to the heart where there are clear differences in cardiac work between the right, left, and septal ventricular walls. Until now, there has been no way to quantitate this difference in terms of O 2 consumption. Differences in blood flow have been reported between the ventricular walls, 6 ' 7 but no disparity has been found between the average arteriovenous O t difference of the right, septal, and left ventricular walls, although within the left ventricular wall some regional arteriovenous O s saturation differences exist. 8 We have studied O t extraction and flow in the same dog and determined differences in O t consumption between the ventricular walls.In the left ventricular free wall, there has been some qualitative evidence for regional differences in O 2 consumption as a function of depth within the wall. The

Upper airway collapsibility may be influenced by both muscular and nonmuscular factors. Because mucosal blood volume (and therefore vascular tone) is an important determinant of nasal airway patency, vascular tone may be an important nonmuscular determinant of pharyngeal collapsibility. This hypothesis was tested in two experimental models. First, upper airway closing (CP) and opening (OP) pressures and static compliance were measured in nine anesthetized, sinoaortic-denervated, paralyzed cats with isolated upper airways. Vascular tone was decreased with either papaverine or sodium nitroprusside (NTP), and increased with phenylephrine (PE), whereas blood pressure and end-tidal CO2 were maintained constant. Vasodilation increased CP (control = -10.4 +/- 1.3, NTP = -7.3 +/- 1.2 cm H2O; p less than 0.05) and OP (control = -7.9 +/- 1.5, NTP = -3.3 +/- 1.8 cm H2O; p less than 0.05). In contrast, vasoconstriction tended to decrease CP (control = -10.7 +/- 1.5, PE = -11.7 +/- 1.4 cm H2O; p less than 0.09) and OP (control = -8.1 +/- 1.2, PE = -9.9 +/- 1.9 cm H2O; p less than 0.1). Thus, vasodilation increased and vasoconstriction tended to decrease upper airway collapsibility. Upper airway static compliance was unchanged during either drug infusion. In order to assess changes in pharyngeal cross-sectional area (CSA) that occurred during vasodilation, magnetic resonance imaging was utilized in seven cats. During vasodilation with NTP, pharyngeal CSA was reduced from 0.44 +/- 0.10 to 0.30 +/- 0.09 cm2 (p less than 0.05), and pharyngeal volume was reduced from 15.3 +/- 2.4 to 13.9 +/- 2.7 cm3 (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Neurons within cardiorespiratory regions of the rostral ventrolateral medulla (RVLM) have been shown to be excited by local hypoxia. To determine the electrophysiological properties of these excitatory responses to hypoxia, we developed a primary dissociated cell culture system to examine the intrinsic response of RVLM neurons to hypoxia. Neonatal rat neurons plated on medullary astrocyte monolayers were studied using the whole cell perforated patch-clamp technique. Sodium cyanide (NaCN, 0.5-10 mM) was used, and membrane potential (V(m)), firing frequency, and input resistance were examined. In 11 of 19 neurons, NaCN produced a V(m) depolarization, an increase in firing frequency, and a decrease in input resistance, suggesting the opening of a cation channel. The hypoxic depolarization had a linear dose response and was dependent on baseline V(m), with a greater response at more hyperpolarized V(m). In 8 of 19 neurons, NaCN produced a V(m) hyperpolarization, decrease in firing frequency, and variable changes in input resistance. The V(m) hyperpolarization exhibited an all-or-none dose response and was independent of baseline V(m). These differential responses to NaCN were retained after synaptic blockade with low Ca(2+)-high Mg(2+) or TTX. Thus hypoxic excitation 1) is maintained in cell culture, 2) is an intrinsic response, and 3) is likely due to the increase in a cation current. These hypoxia-excited neurons are likely candidates to function as central oxygen sensors.