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The ventilatory response to acute hypoxia in mammalian species is biphasic, an initial hyperventilatory response is followed by a reduction in ventilation within 2-3 min below the peak level (roll-off). Brain amino acid neurotransmitters also change during hypoxia. This study explores the role of neurotransmitters in anesthetized adult Sprague Dawley rats mechanically ventilated during 20 min of 10% O2 breathing. Phrenic nerve activity was recorded, and microdialysate concentrations of selected amino acids were determined at 3- to 5-min intervals in respiratory chemosensitive areas of the ventrolateral medulla (VMS) 1.25-2.00 mm below the surface. Phrenic nerve output was biphasic during hypoxia, concurrent with a rapid glutamate and gradual GABA increase. Taurine first decreased, then increased. In both intact and chemodenervated animals, time-dependent change in phrenic nerve activity during hypoxia was associated with corresponding changes in glutamate, GABA, and taurine concentrations, suggesting that cumulative effects of changes in the concentration of these three amino acids could account for response of the phrenic nerve to hypoxia.

Acute sustained hypoxia causes an early rise in ventilation, followed by a reduction in ventilation ("roll off") after several minutes to levels below the peak but above baseline. The underlying mechanism(s) of this biphasic response is unclear. Hypoxia induces changes in the release and metabolic turnover of glutamate and gamma aminobutyric acid (GABA). These endogenous neuroactive agents may play a role in mediating the biphasic hypoxic ventilatory response. Therefore, their role was studied in anesthetized (isoflurane), isocapnic, mechanically ventilated rats. Hypoxia alone (FIO2 = 0.1) produced the characteristic biphasic response in the phrenic neurogram (n = 6). When the glutamate receptor was blocked with application of two different N-methyl-D-aspartate (NMDA) antagonists, MK-801 or AP-5, to the ventrolateral medullary surface (VMS), the phrenic output fell by 90% during normoxia and demonstrated no response to hypoxia (n = 6 for each group). There was a rise of 60% in phrenic nerve output during normoxia when GABA antagonist bicuculline was applied to the VMS, and with hypoxia it rose another 15%, and no fall off was seen during hypoxia (n = 6). These findings suggest that during hypoxia the initial hyperventilation has a glutamatergic component and the subsequent fall off its mediated by GABAergic mechanisms.

Recent data suggest that the increase in ventilation during hypoxia may be related to the release of the excitatory amino acid neurotransmitter glutamate centrally. To further investigate this, we studied the effects of MK-801, a selective noncompetitive N-methyl-D-aspartate receptor antagonist, on the hypoxic ventilatory response in lightly anesthetized spontaneously breathing intact dogs. The cardiopulmonary effects of sequential ventriculocisternal perfusion (VCP) at the rate of 1 ml/min with mock cerebrospinal fluid (CSF, control) and MK-801 (2 mM) were compared during normoxia and 8 min of hypoxic challenge with 12% O2. Minute ventilation (VE), tidal volume (VT), and respiratory frequency (f) were recorded continuously, and hemodynamic parameters [heart rate (HR), blood pressure (MAP), cardiac output (CO), pulmonary arterial pressure, and pulmonary capillary wedge pressure] were measured periodically. Each dog served as its own baseline control before and after each period of sequential VCP under the two different O2 conditions. During 15 min of normoxia, there were no significant changes in the cardiopulmonary parameters with mock CSF VCP, whereas with MK-801 VCP for 15 min, VE decreased by approximately 27%, both by reductions in VT and f (17 and 9.5%, respectively). HR, MAP, and CO were unchanged. During 8 min of hypoxia with mock CSF VCP, VE increased by 171% associated with increased VT and f (25 and 125%, respectively). HR, MAP, and CO were likewise augmented. In contrast, the hypoxic response during MK-801 VCP was characterized by an increased VE of 84%, mainly by a rise in f by 83%, whereas the VT response was abolished. The cardiovascular excitation was also inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)

Glutamate stimulates resting ventilation by altering neural excitability centrally. Hypoxia increases central ventilatory drive through peripheral chemoreceptor stimulation and may also alter cerebral perfusion and glutamate metabolism locally. Therefore the effect of hypoxia and peripheral chemodenervation on cerebrospinal fluid (CSF) transfer rate of in vivo tracer amidated central nervous system glutamate was studied in intact and chemodenervated pentobarbital-anesthetized dogs during normoxia and after 1 h of hypoxia induced with 10 or 12% O2 in N2 breathing at constant expired ventilation and arterial CO2 tension. Chemodenervation was performed by bilateral sectioning of the carotid body nerves and cervical vagi. CSF transfer rates of radiotracer 13NH4+ and [13N]glutamine synthesized via the reaction, glutamate + NH4(+)----glutamine, in brain glia were measured during normoxia and after 1 h of hypoxia. At normoxia, maximal glial glutamine efflux rate jm = 103.3 +/- 11.2 (SE) mumol.l-1.min-1 in all animals. After 1 h of hypoxia in intact animals, jm = 78.4 +/- 10.0 mumol.l-1.min-1. In denervated animals, jm was decreased to 46.3 +/- 4.3 mumol.l-1.min-1. During hypoxia, mean cerebral cortical glutamate concentration was higher in denervated animals (9.98 +/- 1.43 mumol/g brain tissue) than in intact animals (7.63 +/- 1.82 mumol/g brain tissue) and corresponding medullary glutamate concentration tended to be higher in denervated animals. There were no differences between mean glutamine and gamma-aminobutyric acid concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

The lung vasculature responds to alveolar hypoxia by constriction and when the hypoxia is localized to one region of the lung, vasoconstriction is also localized to that region. Histamine has been alleged to have a role in the vasoconstrictor response with generalized alveolar and thus systemic hypoxia, but the role for histamine is not clear in localized alveolar hypoxia. Studies were, therefore, undertaken to determine the contribution of histamine to the localized pulmonary vasoconstrictor response to hypoxia. A divided tracheal cannula was used in anesthetized dogs which allowed for ventilation of one lung with oxygen to maintain normal systemic oxygenation (mean PaO2 =73 mm Hg) while the other lung was ventilated with nitrogen as an alveolar hypoxic stimulus. Perfusion to each lung was determined with the 133Xe technique utilizing external counters over the chest. Perfusion (Q) was decreased by 32% (P = 0.002) to the hypoxic lung after 10 minutes of unilateral nitrogen breathing. After intravenous infusion of 20 mg of chlorpheniramine maleate, a potent antihistamine, the decrease in Q to the hypoxic lung was unchanged at 30%. After 40-100 mg chlorpheniramine the decrease in perfusion was again unchanged at 34%. Therefore a significant role was not demonstrated for histamine in the regional pulmonary vasoconstrictor response to alveolar hypoxia in the absence of systemic hypoxemia.

Regional alveolar hypoxia in the lung induces regional pulmonary vasoconstriction which diverts blood flow from the hypoxic area. However, the predominant determinant of the distribution of perfusion in the normal erect lung is gravity so that more perfusion occurs at the base than at the apex. To determine the strength of the regional alveolar hypoxic response in diverting flow with or against the gravity gradient a divided tracheal cannula was placed in anesthetized dogs and unilateral alveolar hypoxia created by venilating one lung with nitrogen while ventilating the other lung with oxygen to preserve normal systemic oxygentation. Scintigrams of the distribution of perfusion obtained with intravenous 13-N and the MGH positron camera revealed a 34 and 32 per cent decrease in perfusion to the hypoxic lung in the supine and erect positions and a 26 per cent decrease in the decubitus position with the hypoxic lung dependent (P equal to 0.94 from supine shift), indicating nearly equal vasoconstriction with shift of perfusion away from the hypoxic lung in all positions. Analysis of regional shifts in perfusion revealed an equal vasoconstrictor response from apex to base in the supine position but a greater response in the lower lung zones in the erect position where perfusion was also greatest.

The role of prostaglandins as mediators of alveolar hypoxic vasoconstriction was investigated in dogs with the use of the prostaglandin synthesis inhibitors, aspirin and indomethacin. Alveolar hypoxia was induced by inserting double-lumened endotracheal tube into the carina and ventilating one lung with nigrogen while maintaining normal systemic oxygenation with 100% O(2) ventilation to the other lung. Relative perfusion to each lung was determined with 133Xenon and external counters. Infusions up to 25 mg/kg of indomethacin and up to 250 mg/kg of aspirin did not block the shift in perfusion from the alveolar hypoxic lung. In fact, the shift in perfusion from the alveolar hypoxic lung was slightly augmented by aspirin (P = 0.03). Thus, no positive role was demonstrated in the dog for prostaglandins in producing the vasoconstriction of alveolar hypoxia.

The role of angiotensin II in the pulmonary vasoconstriction induced by alveolar hypoxia was investigated with the competitive inhibitor of angiotensin, saralasin acetate. Unilateral alveolar hypoxia was induced in dogs by ventilation of one lung with 100% N2 through a double lumened endotracheal cannula while maintaining adequate systemic oxygenation by ventilating the other lung with 1oo% O2. Pulmonary perfusion was monitored with 133Xe and external detectors. In 8 dogs perfusion to the test lung on room air before N2 ventilation was 49.2% (SEM +/- 3.8) of total lung perfusion. After 7 min of nitrogen ventilation, perfusion to that lung was 35.6% (SEM +/- 2.9) of cardiac output (P less than 0.001), a reduction of 27.5% (SEM +/- 2.4). After infusion of 6--24 microgram.kg-1/min of saralasin acetate, beginning 2 min before the alveolar hypoxic challenge and continuing through it, unilateral alveolar hypoxia continued to reduce perfusion to that lung by 28.8% (P = 0.6 from control). In 2 dogs a higher infusion of 60 microgram.kg-1/min failed to reduce the alveolar hypoxic vasoconstriction and in 2 dogs a 15 min infusion of 6 microgram.kg-1 of saralasin acetate before alveolar hypoxia and continuing through it, still failed to inhibit alveolar hypoxic vasoconstriction. Thus, no role was demonstrated for angiotensin II in acute alveolar hypoxic vasoconstriction of the dog.

Central respiratory drive is very much dependent upon the CO2-tension, the H+-content and the ionic composition of the blood and the extracellular fluid of the brain. Ventilation is linearly related in the steady state to the H+-content in the cerebrospinal fluid (CSF). Semiaquatic turtles are an excellent model to study central chemical control of ventilation, and in particular their tolerance to asphyxia. Their ability to maintain prolonged dives is seemingly incongruous with highly-developed mechanisms of central chemical control of ventilation. Experiments were performed on four groups of turtles subjected to two hours of either apneic dives, hypercapnia, anoxia or anoxia plus hypercapnia. One additional group was breathing room air and served as control. At the end of the two-hour period the animals were immediately decapitated and the heads instantly frozen in liquid nitrogen. Brain tissue was removed from the skull and free aminoacids were measured chromatographically. Gamma-aminobutyric acid (GABA) increased significantly in those animals subjected to anoxia (p less than 0.01). These results suggest that the central ventilatory drive during diving and related experimental conditions may be related to alterations in brain concentrations of aminoacid neurotransmitters. GABA is a potent inhibitor of respiratory responses which may function under physiologic and pathophysiologic circumstances to modify ventilatory drive. The role of taurine is not yet clear and has to be further investigated.

Decreased ventilatory response to hypoxia has been reported in patients with CO2 retention. The CO2 retention increases cerebrospinal fluid (CSF) [HCO3-], which could modify the ventilatory response to hypoxia. In order to evaluate the effect of increased CSF [HCO3-] as a consequence of hypercapnia on the response to hypoxia, phrenic nerve output during 5 min of progressive hypoxia was measured in anesthetized vagotomized and mechanically ventilated dogs when their acid-base was normal and when CSF [HCO3-] had increased. Peak phrenic nerve activity (PPNA), inspiratory time (TI), and expiratory time (TE) were recorded in 2 groups of dogs. Two hypoxic tests were conducted 2.5 h apart in each group. One group had normal acid-base status and the second group after the first hypoxic challenge breathed 10% CO2 for 2 h, and then ventilation was adjusted to bring CSF pH back to normal. The CSF [HCO3-] then had increased by 5.2 mEq/L and CSF PCO2 was 14.6 mmHg higher. With CSF [HCO3-] elevation, PPNA activity in response to hypoxia was significantly depressed, compared with that in animals with normal acid-base balance, TI was increased indicating slowing of nerve discharge, and TE was minimally increased indicating lessening of frequency of neural bursts. We conclude that the metabolic component of acid-base balance in the central nervous system can influence the neural output of the respiratory centers in response to hypoxia as manifested by phrenic nerve output, and increased CSF [HCO3-] seen with hypercapnia is associated with depressed hypoxic response.