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We utilized selective carotid body (CB) perfusion while changing inspired O2 fraction in arterial isocapnia to characterize the non-CB chemoreceptor ventilatory response to changes in arterial PO2 (PaO2) in awake goats and to define the effect of varying levels of CB PO2 on this response. Systemic hyperoxia (PaO2 greater than 400 Torr) significantly increased inspired ventilation (VI) and tidal volume (VT) in goats during CB normoxia, and systemic hypoxia (PaO2 = 29 Torr) significantly increased VI and respiratory frequency in these goats. CB hypoxia (CB PO2 = 34 Torr) in systemic normoxia significantly increased VI, VT, and VT/TI; the ventilatory effects of CB hypoxia were not significantly altered by varying systemic PaO2. We conclude that ventilation is stimulated by systemic hypoxia and hyperoxia in CB normoxia and that this ventilatory response to changes in systemic O2 affects the CB O2 response in an additive manner.

This study was designed to examine the influence of carotid body (CB) hypocapnia on ventilation by selectively perfusing the CB through an extracorporeal circuit in 19 goats. When PcbCO2 was decreased from normocapnic levels in 14 awake goats (delta PcbCO2 = 10.9 Torr), PaCO2 increased 5.6 Torr (P less than 0.05) and VE decreased 24% (P less than 0.001) (mean values). The ventilatory sensitivity to inspired CO2 was not changed by CB hypocapnia in 5 of these goats, but the response was shifted to the right. During CB hypocapnia, ventilatory instability, including apnea, was observed in 4 of 14 goats; this irregular breathing continued at elevated levels of PaCO2. In 5 anesthetized goats, CB hypocapnia (delta PcbCO2 = 18.0 Torr) decreased VE by 70% in the intact state, but produced no significant ventilatory depression after CB denervation. We conclude that CB hypocapnia depresses ventilation in both awake and anesthetized goats mostly through CB chemoreceptor effects, and suggest that this hypoventilation may predispose to ventilatory instability in some animals.

Hypoxia isolated to the carotid body (CB) can induce time-dependent progressive hyperventilation (ventilatory acclimatization) in the absence of brain hypoxia. The studies reported in this paper were designed to determine if CNS hypoxia in the absence of CB hypoxia would affect ventilation over a 4 h period. In addition, the effect of 4 h of CNS hypoxia on the ventilatory responses to central chemoreceptor stimulation and to isolated CB stimulation were also determined. The studies were carried out in awake goats with CB blood gases controlled by an extracorporeal circuit while systemic (CNS) blood gases were determined independently by the level of inhaled gases. Systemic arterial P o 2 was reduced to 40 Torr while the CB was maintained normoxic and normocapnic. Systemic arterial P co 2 was kept isocapnic. The data obtained indicate that 4 h of CNS hypoxia produced mild hyperventilation that reached a peak after 30 min of hypoxia and was sustained for the entire period of hypoxia. There was no evidence of a time-dependent progressive hyperventilation, i.e. no acclimatization. In contrast to studies in which whole body hypoxia is induced, CNS hypoxia did not result in any changes in the ventilatory responses to either central or peripheral chemoreceptor stimulation after return to normoxic conditions. These findings suggest no significant role for CNS mechanisms induced by hypoxia in ventilatory acclimatization to hypoxia in goats.

Ventilatory afterdischarge (VAD) has been defined as a persistent gradually diminishing elevation of ventilatory activity that occurs after withdrawal of a variety of respiratory stimuli. The phenomenon has been well documented in the anesthetized cat, piglet, and lamb in response to electrical stimulation of the carotid sinus nerve. We sought to determine whether VAD could be demonstrated in the standing awake goat (n = 7) by use of an extracorporeal circuit to provide square-wave physiological stimulation of the carotid chemoreceptor (carotid body PO2 40 Torr). After 5 min of isolated carotid body stimulation, the mean time constants for diminishing inspired minute ventilation, tidal volume, and respiratory frequency were 27.7, 34.5, and 25.5 s, respectively. These results indicate that VAD does exist in the awake goat model. A critical factor for the demonstration of VAD is the maintenance of systemic arterial PCO2 (isocapnia) during the period of increased ventilatory activity. If arterial PCO2 is allowed to decrease even slightly during the hyperventilation, the magnitude and duration of VAD are greatly attenuated.

We have compared the ventilatory responses of intact and carotid body-denervated (CBD) goats to moderate [partial pressure of O2 in arterial blood; (Pao2) approximately 44 Torr] and severe (Pao2 approximately 33 Torr) many time points for up to 7 days of hypobaria. In the intact group there were significant time-dependent decreases in partial pressure of CO2 in arterial blood (PaCO2) in both moderate and severe hypoxemia (approximately-7 and -11 Torr) that were largely complete by 8 h of hypoxemia and maintained throughout. Acute restoration of normoxia in chronically hypoxic intact animals produced time-dependent increases in Paco2 over 2 h, but hypocapnia persisted relative to sea-level control. Arterial plasma [HCO3-] and [H+] decreased, and [Cl-] increased with a time course and magnitude consistent with developing hypocapnia. Chronic CBD, per se, resulted in a sustained, partially compensated respiratory acidosis, as PaCO2 rose 6 Torr and base excess rose 3 mEq/1, [Cl-] fell 1 mEq/1, and pHa fell 0.01 units. During exposure to identical levels of arterial hypoxemia as in the intact group. CBD animals showed no significant changes in PaCO2, [H+]a, or [HCO3-]a at any time during moderate or severe hypoxemia. Plasma [C1-] remained within the normal range throughout exposure to moderate hypoxia and increased in severe hypoxia. In a few instances some hypocapnia was observed, but this was highly inconsistent and was always less than one-third of that observed in intact goats. In contrast to intact goats, acute restorations of normoxia in the chronically hypoxic CBD goats always caused hyperventilation.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was designed to characterize the ventilatory interaction between central and carotid body (CB) chemoreceptor stimulation in awake goats undergoing selective CB perfusion. This model allowed us to expose central and CB chemoreceptors to separate blood gas conditions in an animal that is conscious and not systemically hypoxic. Systemic CO 2 ventilatory response curves, performed by progressively increasing FI CO2 in systemic hyperoxia, were completed in 7 goats during CB perfusion with hypercapnic-hypoxic blood and normocapnic-normoxic blood, and in 3 goats without CB perfusion. The slopes of the curves done with perfusion were not significantly different ( P > 0.05 ) in CB hypercapnic hypoxia and CB normocapnic normoxia for V E , V T , f and V T /T I , and the coefficients of variation of slopes generated with and without perfusion were similar. Our data indicate there is addition of central and CB chemoreceptor input in respiratory control, and we conclude that the previously demonstrated stimulus interaction at the CB is the primary source of the hyperadditive hypercapnic-hypoxic ventilatory interaction in an animal unaffected by anesthetics or brain hypoxia.

Dopamine (DA) is generally accepted to be an inhibitory neurotransmitter in the carotid body (CB). It is released and depleted from the CB by acute hypoxia. From this background we made the hypothesis that hypoxic depletion of CB DA could be responsible for a time-dependent increase in CB afferent output and the early phase of ventilatory acclimatization to hypoxia (VAH) in goats. We reasoned, then, that blockade of DA receptors in the CB would accelerate the time course of VAH in the goat, i.e. produce a greater acute response to hypoxia (first 15 min) followed by a reduced rate of change of the subsequent time-dependent hyperventilation. We tested this hypothesis by exposing 7 adult female goats to up to 28 h of hypobaric hypoxia (PB = 380 Torr) on 3 different occasions separated by at least 2 months. The first was as control. During the second and third exposures different doses of the DA antagonist, domperidone, were administered prior to and during the hypoxic exposure (0.5 mg/kg followed by 0.25 mg/kg every 3 h and in the second study 1.0 mg/kg followed by 0.5 mg/kg every 2 h). The time course of acclimatization was assessed by measurement of arterial blood gases and pH in the awake goats. The data obtained in the first 4-5 h of hypoxia in domperidone treated animals appeared to support the hypothesis. Domperidone treated animals had a significantly greater acute ventilatory response to hypoxia followed by a lower rate of progressive hyperventilation in this period. However, variation in control values, greater respiratory alkalosis and a secondary significant hyperventilation after 6-7 h of hypoxia in the domperidone treated animals prevents a clear conclusion as to the precise role of CB dopaminergic mechanisms in acclimatization to hypoxia. Nevertheless, peripheral DA receptor blockade with domperidone does alter the time course and magnitude of hyperventilation during the first 7 h of hypobaric hypoxia in goats.

Neurophysiological studies have demonstrated that a positive interaction between hypoxic and hypercapnic stimuli occurs at the carotid body (CB). The present study was designed to confirm that this interaction at the CB was translated into a similar interaction in the ventilatory response. By utilizing an awake goat model in which the CB could be selectively perfused using an extracorporeal circuit we avoided confounding central effects. In six goats the CB was stimulated by progressively decreasing PcbO2 from 160 to 40 Torr at two constant levels of PcbCO2, 36 and 61 Torr. The animals breathed room air with supplemental CO2 to maintain systemic isocapnia. The response to CB hypoxia was significantly greater in CB hypercapnia than in CB normocapnia for minute ventilation, tidal volume, respiratory frequency, and mean inspiratory flow rate. We conclude that the hypercapnic-hypoxic interaction at the CB is reflected in the ventilatory responses of the animal.

The carotid body (CB) perfusion model utilizes surgical vascular ligations to allow isolated blood supply to a single in situ CB in awake goats. The contralateral CB was excised. By use of an extracorporeal pump-oxygenator system the blood gas composition perfusing the CB can be controlled independently from that of the systemic arterial system including the brain. Using this model we compared the responses of systemically normoxic goats to CB hypercapnia and CB hypoxia. In 6 goats CB stimulation with hypercapnic-normoxic blood (mean PcbCO2 = 78 Torr, mean PcbO2 congruent to 100 Torr) produced acute hyperventilation (mean decrease in PaCO2 of 5.2 Torr, P less than 0.05) which remained constant over the 4-h perfusion period. Lack of a progressively increasing hyperventilation indicates that ventilatory acclimatization did not occur with hypercapnic CB perfusion. Hypoxic-normocapnic CB stimulation (mean PcbO2 = 40 Torr, mean PcbCO2 = 39 Torr) produced an acute mean decrease in PaCO2 of 5.5 Torr (P less than 0.05) in 6 additional goats. In contrast to CB hypercapnia, the acute hyperventilation induced by CB hypoxia was followed by a progressive time-dependent additional mean decrease in PaCO2 of 5.6 Torr (P less than 0.05) over a 4-h period (ventilatory acclimatization). These data are compatible with the concept of separate receptor mechanisms for hypercapnia and hypoxia in the CB and suggest that the early phase of ventilatory acclimatization to hypoxia in goats may result from a time-dependent increase in CB afferent output.