Patrick L. Janssen

Lack of long-term facilitation of ventilation after exposure to hypoxia in goats.

Episodic hypoxia has been shown to induce augmented normoxic ventilatory drive or long-term facilitation (LTF, continued hyperventilation after termination of hypoxic stimulation) in awake dogs and awake goats. The main objective of these experiments was to examine whether continuous isocapnic hypoxia in awake goats elicits LTF and additionally, to determine if goats exhibit hypoxic ventilatory decline (roll-off) during the hypoxic exposure. Goats were exposed to either 4 h of isocapnic hypoxia (n = 10) or 30 min of isocapnic hypoxia (n = 7). Ventilation (VE), tidal volume and frequency were measured before, during and following the end of the isocapnic hypoxia (PaO2 40 Torr) exposure. During the 4 h period of hypoxia, VE increased in a time-dependent manner in a typical pattern of acclimatization, reaching a mean of 40.8 +/- 3.6 L/min at the end of 4 h. Five minutes after return to normoxia, VE was 13.0 +/- 0.8 L/min, not different than control VE (13.1 +/- 0.9 L/min) measured prior to the hypoxic exposure and remained unchanged from this value for another 30 min. During the 30 min hypoxic exposure, VE increased upon exposure to hypoxia, remained significantly elevated throughout the hypoxic exposure, but promptly returned to control levels upon return to normoxia. These results indicate that continuous isocapnic hypoxia elicits neither long term facilitation of ventilation nor hypoxic ventilatory decline in awake goats.

Carotid body dopaminergic mechanisms are functional after acclimatization to hypoxia in goats

Ventilatory acclimatization to sustained hypoxia (VASH) is the time-dependent increase in ventilation that occurs during prolonged exposure to hypoxia. We tested the hypothesis that carotid body (CB) dopaminergic mechanisms are down-regulated during VASH, which would allow CB afferent discharge and ventilation to increase beyond the initial response to hypoxia. Domperidone (DOM; 1.0 mg.kg-1) was administered intravenously to block CB dopamine (DA) receptors after VASH was complete in awake goats. DOM caused a significant augmentation of the ventilatory response to hypoxia in acclimatized goats, failing to support the hypothesis. We conclude that inhibitory CB dopaminergic function is not significantly reduced following prolonged hypoxia, and that down-regulation of CB dopaminergic mechanisms may not be involved in VASH in the goat.

Intracarotid dopamine infusion does not prevent acclimatization to hypoxia

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation that occurs during sustained exposure to hypoxia. The mechanism for VAH remains elusive. We sought to determine whether a deficiency in the availability of carotid body dopamine is the mechanism of increased ventilatory responsiveness to hypoxia during VAH in awake goats. This was based on the evidence that dopamine (DA) is primarily an inhibitory neuromodulator of carotid body (CB) function. The hypothesis was tested by intracarotid infusion of DA (5.0 micrograms kg-1 min-1) throughout VAH. VAH was not prevented by DA infusion, failing to support the hypothesis. We conclude that a deficiency in the availability of inhibitory DA release within the CB is probably not responsible for VAH. However, increased ventilatory responses to acute hypoxia after either prolonged DA infusion or hypoxia may have similar CB mechanisms.

Dopaminergic excitation in goat carotid body may be mediated by serotonin receptors.

Dopamine (DA) is a prominent neurotransmitter that is found in relatively large quantities in type I cells of the carotid body (CB) of different mammals (Engwall et al. 1989; Gonzalez et al. 1994). The role of DA in CB function has been studied extensively yet it remains controversial (Gonzalez et al. 1994; Bisgard and Neubauer 1995). There is strong evidence indicating that DA has a modulatory role that is inhibitory to the chemosensory activity of the CB. Thus, exogenous administration of DA inhibits CB discharge in dogs (Bisgard et al 1979), cats (Black et al. 1972; Zapata 1975; Llados and Zapata 1978; Nishino and Lahiri 1981; Okajima and Nishi 1981), rabbits (Docherty and McQueen 1979), rats (Cardenas and Zapata 1981) and goats (Bisgard et al. 1997). Consistent with these observations exogenous DA depresses ventilation in animals (Black et al. 1972; Zapata and Zuazo 1980; Cardenas and Zapata 1981; Nishino and Lahiri 1981; Kressin et al. 1986; Janssen et al. 1998; O’Halloran et al. 1998) and human subjects (Welsh et al. 1978) whereas peripheral DA-receptor blockade stimulates ventilation and CB neural activity (Zapata and Torrealba 1984; Kressin et al. 1986; Janssen et al. 1998) and attenuates

Effects of Continuous Intracarotid Infusion of Dopamine During Long-Term Hypoxia in Awake Goats

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation that occurs in mammals (including humans) during prolonged exposure to hypoxic environments. Goats acclimatize rapidly, reaching a ventilatory plateau within 4–6 hours of breathing hypoxic gas (Engwall & Bisgard, 1990). Evidence strongly suggests that VAH is caused by a time-dependent increase in carotid body (CB) sensitivity to hypoxia in goats (Nielsen et al, 1988). However, the mechanism for increased CB hypoxic sensitivity remains unknown.

Carotid body dopaminergic mechanisms during acclimatization to hypoxia

Increased carotid body sensitivity to hypoxia has been found to be an important component of the mechanism of ventilatory acclimatization to chronic hypoxia. Considerable attention has been focused on the potential role of dopamine in the mechanism of increased carotid body sensitivity to hypoxia. This is related to the likely important role dopamine plays in carotid body function. Dopamine has a well-established role as having an inhibitory modulatory effect on the carotid body. For example, dopamine infusion inhibits carotid body responses to hypoxia and dopamine D2 receptor blockade causes an increased response of the carotid body to hypoxia. Thus, it has been hypothesized that a down-regulation of dopaminergic inhibition could be occurring within the carotid body making it more responsive to hypoxia during ventilatory acclimatization to prolonged hypoxia. A study in cats [1] supported this hypothesis. The investigators used domperidone, a peripheral dopamine D2 receptor antagonist, and found that it was no longer effective in increasing the ventilatory and carotid body responses to hypoxia after acclimatization, suggesting that dopamine inhibition had been abolished. However, similar studies failed to support this finding in goats [2] or human subjects [3]. In goats and dogs dopamine has a biphasic effect on carotid body activity, eg a bolus intra-carotid infusion of dopamine causes a burst of excitation followed by prolonged inhibition of afferent discharge frequency. A low affinity excitatory carotid body dopamine receptor has been postulated [4]. We made the hypothesis that there could be a facilitated dopaminergic excitation within the carotid body during acclimatization to hypoxia. This hypothesis would be compatible with the greatly increased metabolism of dopamine that occurs in the carotid body during chronic hypoxia [5]. If the dopamine-mediated excitation could be blocked, then one could test this hypothesis. After an extensive search of dopaminergic antagonists, we found that the dopamine excitatory activity was mediated by the serotonin type 3 receptor (5HT3) and that this excitatory activity could be blocked by specific 5HT3 antagonists such as tropisetron.Tropisetron blocked not only the excitatory activity induced by serotonin, but also that produced by dopamine and by the specific 5HT3 agonist, chlorophenylbiguanide, in the goat carotid body. Carotid sinus nerve recording studies showed that the response of the goat carotid body to acute hypoxia was significantly attenuated by tropisetron. Further studies in awake goats were carried out in order to test the hypothesis that 5HT3 antagonists could block ven- tilatory acclimatization to hypoxia. Blockade with tropisetron failed to modify the time-dependent increase in ventilation that occurs in goats during ventilatory acclimatization. Our data provide no evidence to support the hypothesis that carotid body dopamine acting via either dopaminergic or 5HT3 receptors mediates ventilatory acclimatization to hypoxia in the goat.

The Role of Carotid Body CO2 During Ventilatory Acclimatization to Hypoxia in the Goat

During a prolonged exposure to hypoxia, ventilation ( VE ) increases in a time-dependent manner. Ventilatory acclimatization to hypoxia (VAH) is associated with an increase in carotid body (CB) hypoxic sensitivity (Engwall & Bisgard, 1990; Ryan et al, 1993). The increased hypoxic sensitivity has been demonstrated under both systemic isocapnic or poikilocapnic conditions (Engwall & Bisgard, 1990). However, carotid body (CB) hypocapnia has a fairly strong inhibitory influence on normoxic ventilation in the awake goat (Daristotle et al, 1990) and dog (Smith et al, 1995). The objective of this study was to determine whether the increase in CB hypoxic sensitivity is dependent on the level of CB CO2 pressure (PcbCO2) during the hypoxic exposure.

Inhibitory Dopaminergic Mechanisms are Functional in Peripherally Chemodenervated Goats

Dopamine (DA) is a prominent amine that is found in relatively large quantities in type I cells of the carotid body (CB) of different mammals9. Studies have indicated that DA in the CB acts as a neuromodulator of CB function. Much evidence indicates that DA has a modulatory role which is inhibitory to the chemosensory activity of the CB. Thus, exogenous administration of DA inhibits CB discharge1,4,5,7,14,18,21–23and depresses ventilation2,5,6,10,18,22in animals and human subjects20, while peripheral DA receptor blockade stimulates ventilation and CB neural activity4,10,12,23. However, there have been a number of observations which suggest that CB inhibition may not be the only mechanism by which DA can inhibit ventilation. Ventilatory depressant effects of DA persist in hyperoxia2, 18,22and in CB denervated (CBD) animals1,2,6,22. It is not clear, however, whether these effects are mediated through dopaminergic mechanisms. In the present study, we wished to: 1) examine if inhibitory dopaminergic mechanisms are functional in peripherally chemodenervated goats and 2) determine what proportion of the inhibitory ventilatory response to DA is mediated through CB mechanisms. Our data provides evidence for both CB mediated and non-CB mediated inhibitory effects of DA on respiratory motor output in anesthetized goats.