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.