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Hypoxia-induced dopamine (DA) release from carotid body (CB) glomus cells and activation of postsynaptic D(2) receptors have been proposed to play an important role in the neurotransmission process between the glomus cells and afferent nerve endings. To better resolve the role of D(2) receptors, we examined afferent nerve activity, catecholamine content and release, and ventilation of genetically engineered mice lacking D(2) receptors (D(2)(-/-) mice). Single-unit afferent nerve activities of D(2)(-/-) mice in vitro were significantly reduced by 45% and 25% compared with wild-type (WT) mice during superfusion with saline equilibrated with mild hypoxia (Po(2) approximately 50 Torr) or severe hypoxia (Po(2) approximately 20 Torr), respectively. Catecholamine release in D(2)(-/-) mice was enhanced by 125% in mild hypoxia and 75% in severe hypoxia compared with WT mice, and the rate of rise was increased in D(2)(-/-) mice. We conclude that CB transduction of hypoxia is still present in D(2)(-/-) mice, but the response magnitude is reduced. However, the ventilatory response to acute hypoxia is maintained, perhaps because of an enhanced processing of chemoreceptor input by brain stem respiratory nuclei.

The regulation of the chemoreceptor cell function by G proteins has been studied by measuring the release of 3H-labeled catecholamines ([3H]CA) in carotid bodies (CBs) treated with fluoride, cholera toxin (CTX), and pertussis toxin (PTX). Fluoride augmented the basal release of [3H]CA in a dose- (5-20 mM) and Ca(2+)-dependent manner. Nisoldipine (1 microM) and ethylisopropyl amiloride (EIPA; 10 microM) inhibited this effect by approximately 60%, and both drugs combined inhibited it in full. BAY K 8644 (1 microM) doubled the effect of fluoride. The effects of fluoride on the stimulus-evoked release of [3H]CA varied with the type of stimulus and the duration of the treatment. Simultaneous application of fluoride with the stimulus increased by five times the release evoked by hypoxia and by two times that by K+ and dinitrophenol (DNP). Preincubation with fluoride for 1 h caused an inhibition (approximately 70%) of the release evoked by high K+ and veratridine, whereas that evoked by DNP and low PO2 was still augmented (approximately 2 times). Preincubation (4 h) of the CBs with CTX (3 micrograms/ml) reduced by 54% the release of [3H]CA evoked by 35 mM K+ but did not affect that evoked by low PO2 or DNP. A similar treatment with PTX (1 microgram/ml) affected only the release of [3H]CA evoked by DNP, reducing it by 65%. The data show that fluoride, CTX, and PTX have different effects on the release of [3H]CA evoked by high external K+, DNP, and low PO2, indicating that the stimulus-secretion coupling process for each stimulus is differently regulated by G proteins.

Hypoxia-induced dopamine (DA) release from carotid body (CB) glomus cells and activation of postsynaptic D2 receptors have been proposed to play an important role in the neurotransmission process between the glomus cells and afferent nerve endings. To better resolve the role of D2 receptors, we examined afferent nerve activity, catecholamine content and release, and ventilation of genetically engineered mice lacking D2 receptors (D2-/- mice). Single-unit afferent nerve activities of D2-/- mice in vitro were significantly reduced by 45% and 25% compared with wild-type (WT) mice during superfusion with saline equilibrated with mild hypoxia (Po2 ∼50 Torr) or severe hypoxia (Po2 ∼20 Torr), respectively. Catecholamine release in D2-/- mice was enhanced by 125% in mild hypoxia and 75% in severe hypoxia compared with WT mice, and the rate of rise was increased in D2-/- mice. We conclude that CB transduction of hypoxia is still present in D2-/- mice, but the response magnitude is reduced. However, the ventilatory response to acute hypoxia is maintained, perhaps because of an enhanced processing of chemoreceptor input by brain stem respiratory nuclei. [ABSTRACT FROM AUTHOR]