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. 2014 Jan 1:190:62-9.
doi: 10.1016/j.resp.2013.09.009. Epub 2013 Oct 2.

Non-additive interactions between mitochondrial complex IV blockers and hypoxia in rat carotid body responses

David F Donnelly  1 , Insook Kim, Eileen M Mulligan, John L Carroll
Affiliations

Non-additive interactions between mitochondrial complex IV blockers and hypoxia in rat carotid body responses

David F Donnelly et al. Respir Physiol Neurobiol. .

Abstract

The metabolic hypothesis of carotid body chemoreceptor hypoxia transduction proposes an impairment of ATP production as the signal for activation. We hypothesized that mitochondrial complex IV blockers and hypoxia would act synergistically in exciting afferent nerve activity. Following a pre-treatment with low dosage sodium cyanide (10-20μM), the hypoxia-induced nerve response was significantly reduced along with hypoxia-induced catecholamine release. However, in isolated glomus cells, the intracellular calcium response was enhanced as initially predicted. This suggests a cyanide-mediated impairment in the step between the glomus cell intracellular calcium rise and neurotransmitter release from secretory vesicles. Administration of a PKC blocker largely reversed the inhibitory actions of cyanide on the neural response. We conclude that the expected synergism between cyanide and hypoxia occurs at the level of glomus cell intracellular calcium but not at downstream steps due to a PKC-dependent inhibition of secretion. This suggests that at least one regulatory step beyond the glomus cell calcium response may modulate the magnitude of chemoreceptor responsiveness.

Keywords: Calcium; Carotid body; Chemoreceptors; Hypoxia; Mitochondria.

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Figures

Fig. 1
Fig. 1
Cyanide impairs the chemoreceptor response to graded hypoxia. (top) Polygraphic trace of action potentials recorded extracellularly from the soma of a petrosal neuron with projections to the carotid body. (middle) Rate tracing and superfusate oxygen level vs. time for unit pictured at top. Cyanide (NaCN, 10μM) was applied (solid bar) for 10 min starting around minute 7 prior to the start of a hypoxia challenge. Note transient increase in discharge frequency with cyanide and accommodation to the stimulus (**). (lower) Rate vs. O2 levels for the three hypoxia-trials. Note discharge frequency during hypoxia was lower in the presence of cyanide. Lines were fit to a Boltzman function.
Fig. 2
Fig. 2
Low dosages of cyanide cause little or transient increases in glomus cell calcium. Intracellular calcium responses of glomus cells to anoxia and different dosages of cyanide. At low dosages of cyanide (2-20μM) calcium either did not change or increased transiently. High dosages (>1mM) produced a maximal change in intracellular calcium.
Fig 3
Fig 3
Cyanide enhances the glomus cell calcium response to hypoxia. (top) Example of glomus cell [Ca+2]i response to graded hypoxia before, during and following cyanide (10μM) application. (lower) Mean±SEM calcium response for 15 glomus cells. Note the right-shift in the calcium/O2 relationship during cyanide exposures.
Fig. 4
Fig. 4
Cyanide impairs hypoxia-induced catecholamine release in addition to the afferent nerve activity. (top) Polygraphic trace of action potentials from a chemoreceptor unit recorded from the soma in the petrosal ganglion. (middle) Action potential rate and superfusate PO2 vs. time for unit pictured at top. Note reduced nerve response to hypoxia, similar to that presented in figure 1. Cyanide application indicated by a bar. (lower) Tissue catecholamine vs. time. Note reduced hypoxia-induced catecholamine release in the presence of cyanide.
Fig. 5
Fig. 5
Cyanide induced inhibition of the nerve response to hypoxia is reduced by pharmacologic PKC inhibition. (top) Polygraphic tracing of unit chemoreceptor AP activity recorded from the soma in the petrosal ganglia. (middle) AP rate and superfusate oxygen level vs. time. PKC blocker, Go-6983, and cyanide were applied at the same time for 10min before the hypoxia challenge. (lower). AP rate vs superfusate oxygen level for the three trials. Note that AP activity due to hypoxia was not reduced by cyanide in the presence of Go-6983, a PKC blocker as it was without the PKC blocker (see Fig 1).
Fig. 6
Fig. 6
Azide, like cyanide, reduces the afferent nerve response to hypoxia. (top) Polygraphic tracing of unit chemoreceptor activity recorded from the petrosal ganglion. (middle) AP rate and superfusate oxygen level vs. time. Azide application indicated by bar. (lower) AP rate vs. superfusate oxygen level for the three trials. Note that AP activity in response to hypoxia was reduced by azide.
Fig. 7
Fig. 7
H2S, like cyanide, reduces the afferent nerve response to hypoxia. (top) Polygraphic tracing of unit chemoreceptor activity recorded from the petrosal ganglion. (middle) AP rate and superfusate oxygen level vs. time. H2S application indicated by bar. (lower) AP rate vs. superfusate oxygen level for the three trials. Note that baseline AP activity was slightly enhanced by H2S but the response to hypoxia was greatly reduced.
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