Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas

Abstract

Reflexes from the carotid body have been implicated in cardiorespiratory disorders associated with chronic intermittent hypoxia (CIH). To investigate whether CIH causes functional and/or structural plasticity in the carotid body, rats were subjected to 10 days of recurrent hypoxia or normoxia. Acute exposures to 10 episodes of hypoxia evoked long-term facilitation (LTF) of carotid body sensory activity in CIH-conditioned but not in control animals. The magnitude of sensory LTF depended on the length of CIH conditioning and was completely reversible and unique to CIH, because conditioning with a comparable duration of sustained hypoxia was ineffective. Histological analysis revealed no differences in carotid body morphology between control and CIH animals. Previous treatment with superoxide anion (O2.-) scavenger prevented sensory LTF. In the CIH-conditioned animals, carotid body aconitase enzyme activity decreased compared with controls. These observations suggest that increased generation of reactive oxygen species contribute to sensory LTF. In CIH animals, carotid body complex I activity of the mitochondrial electron transport is inhibited, suggesting mitochondria as one source of O2.- generation. These observations demonstrate that CIH induces a previously uncharacterized form of reactive oxygen species-dependent, reversible, functional plasticity in carotid body sensory activity. The sensory LTF may contribute to persistent reflex activation of sympathetic nerve activity and blood pressure in recurrent apnea patients experiencing CIH.

Fig. 1.

AIH induces sensory LTF in the carotid body in CIH animals. (A) Carotid body sensory activity in a control (Upper) and CIH-conditioned (Lower) animal. Pre-AIH is baseline activity; AIH #1 and AIH #10 represent the first and 10th episodes of AIH; impulses (Imp) per sec, integrated sensory discharge; A.P., action potentials. (B) Average changes in the sensory activity during AIH and during every 5 min of the post-AIH period. Average data represent mean ± SEM from control (n = 7) and 10 days CIH-conditioned (n = 7) animals. The shaded area represents the difference in baseline activity in CIH and control animals during the post-AIH period.

Fig. 2.

Characterization of CIH-induced sensory LTF in the carotid body. (A) Animals were conditioned with 0 (control, n = 7), 1 (1D, n = 5), 3 (3D, n = 6), and 10 days (10D, n = 7) of CIH. (B) Reversibility of LTF. Animals conditioned with 10 days of CIH were placed in room air for 3 (3D, n = 5) or 10 (10D, n = 6) days, and LTF was determined in response to AIH. (C) The effect of severity of hypoxia during CIH conditioning on the magnitude of sensory LTF. Animals were conditioned with either 5% (5% O₂, n = 7) or 10% (10% O₂, n = 6) inspired oxygen. From A to C, LTF was determined and expressed as the average percent of baseline activity during 60 min of post-AIH. Data are presented as mean ± SEM. **, P < 0.01; *, P < 0.05.

Fig. 3.

Conditioning with comparable cumulative duration of SH does not elicit sensory LTF. The effects of AIH were examined in control (n = 6) and animals conditioned with 4 h of SH (equivalent to the duration of hypoxia accumulated over 10 days of CIH conditioning, n = 5) as well as with multiple exposures to SH 4 h/day for 10 days (CSH, n = 7). Data represent mean ± SEM. Note the absence of significant sensory LTF in both groups of animals.

Fig. 4.

Sensory LTF in ex vivo carotid bodies. (A) Representative tracings of ex vivo carotid body activity from control (Upper) and CIH-conditioned (Lower) animals. Pre-AIH is baseline activity, and AIH #1 and AIH #10 represent the first and 10th AIH episodes, respectively. Impulses (Imp) per sec, integrated sensory discharge; A.P., action potentials. (B) Average changes in the sensory activity during AIH and during every 5 min of post-AIH. Data represent mean ± SEM from control and CIH animals (n = 6 carotid bodies in each group). The shaded area represents the differences in baseline activity in CIH-conditioned and control animals during the post-AIH period.

Fig. 5.

Involvement of in CIH-induced sensory LTF. Effect of CIH conditioning on mitochondrial complex I (A) and III (B) activities (eight rats, 16 carotid bodies in each group). (C) Effect of CIH on aconitase activity (eight rats, 16 carotid bodies in each group). (D) Effect of superoxide dismutase mimetic (MnTMPyP, 5 mg/kg per day for 10 days, n = 6) or vehicle (saline, n = 6) on CIH-induced sensory LTF. MnTMPyP prevents CIH-induced sensory LTF. Data are mean ± SEM. **, P < 0.01.