Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways

Maladaptive changes in the carotid body (CB) induced by chronic intermittent hypoxia (IH) account for the pathogenesis of cardiovascular morbidity in patients with sleep-disordered breathing. We postulated that the proinflammatory cytokines, namely interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and cytokine receptors (IL-1r1, gp130 and TNFr1) locally expressed in the rat CB play a pathophysiological role in IH-induced CB inflammation. Results showed increased levels of oxidative stress (serum 8-isoprostane and nitrotyrosine in the CB) in rats with 7-day IH treatment resembling recurrent apneic conditions when compared with the normoxic control. Local inflammation shown by the amount of ED1-containing cells (macrophage infiltration) and the gene transcripts of NADPH oxidase subunits (gp91phox and p22phox) and chemokines (MCP-1, CCR2, MIP-1α, MIP-1β and ICAM-1) in the CB were significantly more in the hypoxic group than in the control. In addition, the cytokines and receptors were expressed in the lobules of chemosensitive glomus cells containing tyrosine hydroxylase and the levels of expressions were significantly increased in the hypoxic group. Exogenous cytokines elevated the intracellular calcium ([Ca2+]i) response to acute hypoxia in the dissociated glomus cells. The effect of cytokines on the [Ca2+]i response was significantly greater in the hypoxic than in the normoxic group. Moreover, daily treatment of IH rats with anti-inflammatory drugs (dexamethasone or ibuprofen) attenuated the levels of oxidative stress, gp91phox expression and macrophage infiltration in the CB. Collectively, these results suggest that the upregulated expression of proinflammatory cytokine pathways could mediate the local inflammation and functional alteration of the CB under chronic IH conditions

Involvement of nitric oxide in reduced large conductance calcium-activated potassium channel activity in rat hippocampal CA1 neurons in intermittent hypoxia

Poster SessionsThe aim of our study is to test the hypothesis that endogenous nitric oxide (NO) production is involved in the change of large conductance calcium-activated (BKca) channel activity in rat hippocampal CA1 neurons in intermittent hypoxia (IH). SpragueDawley rats (ca. 90 g) were exposed to IH (inspired oxygen levels cyclic between 5% and 21% at 60 cycle/h for 8 h diurnally for 3–10 days) or normoxia (N, in room air). The level of NO in hippocampal CA1 region was measured by NO microsensor with electrochemical method. Patch-clamping study with the excised inside-out configuration was performed on CA1 pyramidal neurons freshly dissociated from the hippocampal slices of IH or N rats. The effect of NO synthase inhibitor L-NMMA (100 lM) on the NO level was significantly less in the IH group than that of the N group, suggesting that the endogenous NO production decreased in the IH. There were no differences in unitary conductance between the IH and N groups with symmetrical 140/140 K+ on both sides of the excised membrane. The open probability of BKca channel activity reduced in the IH compared with that of the N group, due to a shortening of mean open time and prolongation of mean close time. NO donor SNP (100 lM) partially recovered the decrease in BKca channel activity in the IH group. The SNP action was prevented by pretreatment of thiol-specific alkylating agent NEM (1 mM), confirming an involvement of the NO mechanism. Taken together, our results suggest that lowering of NO level can cause a decrease in BKca channel activity in the hippocampal neuron during IH, which may lead to the neuronal hyperexcitability and hippocampal injuries in patients with severe sleep apnea. Acknowledgement: Study was supported by research grants from Research Grants Council, HKSAR, and the University Research Council of the University of Hong Kong.link_to_OA_fulltex