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Peripheral chemoreflex stimulation and adrenomedullin in the rostral ventrolateral medulla induces long-term facilitation of sympathetic activity in rats exposed to chronic intermittent hypoxia

      Adrenomedullin (ADM) increases mean arterial pressure and sympathetic nerve activity (SNA) when microinjected into the rostral ventrolateral medulla (RVLM) of anesthetized normotensive rats (Xu and Krukoff, 2007; AJP, 287, p R729). In conditions of hypoxia, ADM expression is elevated in the brain (Serrano et al., 2008; Brain Pathology, 18, p 434). Since acute intermittent hypoxia (10% O2) induces long term facilitation (LTF) of SNA in anesthetized rats (Xing & Pilowski, 2010; J. Physiol., 588, p 3075), we hypothesized that the combination of ADM injected into the RVLM with multiple peripheral chemoreflex activation induces LTF of SNA of rats submitted to chronic intermittent hypoxia (CIH). For 10 days male Wistar rats (19–21 days) were submitted to CIH (6% O2 for 40 s, every 9 min, 8 h/day, n=7) or maintained in normoxia (controls, n=8). On the 11th day, in situ working heart-brainstem preparations were made and the activity of thoracic sympathetic nerve (SNA) was recorded. Five sequential activations of peripheral chemoreceptors (0.05% KCN, 50 μl, i.a.) were performed before and after either bilateral ADM (100 fmol/100 nl) or saline injections (100 nl) into the RVLM. We observed that the combination of ADM injections and peripheral chemoreflex stimulations evoked LTF of SNA only in CIH but not in controls rats (140±47%, vs. control: 35±23% of baseline at 60 min, p<0.05). There was no LTF of SNA in CIH or control rats that were submitted to multiple peripheral chemoreflex activation with saline injected into RVLM. These results demonstrate that in rats submitted to CIH, ADM associated with multiple chemoreflex activation is involved in the development of LTF of SNA. These findings may explain, at least in part, the sympathetic overactivity observed in CIH rats.
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