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Peripheral chemoreflex induced long term facilitation of sympathetic nerve activity: Role of adrenomedullin in the rostral ventrolateral medulla

      Data from our laboratory indicates that protein levels for the adrenomedullin (ADM) receptor (Calcrl) are upregulated in the rostral ventrolateral medulla (RVLM) of the spontaneously hypertensive rat (SHR) compared to Wistar-Kyoto (WKY) rat. Further, ADM increases mean arterial pressure when microinjected into the RVLM of anesthetized normotensive rats (Xu and Krukoff, 2007; AJP, 287, p R729). In the present study we tested the hypothesis that ADM in the RVLM would cause a greater increase in sympathetic activity in the SHR than the WKY rat. Male WKY or SHR (4–5 weeks) were decorticated to make insentient and perfused intra-arterially (n=4–7/group). Five sequential activations of peripheral chemoreceptors (0.03% NaCN, 50 μl, i.a.) were performed before and after either bilateral ADM (100 fmol/100 nl) or saline injections (100 nl) into the RVLM. ADM in the RVLM with repeated peripheral chemoreflex challenges induced long term facilitation (LTF) of SNA in the SHR (100±19%, at 60 min), but not in the WKY rat. In contrast, multiple peripheral chemoreflex stimulation associated with saline into the RVLM did not induce LTF in the SNA in either SHR or WKY rats. The LTF of SNA observed in SHR was reduced by pre-treatment of the RVLM with ADM 22–52 (100 pmol/100 nl; ADM antagonist), H-89 (100 pmol/100 nl; PKA inhibitor) or by inhibiting PKA via virally mediated expression of a dominant negative form of PKA (PKIa), respectively, 9±12%, 29±12%, −21±7% (at 60 min, p<0.05 vs. ADM). These results demonstrate that in the SHR, but not WKY rats, ADM is involved in the development of LTF of SNA induced by repeated peripheral chemoreceptor stimulation, which is dependent on activation of PKA. These observations may have relevance to the excessive sympathetic activity generated in sleep apnoea patients.
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