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The Role of RVLM and PACAP in Sympathetic Response and Breathing Stability

Published online by Cambridge University Press:  10 December 2015

F. Derakhshan ,
E. Mosca ,
P. Ciechanski ,
A. Roy  and
R. Wilson
F. Derakhshan
Affiliation:
Dept. of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary Dept. of Pathology, University of British Columbia
E. Mosca
Affiliation:
Dept. of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary
P. Ciechanski
Affiliation:
Dept. of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary
A. Roy
Affiliation:
Dept. of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary
R. Wilson
Affiliation:
Dept. of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary
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Abstract

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Canadian Journal of Neurological Sciences , Volume 42 , Issue S3: ABSTRACTS: 55th Annual Canadian Association of Neuropathologists Meeting , December 2015 , pp. S7
Copyright
Copyright © The Canadian Journal of Neurological Sciences Inc. 2015 

Intermittent hypoxic (IHx) episodes are typically a consequence of sleep apnea in adults and immature respiratory control in preterm infants. Chronic IHx contributes to immediate and long term co-morbidities including long-term cardiorespiratory instability. Despite intensive investigation, molecular mechanisms linking IHx to cardiorespiratory instability remain poorly understood.

We report that PACAP, a highly conserved excitatory neuropeptide which can function as an "emergency response" co-transmitter in the sympathoadrenal axis, plays a significant role in activating the sympathetic responses to hypoxia and stabilizing respiration. Further, we show that the effect of PACAP on the sympathetic response to intermittent hypoxia in adult rats is mainly regulated at the rostro-ventral-lateral medulla (RVLM).

To show the role of RVLM and PACAP in sympathetic response and breathing stability we used an in vivo anesthetized artificially ventilated rat preparation, as well as a neonatal rat in situ working heart-brainstem preparation and whole-body plethysmography.

Our data showed that inhibition of PACAP at the RVLM is able to dampen facilitated sympathetic activity caused by IHx. PACAP treated in-situ neonatal rat preparations with carotid bodies denervated showed less short-term variability in phrenic nerve output frequency when compared with vehicle treated preparations. All PACAP-null mice (n=5) died when exposed to acute IHx while all wild-type mice survived. Both frequency and minute ventilation were significantly decreased in PACAP-null mice during the last hypoxia. In another set of experiments we showed that exogenous PACAP replacement in PACAP-null mice can increase the survival rate by up to 80%.

Our data suggests a regulatory role for PACAP in the development of the sympathetic response and cardiorespiratory stability after exposure to IHx in adult and neonatal mice. The effect of PACAP on sympathetic plasticity is shown to be mediated through its action in the RVLM. To our knowledge and of great importance, PACAP is the first neuropeptide that is shown to be necessary to survive IHx.

Conflictsof Interest:

None.