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Received August 5, 2003
Revised September 11, 2003
Accepted after revision November 3, 2003
1 University of Calgary
2 University of Victoria
* To whom correspondence should be addressed. E-mail: wilsonr{at}ucalgary.ca.
Pituitary-Adenylate-Cyclase-Activating Polypeptide (PACAP)-deficient mice are more prone to sudden death during postnatal weeks 1-3 than wildtype littermates. Given that PACAP is localized in brainstem regions associated with respiratory chemosensitivity, we examined whether PACAP-null neonates have reduced respiratory responses to hypoxia and hypercapnia. Using unrestrained, whole-body, flow-through plethysmography we found that, by post-natal day 4, the PACAP-null neonates had significantly reduced ventilation during baseline breathing, and blunted responses to both hypoxia (10% O2/90% N2) and hypercapnia (8% CO2/92% air). To determine whether the respiratory phenotype of the PACAP-null mice may contribute to their greater neonatal mortality, we used ECG to examine respiration and cardiovascular function of littermates. We demonstrate that, under conditions that exacerbate mortality of knockout but not wildtype animals, PACAP- deficient mice experience prolonged apneas that precede atrio-ventricular block. Both apneas and atrio- ventricular block were absent in wildtype littermates. These data suggest that PACAP-deficiency results in higher neonatal mortality primarily as a result of respiratory control defects and raise the possibility that mutations in genes coding components of PACAP signaling pathway may contribute to neonatal breathing disorders in humans.
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