Sudden neonatal death in PACAP‐deficient mice is associated with reduced respiratory chemoresponse and susceptibility to apnoea

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient mice are more prone to sudden death during postnatal weeks 1-3 than wild-type 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 postnatal day 4, the PACAP-null neonates had significantly reduced ventilation during baseline breathing, and blunted responses to both hypoxia (10% O 2 -90% N 2 ) and hypercapnia (8% CO 2 -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 wild-type animals, PACAP-deficient mice experience prolonged apnoeas that precede atrioventricular block. Both apnoeas and atrio-ventricular block were absent in wild-type 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 encoding components of the PACAP signalling pathways may contribute to neonatal breathing disorders in humans.

Pulmonary Hypertension and Right Heart Failure in Pituitary Adenylate Cyclase–Activating Polypeptide Type I Receptor–Deficient Mice

“…Recently, it has been suggested that PACAPdeficient mice suffer from reduced ventilation and a blunted response to hypoxia. 31 Taking into account these findings may lead to the assumption that bronchoconstriction promotes secondary pulmonary hypertension in PAC1-deficient mice. However, the observation that hypoxia in our PAC1-mutant mice occurred in rather late stages of the disease may account for the opposite, ie, the existence of primary pulmonary hypertension in PAC1-deficient mice.…”

Reproductive Endocrinology

“…Of note, other factors could influence testicular aging in this setting. It has been shown that PACAP Ϫ/Ϫ mice present numerous phenotypes, including high mortality and reduction in glucose levels [6]. In addition, PACAP has some structural homology with vasoactive intestinal peptide (VIP) and in a more limited fashion with GHRH, although testicular GnRH receptor expression seems to play a less important role than originally proposed.…”

Neural control of breathing: insights from genetic mouse models

“…PACAP is central to the early development of the central nervous system. Null mutant mice lacking PACAP exhibited hypoventilation during the neonatal period and were prone to sudden death preceded by prolonged apneas between 1 and 3 wk after birth (18). Furthermore, hypothermia worsened the respiratory depression.…”

“…Furthermore, studies have shown that PACAP is involved in chemosensitivity to oxygen. Null mutant newborn mice lacking the gene for PACAP had blunted ventilatory responses to hypoxia (18). In vitro data indicated that PACAP stimulated the carotid bodies (17).…”

“…Null mutant newborn mice with PACAP deficiency had a blunted ventilatory response to hypercapnia, suggesting that the PACAP signaling pathway may also contribute to the mechanisms underlying chemosensitivity to carbon dioxide (18). The role for potassium (K ϩ ) channels in the mechanisms underlying chemosensitivity to carbon dioxide was investigated using gene inactivation.…”