Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary , Calgary, Alberta , Canada.
Department of Pediatrics, Alberta Children's Hospital Research Institute, University of Calgary , Calgary, Alberta , Canada.
Am J Physiol Regul Integr Comp Physiol. 2019 May 1;316(5):R594-R606. doi: 10.1152/ajpregu.00250.2018. Epub 2019 Feb 13.
The stress peptide pituitary adenylate cyclase activating polypeptide (PACAP) and its specific receptor PACAP type 1 receptor (PAC1) have been implicated in sudden infant death syndrome (SIDS). PACAP is also critical to the neonatal cardiorespiratory response to homeostatic stressors identified in SIDS, including hypoxia. However, which of PACAP's three receptors, PAC1, vasoactive intestinal peptide receptor type 1 (VPAC1), and/or vasoactive intestinal peptide receptor type 2 (VPAC2), are involved is unknown. In this study, we hypothesized that PAC1, but not VPAC2, is involved in mediating the cardiorespiratory response to hypoxia during neonatal development. To test this hypothesis, head-out plethysmography and surface ECG electrodes were used to assess the cardiorespiratory variables of unanesthetized postnatal PAC1 and VPAC2-knockout (KO) and wild-type (WT) mice in response to a 10% hypoxic challenge. Our results demonstrate that compared with WT pups, the early and late hypoxic rate of expired CO (V̇co), V̇co and ventilatory responses were blunted in PAC1-KO neonates, and during the posthypoxic period, minute ventilation (V̇e), V̇co and heart rate were increased, while the increase in apneas normally associated with the posthypoxic period was reduced. Consistent with impaired cardiorespiratory control in these animals, the V̇e/V̇co slope was reduced in PAC1-KO pups, suggesting that breathing was inappropriately matched to metabolism. In contrast, VPAC2-KO pups exhibited elevated heart rate variability during hypoxia compared with WT littermates, but the effects of the VPAC2-KO genotype on breathing were minimal. These findings suggest that PAC1 plays the principal role in mediating the cardiorespiratory effects of PACAP in response to hypoxic stress during neonatal development and that defective PACAP signaling via PAC1 may contribute to the pathogenesis of SIDS.
应激肽垂体腺苷酸环化酶激活肽（PACAP）及其特异性受体 PACAP 型 1 受体（PAC1）与婴儿猝死综合征（SIDS）有关。PACAP 对于新生儿对 SIDS 中确定的稳态应激的心肺反应也很关键，包括缺氧。然而，哪种 PACAP 的三种受体，PAC1、血管活性肠肽受体 1 型（VPAC1）和/或血管活性肠肽受体 2 型（VPAC2）参与其中尚不清楚。在这项研究中，我们假设 PAC1，但不是 VPAC2，参与介导新生儿发育过程中缺氧的心肺反应。为了验证这一假设，我们使用头外体积描记法和表面心电图电极来评估未麻醉的 PAC1 和 VPAC2 敲除（KO）和野生型（WT）小鼠在 10%低氧挑战下的心肺变量。我们的结果表明，与 WT 幼鼠相比，PAC1-KO 新生儿的早期和晚期缺氧呼气 CO 速率（V̇co）、V̇co 和通气反应减弱，在缺氧后期间，分钟通气量（V̇e）、V̇co 和心率增加，而通常与缺氧后期间相关的呼吸暂停增加减少。与这些动物心肺控制受损一致，PAC1-KO 幼鼠的 V̇e/V̇co 斜率降低，表明呼吸与代谢不匹配。相比之下，与 WT 同窝仔相比，VPAC2-KO 幼鼠在缺氧期间表现出更高的心率变异性，但 VPAC2-KO 基因型对呼吸的影响最小。这些发现表明，PAC1 在介导 PACAP 对新生儿发育期间缺氧应激的心肺作用中起主要作用，而通过 PAC1 的缺陷 PACAP 信号可能导致 SIDS 的发病机制。
