The evidence is mounting for a role for abnormal signaling of the stress peptide, pituitary adenylate cyclase activating polypeptide (PACAP), and its canonical receptor, PAC1, in the pathogenesis of sudden infant death syndrome (SIDS). In this study, we investigated whether the PACAP receptors, PAC1 or VPAC2, are involved in the neonatal cardiorespiratory response to hypercapnic stress. We used head-out plethysmography and surface ECG electrodes to assess cardiorespiratory responses to an 8% hypercapnic challenge in unanesthetized and spontaneously breathing 4 days old PAC1 or VPAC2 knockout (KO) and wildtype (WT) mouse pups. We demonstrate that compared to WTs, breathing frequency (RR) and minute ventilation () in PAC1 KO pups were significantly blunted in response to hypercapnia. Although heart rate was unaltered in PAC1 KO pups during hypercapnia, heart rate recovery post-hypercapnia was impaired. In contrast, cardiorespiratory impairments in VPAC2 KO pups were limited to only an overall higher tidal volume (V_T), independent of treatment. These findings suggest that PACAP signaling through the PAC1 receptor plays a more important role than signaling through the VPAC2 receptor, in neonatal respiratory responses to hypercapnia. Thus, deficits in PACAP signaling primarily via PAC1 may contribute to the inability of infants to mount an appropriate protective response to homeostatic stressors in childhood disorders such as SIDS.

中文翻译：

---

缺乏PAC1但没有VPAC2受体的新生小鼠对高碳酸血症的心肺反应受损

越来越多的证据表明，应激肽，垂体腺苷酸环化酶激活多肽（PACAP）及其规范受体PAC1的异常信号在婴儿猝死综合征（SIDS）的发病机理中起作用。在这项研究中，我们调查了PACAP受体PAC1或VPAC2是否参与了新生儿对高碳酸血症应激的心肺反应。我们使用抬头体积描记法和表面ECG电极评估了在麻醉和自发呼吸4天大的PAC1或VPAC2敲除（KO）和野生型（WT）小鼠幼崽时对8％高碳酸血症挑战的心肺反应。我们证明，与WTs相比，PAC1 KO幼崽的呼吸频率（RR）和分钟通气量（）对高碳酸血症的反应明显减弱。尽管在高碳酸血症期间PAC1 KO幼崽的心率没有改变，但高碳酸血症后的心率恢复受到损害。相比之下，VPAC2 KO幼崽的心肺功能障碍仅限于总体较高的潮气量（V_T），与治疗无关。这些发现表明，在新生儿对高碳酸血症的呼吸反应中，通过PAC1受体发出的PACAP信号比通过VPAC2受体发出的信号更重要。因此，主要通过PAC1引起的PACAP信号转导不足可能会导致婴儿无法对儿童疾病（如SIDS）中的稳态压力产生适当的保护性反应。