Maternal nicotinic exposure produces a depressed hypoxic ventilatory response and subsequent death in postnatal rats

Abstract

In this study, we asked whether a “full term” prenatal nicotinic exposure (fPNE, 6 mg·kg−1·day−1 nicotinic delivery) over the full gestation, compared to a traditional PNE (tPNE) over the last two‐thirds of the gestation, caused a higher mortality following a remarkable depressed hypoxic ventilatory response (dHVR) independent of brain and pulmonary edema and change in serum corticosterone. P12‐14 pups pretreated with tPNE, fPNE or their vehicle (tCtrl and fCtrl) were exposed to 5% O2 for up to 60 min followed by harvesting the brain and lungs or anesthetized to collect blood for detecting arterial blood pH/gases and serum cotinine and corticosterone levels. We found that fPNE had little effect on baseline VE and heart rate, but consistently induced a dHVR and prolonged apnea that were rarely observed after tPNE. The severity of the dHVR in PNE pups were closely correlated to an earlier appearance of lethal ventilatory arrest (the hypoxia‐induced mortality). PNE did not induce brain and pulmonary edema, but significantly increased serum corticosterone levels similarly in tPNE and fPNE pups. Moreover, the accumulated nicotinic dose given to the individual was significantly higher in fPNE than tPNE pups, though there was no difference in serum cotinine levels and arterial blood pH/gases between the two groups. Our results suggest that nicotinic exposure at the early stage of gestation achieved by fPNE, rather than tPNE, is critical in generating the dHVR and subsequent death occurring independently of brain/pulmonary edema and changes in arterial blood pH/gases and serum corticosterone.

Prenatal nicotinic exposure upregulates pulmonary C-fiber NK1R expression to prolong pulmonary C-fiber-mediated apneic response

“…, 2000; Hafstrom et al , 2002). We previously showed that PNE significantly prolonged the apneic response and augmented pulmonary C-neural response to right atrial injection of capsaicin, proving the PNE-induced PCF plasticity (Zhuang J, 2014). Because PCF activation depresses hypoxic and hypercapnic ventilation that could be responsible for respiratory failure (see discussion in ref.…”

“…Our recent studies have shown that PNE sensitizes PCFs and prolongs the apneic response to right atrial bolus injection of capsaicin (Zhuang J, 2014). However, the mechanisms underlying this PNE modulation is unknown.…”

“…Because PCF activation depresses hypoxic and hypercapnic ventilation that could be responsible for respiratory failure (see discussion in ref. (Zhuang J, 2014)), it is important to investigate how PNE sensitizes and activates PCFs. Our results provide the first evidence to show that PCF NK1R upregulation by PNE is likely responsible for prolongation of the PCF-mediated apneic response.…”

“…Most importantly, these results are relevant to pathogenesis of SIDS as an overexpression of C-fibers has been observed in SIDS victims (Becker et al , 1993). Our previous study has shown that PNE-induced lethal apnea during hypoxia is causal to animal death (Zhuang et al , 2014). However, questions remain as to whether upregulation of PCF NK1R by PNE is uniquely involved in the respiratory failure in our study, and if so, how.…”

“…We targeted peripheral NK1R because PNE only increased NK1R expression in pulmonary C-neurons in our preliminary study. Ctrl (n = 6) and PNE pups (n = 10) were anesthetized and the right jugular vein was cannulated as reported before (Zhuang J, 2014). The ventilatory responses to bolus injection of capsaicin (10 μg/kg) into the right atrium were compared without and with right atrial injection of SR140333 (100 μg/kg), a peripheral and selective NK1R antagonist that completely blocked neurogenic inflammation (Emonds-Alt et al , 1993; Amann et al , 1995; Rupniak et al , 2003).…”