Prenatal nicotinic exposure augments cardiorespiratory responses to activation of bronchopulmonary C-fibers

Abstract

Rat pups prenatally exposed to nicotine (PNE) present apneic (lethal ventilatory arrest) responses during severe hypoxia. To clarify whether these responses are of central origin, we tested PNE effects on ventilation and diaphragm electromyography (EMGdi) during hypoxia in conscious rat pups. PNE produced apnea (lethal ventilatory arrest) identical to EMGdi silencing during hypoxia, indicating a central origin of this apneic response. We further asked whether PNE would sensitize bronchopulmonary C-fibers (PCFs), a key player in generating central apnea, with increase of the density and transient receptor potential cation channel subfamily V member 1 (TRPV1) expression of C-fibers/neurons in the nodose/jugular (N/J) ganglia and neurotrophic factors in the airways and lungs. We compared 1) ventilatory and pulmonary C-neural responses to right atrial bolus injection of capsaicin (CAP, 0.5 μg/kg), 2) bronchial substance P-immunoreactive (SP-IR) fiber density, 3) gene and protein expressions of TRPV1 in the ganglia, and 4) nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) protein in bronchoalveolar lavage fluid (BALF) and TrkA and TrkB genes in the ganglia between control and PNE pups. PNE markedly strengthened the PCF-mediated apneic response to CAP via increasing pulmonary C-neural sensitivity. PNE also enhanced bronchial SP-IR fiber density and N/J ganglia neural TRPV1 expression associated with increased gene expression of TrkA in the N/G ganglia and decreased NGF and BDNF in BALF. Our results suggest that PNE enhances PCF sensitivity likely through increasing PCF density and TRPV1 expression via upregulation of neural TrkA and downregulation of pulmonary BDNF, which may contribute to the PNE-promoted central apnea (lethal ventilatory arrest) during hypoxia.

Prenatal nicotinic exposure prolongs superior laryngeal C‐fiber–mediated apnea and bradycardia through enhancing neuronal TRPV1 expression and excitation

“…PNE pretreatment was the same as previously reported (10). Briefly, adult female rats were randomly designated to receivesaline(n =7,Ctrl)andnicotine(n =9,PNE)via a miniosmotic pump (0.25 ml/h for 28 d) (Alza, Palo Alto, CA, USA).…”

“…We recently found that PNE-induced death immediately after severe bradycardia and apneas during acute hypoxic exposure in rat pups at postnatal day (P)11-P14 (9). Prior to death, PNE also induced a remarkably prolonged apneic response to stimulation of bronchopulmonary C fibers (PCFs) (10). Besides PCFs, the superior laryngeal nerve (SLN) innervating the larynx (11,12) plays an important role in causing central apnea and bradycardia (13)(14)(15).…”

“…The SLCF-mediated apnea and bradycardia could be triggered by capsaicin (Cap) (18), a selective stimulant to transient receptor potential vanilloid 1 (TRPV1) (19). TRPV1 channels are located at the terminals of laryngeal afferents and in their cell bodies in the nodose/jugular (N/J) ganglia (10,20). To date, it has not been fully explored whether PNE affects SLCFs' TRPV1 receptors to alter the apneic and bradycardia responses.…”

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

“…The PNE pretreatment was the same as previously reported (Zhuang et al , 2015). Briefly, the adult females were randomly designated to receive vehicle (n = 25) and nicotine (n = 44) respectively via a mini-osmotic pump (0.25 μL/hr for 28 days, Alza Corp., Palo Alto, CA).…”

“…, 2009; Stephan-Blanchard et al , 2013). Our recent study showed a plasticity of bronchopulmonary C-fibers (PCFs) in PNE rat pups (Zhuang et al , 2015). This plasticity is characterized by a remarkable prolongation of the apneic response and augmentation of pulmonary C-neural response to right atrial injection of capsaicin, a selective stimulant to PCFs.…”