Effect of prenatal nicotine exposure on biphasic hypoxic ventilatory response and protein kinase C expression in caudal brain stem of developing rats

Abstract

Current evidence suggests that maternal smoking is associated with decreased respiratory drive and blunted hypoxic ventilatory response (HVR) in the newborn. The effect of prenatal nicotine exposure on overall changes in HVR has been studied; however, there is limited data on the effect of nicotine exposure on each component of biphasic HVR. To examine this issue, 5-day timed-pregnant Sprague-Dawley rats underwent surgical implantation of an osmotic minipump containing either normal saline (Con) or a solution of nicotine tartrate (Nic) to continuously deliver free nicotine at 6 mg.kg of maternal weight(-1).day(-1). Rat pups at postnatal days 5, 10, 15, and 20 underwent hypoxic challenges with 10% O(2) for 20 min using whole body plethysmography. At postnatal day 5, Nic was associated with attenuation of peak HVR; peak minute ventilaton increased 44.0 +/- 6.8% (SE) from baseline in Nic pups, whereas that of Con pups increased 62.9 +/- 5.1% (P < 0.05). Nic pups also had a reduction in the magnitude of ventilatory roll-off; minute ventilation at 15 min decreased 7.3 +/- 7.1% in Nic pups compared with 27.3 +/- 4.0% in Con pups (P < 0.05). No significant difference in HVR was noted at postnatal days 10, 15, and 20. Hypercapnic response was similar at all ages. We further investigated the effect of prenatal nicotine exposure on PKC expression in the caudal brain stem (CB) of developing rats. At postnatal day 5, Nic was associated with increased expression of PKC-beta and PKC-delta in CB, whereas other PKC isoforms were not affected. It is concluded that prenatal nicotine exposure is associated with modulation of biphasic HVR and a selective increase in the expression of PKC-beta and PKC-delta within the CB of developing rats.

Prenatal to Early Postnatal Nicotine Exposure Impairs Central Chemoreception and Modifies Breathing Pattern in Mouse Neonates: A Probable Link to Sudden Infant Death Syndrome

“…This is in agreement with previous reports obtained in early postnatal rats and lambs, in which the ventilatory response to a "pure" hypoxic (not combined with hypercarbia) stimulus (StJohn and Leiter, 1999;Hafström et al, 2002;Simakajornboon et al, 2004) or the "Dejours test" (inhalation of 100% O 2 ) (Bamford and Carroll, 1999) were measured. Cells belonging to the peripheral chemosensory input undergo modifications such as increased expression of mRNA for tyrosine hydroxylase in carotid body and petrosal ganglion in P0 -P3 rats, and the augmented levels of dopamine ␤-hydroxylase in carotid bodies of P15 rats (Gauda et al, 2001).…”

“…In agreement with previous reports (Bamford and Carroll, 1999;St-John and Leiter, 1999;Hafström et al, 2002;Robinson et al, 2002;Simakajornboon et al, 2004), the dysfunction induced by perinatal nicotine upon ventilatory responses is transient and defines a vulnerable period from postnatal days 0 to 3-4. Whether this transient effect reflects a delayed process of maturation of the respiratory network or is the result of the time required for an adaptive reconfiguration of the network is unknown.…”

“…Postnatally, exposure to nicotine can be through breast milk or the environment . Although not all studies show similar results (Bamford et al, 1996;Slotkin et al, 1997;Bamford and Carroll, 1999), prenatal nicotine causes hypoventilation in rats (St-John and Leiter, 1999; Huang et al, 2004), increases the frequency of apnea during normoxia in mice and rats (Robinson et al, 2002;Huang et al, 2004), reduces hypoxiainduced ventilatory reflexes in awake rats and in sleeping lambs (St-John and Leiter, 1999;Hafström et al, 2002;Huang et al, 2004;Simakajornboon et al, 2004), reduces hypoxia-induced autoresuscitation from primary apnea in rat newborns (Fewell et al, 2001), and augments the delay in the awakening response induced by hypoxia in lambs (Hafström et al, 2002).…”

“…However, studies in animals have not consistently revealed that hypercarbia-induced ventilatory responses are compromised (Bamford and Carroll, 1999;Simakajornboon et al, 2004). Intense hypercarbia, which is expected during extreme physiological conditions, may be required to unmask subtle nicotine-induced deficits.…”

Differential Control of Central Cardiorespiratory Interactions by Hypercapnia and the Effect of Prenatal Nicotine

“…Maternal cigarette smoking has been reported to have no effect on ventilatory responses to hypoxia or hypercapnia (Lewis and Bosque, 1995) and diminish the hypoxic ventilatory responses and respiratory drive (Ueda et al, 1999). Similarly, it is reported that prenatal nicotine exposure both does not alter (Bamford et al, 1996) and attenuates the ventilatory response to hypoxia or hypercapnia in rats (Simakajornboon et al, 2004). The results from this study indicate that prenatal nicotine exposure does not alter central respiratory responses to hypercapnia and suggests any potential changes in the ventilatory responses to prenatal nicotine in vivo may depend on changes in the activity of peripheral chemoreceptors rather than within the medulla.…”