Functional and developmental studies of the peripheral arterial chemoreceptors in rat: effects of nicotine and possible relation to sudden infant death syndrome.

Abstract

The drive on respiration mediated by the peripheral arterial chemoreceptors was assessed by the hyperoxic test in 3-day-old rat pups. They accounted for 22.5 ± 8.8% during control conditions, but only for 6.9 + 10.0% after nicotine exposure, an effect counteracted by blockade of peripheral dopamine type 2 receptors (DA2Rs). Furthermore, nicotine reduced dopamine (DA) content and increased the expression of tyrosine hydroxylase (TH) in the carotid bodies, further suggesting that DA mediates the acute effect of nicotine on arterial chemoreceptor function. During postnatal development TH and DA2R mRNA levels in the carotid bodies decreased. Thus, nicotine from smoking may also interfere with the postnatal resetting of the oxygen sensitivity of the peripheral arterial chemoreceptors by increasing carotid body TH mRNA, as well as DA release in this period. Collectively these effects of nicotine on the peripheral arterial chemoreceptors may increase the vulnerability to hypoxic episodes and attenuate the protective chemoreflex response. These mechanisms may underlie the well-known relation between maternal smoking and sudden infant death syndrome.Epidemiological studies have shown a dose-dependent relationship between maternal smoking and sudden infant death syndrome (SIDS) (1-6). However, no clear mechanism(s) explaining this relation has been identified. Among numerous compounds present in cigarette smoke, nicotine is of particular interest, since it acts on the peripheral arterial chemoreceptors (7, 8), the most important organs in the defense against hypoxia (9-11). A deficient function of these chemoreceptors has been suggested to be one factor contributing to . This suggestion is supported by the findings that carotid body denervation caused unexpected death not only in lambs at 4-5 weeks of age (15, 16) but also in some children with asthma who were "treated" with bilateral carotid body resection (17). Moreover, denervation impaired survival of infant rats (18) and piglets (19). Nicotine is readily transferred in high concentrations to the fetus via the placenta and to the infant by the breast milk (20-23). In fact, a majority (-75%) of infants who succumbed by SIDS in Stockholm were exposed to nicotine shortly prior to death (24); this should be compared with the fact that only 18% of the mothers in Sweden smoke (25).High levels of dopamine (DA) have been found in carotid bodies of SIDS victims (13). This may be of relevance, since DA modulates peripheral arterial chemoreceptor activity in most species, including rats (26) and humans (27,28), and since DA is probably involved in the postnatal resetting of the peripheral arterial chemoreceptors from the low fetal to the high adult sensitivity (29-31). Furthermore, nicotine induces synthesis and release of carotid body DA in vitro (8). In vivo this effect of nicotine may interfere with the dopaminergic modulation of the hypoxic defense and with the postnatal development of the peripheral arterial chemoreceptors and thus relate smoking to SIDS.The present...

Role of Acetylcholine Receptors and Dopamine Transporter in Regulation of Extracellular Dopamine in Rat Carotid Body Cultures Grown in Chronic Hypoxia or Nicotine

“…In addition, we show that an ingredient of cigarette smoke, i.e., nicotine, which has previously been reported to attenuate the protective CB arterial chemoreflex response when administered chronically in mammals (Holgert et al, 1995), mimics the effect of chronic hypoxia in causing elevation of basal DA release in CB cultures. In general, the regulation of extracellular DA is likely to be important for CB function since the prevailing evidence suggests that released DA, acting via pre-and postsynaptic D 2 receptors, inhibits the CB hypoxic ventilatory response (see Gonzalez et al, 1994;Holgert et al, 1995) and appears to be involved in the resetting of CB chemosensitivity in the perinatal period (Hertzberg et al, 1990). In a recent study (Jackson and Nurse, 1997), we found that basal DA release was substantially elevated in rat CB cultures after chronic hypoxia in vitro.…”

“…Since nicotine can be readily transferred to the infant via the placenta prenatally and in breast milk postnatally (for refs. see Holgert et al, 1995), the possibility of continuous nicotine exposure in the perinatalperiod is quite high for the offspring of smoking mothers. Previous studies suggest that chronic nicotine administration to perinatal rats induces release and synthesis of CB DA, which acts on local D 2 recep-tors to produce inhibition of the hypoxic drive (Holgert et al, 1995).…”

“…see Holgert et al, 1995), the possibility of continuous nicotine exposure in the perinatalperiod is quite high for the offspring of smoking mothers. Previous studies suggest that chronic nicotine administration to perinatal rats induces release and synthesis of CB DA, which acts on local D 2 recep-tors to produce inhibition of the hypoxic drive (Holgert et al, 1995). Also, in the latter study it was suggested that nicotine could also interfere with the normal postnatal resetting of CB chemosensitivity, and collectively, these mechanisms could act to attenuate the protective chemoreflex response.…”

“…Nicotine is an active ingredient of cigarette smoke, and maternal smoking has been identified as a key risk factor in the development of sudden infant death syndrome (see Holgert et al, 1995;Slotkin et al, 1995). Since nicotine can be readily transferred to the infant via the placenta prenatally and in breast milk postnatally (for refs.…”

Environmental tobacco smoke and sudden infant death syndrome: a review

“…Dopamine is an inhibitory neuromodulator in this system, and a decrease in dopamine levels is generally noted after birth to facilitate oxygen sensitivity and normal breathing (Hertzberg et al, 1990). However, 12-24 hr after postnatal nicotine exposure in rat pups, carotid body dopamine and mRNA expression of the catecholamine synthesizing enzyme, tyrosine hydroxylase, increase, resulting in an inhibition of chemoreceptor sensitivity (Holgert et al, 1995). An increase in dopamine levels has also been seen in rat pups after prenatal (6 mg/kg/day) nicotine administration and early in the postnatal period through lactational exposure (Gauda et al, 2001).…”