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. 1995 Aug 1;92(16):7575–7579. doi: 10.1073/pnas.92.16.7575

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

H Holgert 1, T Hökfelt 1, T Hertzberg 1, H Lagercrantz 1
PMCID: PMC41382  PMID: 7638233

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bisgard G. E., Forster H. V., Klein J. P., Manohar M., Bullard V. A. Depression of ventilation by dopamine in goats--effects of carotid body excision. Respir Physiol. 1980 Jun;40(3):379–392. doi: 10.1016/0034-5687(80)90036-5. [DOI] [PubMed] [Google Scholar]
  2. Blanco C. E., Dawes G. S., Hanson M. A., McCooke H. B. The response to hypoxia of arterial chemoreceptors in fetal sheep and new-born lambs. J Physiol. 1984 Jun;351:25–37. doi: 10.1113/jphysiol.1984.sp015229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brodie B. B., Costa E., Dlabac A., Neff N. H., Smookler H. H. Application of steady state kinetics to the estimation of synthesis rate and turnover time of tissue catecholamines. J Pharmacol Exp Ther. 1966 Dec;154(3):493–498. [PubMed] [Google Scholar]
  4. Bunzow J. R., Van Tol H. H., Grandy D. K., Albert P., Salon J., Christie M., Machida C. A., Neve K. A., Civelli O. Cloning and expression of a rat D2 dopamine receptor cDNA. Nature. 1988 Dec 22;336(6201):783–787. doi: 10.1038/336783a0. [DOI] [PubMed] [Google Scholar]
  5. Bureau M. A., Lamarche J., Foulon P., Dalle D. Postnatal maturation of respiration in intact and carotid body-chemodenervated lambs. J Appl Physiol (1985) 1985 Sep;59(3):869–874. doi: 10.1152/jappl.1985.59.3.869. [DOI] [PubMed] [Google Scholar]
  6. Cardenas H., Zapata P. Dopamine-induced ventilatory depression in the rat, mediated by carotid nerve afferents. Neurosci Lett. 1981 Jun 12;24(1):29–33. doi: 10.1016/0304-3940(81)90354-2. [DOI] [PubMed] [Google Scholar]
  7. Czyzyk-Krzeska M. F., Bayliss D. A., Lawson E. E., Millhorn D. E. Regulation of tyrosine hydroxylase gene expression in the rat carotid body by hypoxia. J Neurochem. 1992 Apr;58(4):1538–1546. doi: 10.1111/j.1471-4159.1992.tb11376.x. [DOI] [PubMed] [Google Scholar]
  8. Czyzyk-Krzeska M. F., Lawson E. E., Millhorn D. E. Expression of D2 dopamine receptor mRNA in the arterial chemoreceptor afferent pathway. J Auton Nerv Syst. 1992 Nov;41(1-2):31–39. doi: 10.1016/0165-1838(92)90124-y. [DOI] [PubMed] [Google Scholar]
  9. DEJOURS P. Chemoreflexes in breathing. Physiol Rev. 1962 Jul;42:335–358. doi: 10.1152/physrev.1962.42.3.335. [DOI] [PubMed] [Google Scholar]
  10. Dagerlind A., Friberg K., Bean A. J., Hökfelt T. Sensitive mRNA detection using unfixed tissue: combined radioactive and non-radioactive in situ hybridization histochemistry. Histochemistry. 1992 Aug;98(1):39–49. doi: 10.1007/BF00716936. [DOI] [PubMed] [Google Scholar]
  11. Dahlström A., Lundell B., Curvall M., Thapper L. Nicotine and cotinine concentrations in the nursing mother and her infant. Acta Paediatr Scand. 1990 Feb;79(2):142–147. doi: 10.1111/j.1651-2227.1990.tb11430.x. [DOI] [PubMed] [Google Scholar]
  12. Daly M. D., Angell-James J. E., Elsner R. Role of carotid-body chemoreceptors and their reflex interactions in bradycardia and cardiac arrest. Lancet. 1979 Apr 7;1(8119):764–767. doi: 10.1016/s0140-6736(79)91218-2. [DOI] [PubMed] [Google Scholar]
  13. Dinger B., Gonzalez C., Yoshizaki K., Fidone S. Localization and function of cat carotid body nicotinic receptors. Brain Res. 1985 Jul 29;339(2):295–304. doi: 10.1016/0006-8993(85)90095-2. [DOI] [PubMed] [Google Scholar]
  14. Donnelly D. F., Haddad G. G. Prolonged apnea and impaired survival in piglets after sinus and aortic nerve section. J Appl Physiol (1985) 1990 Mar;68(3):1048–1052. doi: 10.1152/jappl.1990.68.3.1048. [DOI] [PubMed] [Google Scholar]
  15. Etzel R. A., Greenberg R. A., Haley N. J., Loda F. A. Urine cotinine excretion in neonates exposed to tobacco smoke products in utero. J Pediatr. 1985 Jul;107(1):146–148. doi: 10.1016/s0022-3476(85)80637-5. [DOI] [PubMed] [Google Scholar]
  16. Grima B., Lamouroux A., Blanot F., Biguet N. F., Mallet J. Complete coding sequence of rat tyrosine hydroxylase mRNA. Proc Natl Acad Sci U S A. 1985 Jan;82(2):617–621. doi: 10.1073/pnas.82.2.617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Haglund B. Cigarette smoking and sudden infant death syndrome: some salient points in the debate. Acta Paediatr Suppl. 1993 Jun;82 (Suppl 389):37–39. doi: 10.1111/j.1651-2227.1993.tb12872.x. [DOI] [PubMed] [Google Scholar]
  18. Haglund B., Cnattingius S. Cigarette smoking as a risk factor for sudden infant death syndrome: a population-based study. Am J Public Health. 1990 Jan;80(1):29–32. doi: 10.2105/ajph.80.1.29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hellström S., Koslow S. H. Biogenic amines in carotid body of adult and infant rats--a gas chromatographic-mass spectrometric assay. Acta Physiol Scand. 1975 Apr;93(4):540–547. doi: 10.1111/j.1748-1716.1975.tb05846.x. [DOI] [PubMed] [Google Scholar]
  20. Herbst J. J., Book L. S., Bray P. F. Gastroesophageal reflux in the "near miss" sudden infant death syndrome. J Pediatr. 1978 Jan;92(1):73–75. doi: 10.1016/s0022-3476(78)80074-2. [DOI] [PubMed] [Google Scholar]
  21. Hershko A., Ganoth D., Sudakin V., Dahan A., Cohen L. H., Luca F. C., Ruderman J. V., Eytan E. Components of a system that ligates cyclin to ubiquitin and their regulation by the protein kinase cdc2. J Biol Chem. 1994 Feb 18;269(7):4940–4946. [PubMed] [Google Scholar]
  22. Hertzberg T., Hellström S., Holgert H., Lagercrantz H., Pequignot J. M. Ventilatory response to hyperoxia in newborn rats born in hypoxia--possible relationship to carotid body dopamine. J Physiol. 1992 Oct;456:645–654. doi: 10.1113/jphysiol.1992.sp019358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hertzberg T., Hellström S., Lagercrantz H., Pequignot J. M. Development of the arterial chemoreflex and turnover of carotid body catecholamines in the newborn rat. J Physiol. 1990 Jun;425:211–225. doi: 10.1113/jphysiol.1990.sp018099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hertzberg T., Lagercrantz H. Postnatal sensitivity of the peripheral chemoreceptors in newborn infants. Arch Dis Child. 1987 Dec;62(12):1238–1241. doi: 10.1136/adc.62.12.1238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hertzberg T., Srinivasan M., Lagercrantz H. Disturbed chemical neurotransmission and sudden infant death syndrome--the peripheral arterial chemoreceptors as an example. Acta Paediatr Suppl. 1993 Jun;82 (Suppl 389):63–66. doi: 10.1111/j.1651-2227.1993.tb12880.x. [DOI] [PubMed] [Google Scholar]
  26. Holgert H., Dagerlind A., Hökfelt T., Lagercrantz H. Neuronal markers, peptides and enzymes in nerves and chromaffin cells in the rat adrenal medulla during postnatal development. Brain Res Dev Brain Res. 1994 Nov 18;83(1):35–52. doi: 10.1016/0165-3806(94)90177-5. [DOI] [PubMed] [Google Scholar]
  27. Honda Y. Role of carotid chemoreceptors in control of breathing at rest and in exercise: studies on human subjects with bilateral carotid body resection. Jpn J Physiol. 1985;35(4):535–544. doi: 10.2170/jjphysiol.35.535. [DOI] [PubMed] [Google Scholar]
  28. Jeffery H. E., Rahilly P., Read D. J. Multiple causes of asphyxia in infants at high risk for sudden infant death. Arch Dis Child. 1983 Feb;58(2):92–100. doi: 10.1136/adc.58.2.92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Johnson P., Dawes G. S., Robinson J. S. Maintenance of breathing in newborn lamb. Arch Dis Child. 1972 Feb;47(251):151–151. doi: 10.1136/adc.47.251.151-b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kraus J. F., Greenland S., Bulterys M. Risk factors for sudden infant death syndrome in the US Collaborative Perinatal Project. Int J Epidemiol. 1989 Mar;18(1):113–120. doi: 10.1093/ije/18.1.113. [DOI] [PubMed] [Google Scholar]
  31. Laduron P. M., Leysen J. E. Domperidone, a specific in vitro dopamine antagonist, devoid of in vivo central dopaminergic activity. Biochem Pharmacol. 1979 Jul 15;28(14):2161–2165. doi: 10.1016/0006-2952(79)90198-9. [DOI] [PubMed] [Google Scholar]
  32. Lanier B., Richardson M. A., Cummings C. Effect of hypoxia on laryngeal reflex apnea--implications for sudden infant death. Otolaryngol Head Neck Surg. 1983 Dec;91(6):597–604. doi: 10.1177/019459988309100602. [DOI] [PubMed] [Google Scholar]
  33. Luck W., Nau H. Exposure of the fetus, neonate, and nursed infant to nicotine and cotinine from maternal smoking. N Engl J Med. 1984 Sep 6;311(10):672–672. doi: 10.1056/NEJM198409063111014. [DOI] [PubMed] [Google Scholar]
  34. Luck W., Nau H., Hansen R., Steldinger R. Extent of nicotine and cotinine transfer to the human fetus, placenta and amniotic fluid of smoking mothers. Dev Pharmacol Ther. 1985;8(6):384–395. doi: 10.1159/000457063. [DOI] [PubMed] [Google Scholar]
  35. Lugliani R., Whipp B. J., Seard C., Wasserman K. Effect of bilateral carotid-body resection on ventilatory control at rest and during exercise in man. N Engl J Med. 1971 Nov;285(20):1105–1111. doi: 10.1056/NEJM197111112852002. [DOI] [PubMed] [Google Scholar]
  36. Milerad J., Sundell H. Nicotine exposure and the risk of SIDS. Acta Paediatr Suppl. 1993 Jun;82 (Suppl 389):70–72. doi: 10.1111/j.1651-2227.1993.tb12882.x. [DOI] [PubMed] [Google Scholar]
  37. Mir A. K., McQueen D. S., Pallot D. J., Nahorski S. R. Direct biochemical and neuropharmacological identification of dopamine D2-receptors in the rabbit carotid body. Brain Res. 1984 Jan 23;291(2):273–283. doi: 10.1016/0006-8993(84)91259-9. [DOI] [PubMed] [Google Scholar]
  38. Mitchell E. A., Scragg R., Stewart A. W., Becroft D. M., Taylor B. J., Ford R. P., Hassall I. B., Barry D. M., Allen E. M., Roberts A. P. Results from the first year of the New Zealand cot death study. N Z Med J. 1991 Feb 27;104(906):71–76. [PubMed] [Google Scholar]
  39. Monsma F. J., Jr, McVittie L. D., Gerfen C. R., Mahan L. C., Sibley D. R. Multiple D2 dopamine receptors produced by alternative RNA splicing. Nature. 1989 Dec 21;342(6252):926–929. doi: 10.1038/342926a0. [DOI] [PubMed] [Google Scholar]
  40. Murphy J. F., Newcombe R. G., Sibert J. R. The epidemiology of sudden infant death syndrome. J Epidemiol Community Health. 1982 Mar;36(1):17–21. doi: 10.1136/jech.36.1.17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Naeye R. L. Sudden infant death. Sci Am. 1980 Apr;242(4):56–62. doi: 10.1038/scientificamerican0480-56. [DOI] [PubMed] [Google Scholar]
  42. Nicholl J. P., O'Cathain A. Epidemiology of babies dying at different ages from the sudden infant death syndrome. J Epidemiol Community Health. 1989 Jun;43(2):133–139. doi: 10.1136/jech.43.2.133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Olson L. G., Hensley M. J., Saunders N. A. Augmentation of ventilatory response to asphyxia by prochlorperazine in humans. J Appl Physiol Respir Environ Exerc Physiol. 1982 Sep;53(3):637–643. doi: 10.1152/jappl.1982.53.3.637. [DOI] [PubMed] [Google Scholar]
  44. Olson L. G., Hensley M. J., Saunders N. A. Ventilatory responsiveness to hypercapnic hypoxia during dopamine infusion in humans. Am Rev Respir Dis. 1982 Nov;126(5):783–787. doi: 10.1164/arrd.1982.126.5.783. [DOI] [PubMed] [Google Scholar]
  45. Perrin D. G., Cutz E., Becker L. E., Bryan A. C., Madapallimatum A., Sole M. J. Sudden infant death syndrome: increased carotid-body dopamine and noradrenaline content. Lancet. 1984 Sep 8;2(8402):535–537. doi: 10.1016/s0140-6736(84)90763-3. [DOI] [PubMed] [Google Scholar]
  46. Reusz G. S., Hóbor M., Tulassay T., Sallay P., Miltényi M. 24 hour blood pressure monitoring in healthy and hypertensive children. Arch Dis Child. 1994 Feb;70(2):90–94. doi: 10.1136/adc.70.2.90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Schamel A., Verna A. Localization of dopamine D2 receptor mRNA in the rabbit carotid body and petrosal ganglion by in situ hybridization. Adv Exp Med Biol. 1993;337:85–91. doi: 10.1007/978-1-4615-2966-8_13. [DOI] [PubMed] [Google Scholar]
  48. Steele R., Langworth J. T. The relationship of antenatal and postnatal factors to sudden unexpected death in infancy. Can Med Assoc J. 1966 May 28;94(22):1165–1171. [PMC free article] [PubMed] [Google Scholar]
  49. Sullivan C. E. Bilateral carotid body resection in asthma: vulnerability to hypoxic death in sleep. Chest. 1980 Aug;78(2):354–354. doi: 10.1378/chest.78.2.354. [DOI] [PubMed] [Google Scholar]
  50. Thach B. T., Davies A. M., Koenig J. S. Pathophysiology of sudden upper airway obstruction in sleeping infants and its relevance for SIDS. Ann N Y Acad Sci. 1988;533:314–328. doi: 10.1111/j.1749-6632.1988.tb37261.x. [DOI] [PubMed] [Google Scholar]
  51. Wach R. A., Bee D., Barer G. R. Dopamine and ventilatory effects of hypoxia and almitrine in chronically hypoxic rats. J Appl Physiol (1985) 1989 Jul;67(1):186–192. doi: 10.1152/jappl.1989.67.1.186. [DOI] [PubMed] [Google Scholar]
  52. Zapata P., Zuazo A., Llados F. Respiratory and circulatory reflexes induced by nicotine injections: role of carotid body chemoreceptors. Arch Int Pharmacodyn Ther. 1976 Jan;219(1):128–139. [PubMed] [Google Scholar]

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