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. 1993 Nov 1;90(21):10041–10045. doi: 10.1073/pnas.90.21.10041

Selective inhibition of the carotid body sensory response to hypoxia by the substance P receptor antagonist CP-96,345.

N R Prabhakar 1, H Cao 1, J A Lowe 3rd 1, R M Snider 1
PMCID: PMC47709  PMID: 8234254

Abstract

Carotid bodies are sensory organs for monitoring arterial oxygen and CO2. Previous studies have shown that chemoreceptor tissue contains substance P (SP) and exogenously administered SP augments chemosensory discharge. In the present study, we examined the physiological importance of SP in carotid body chemoreception by using a selective nonpeptide SP [neurokinin (NK) 1] receptor antagonist CP-96,345. In experiments performed on anesthetized cats, sensory discharge was recorded from the carotid body in situ. To control for alterations in blood flow, additional studies were conducted on the carotid body in vitro. In in vivo studies, close carotid body (intraarterial) administration of CP-96,345 attenuated the sensory response to hypoxia in a dose-dependent manner with 73% of the response abolished at doses of 0.3-0.6 mg/kg. Comparable doses of the (2R,3R)-enantiomer had no effect on hypoxia-induced excitation, indicating that the effect of CP-96,345 was not due to nonspecific action. In contrast, the carotid body response to high CO2 was not affected by CP-96,345, implying that only the hypoxic response is mediated by NK-1 receptor and confirming that the effect of the SP antagonist was not due to nonspecific actions. Marked attenuation of the sensory response to hypoxia was also obtained in the carotid body in vitro, suggesting that the effects of the NK-1 antagonist were not secondary to cardiovascular changes. These results demonstrate that CP-96,345 attenuates or abolishes the chemosensory response to hypoxia but not to CO2 and suggest that SP mediates the hypoxia-induced sensory excitation in the cat carotid body via NK-1 receptor activation.

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Selected References

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  1. Buck S. H., Burcher E. The rat submaxillary gland contains predominantly P-type tachykinin binding sites. Peptides. 1985 Nov-Dec;6(6):1079–1084. doi: 10.1016/0196-9781(85)90431-0. [DOI] [PubMed] [Google Scholar]
  2. Krause J. E., Chirgwin J. M., Carter M. S., Xu Z. S., Hershey A. D. Three rat preprotachykinin mRNAs encode the neuropeptides substance P and neurokinin A. Proc Natl Acad Sci U S A. 1987 Feb;84(3):881–885. doi: 10.1073/pnas.84.3.881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Maxwell D. L., Fuller R. W., Dixon C. M., Cuss F. M., Barnes P. J. Ventilatory effects of substance P, vasoactive intestinal peptide, and nitroprusside in humans. J Appl Physiol (1985) 1990 Jan;68(1):295–301. doi: 10.1152/jappl.1990.68.1.295. [DOI] [PubMed] [Google Scholar]
  4. McQueen D. S. Effects of substance P on carotid chemoreceptor activity in the cat. J Physiol. 1980 May;302:31–47. doi: 10.1113/jphysiol.1980.sp013228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Otsuka M., Sakuma M., Kobayashi N., Onishi Y., Yanagisawa M., Suzuki H., Yoshioka K. Tachykinin-evoked release of neurotransmitters from isolated spinal cord of the newborn rat. Ann N Y Acad Sci. 1991;632:212–219. doi: 10.1111/j.1749-6632.1991.tb33109.x. [DOI] [PubMed] [Google Scholar]
  6. Pearse A. G. The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic and pathologic implications of the concept. J Histochem Cytochem. 1969 May;17(5):303–313. doi: 10.1177/17.5.303. [DOI] [PubMed] [Google Scholar]
  7. Prabhakar N. R., Landis S. C., Kumar G. K., Mullikin-Kilpatrick D., Cherniack N. S., Leeman S. Substance P and neurokinin A in the cat carotid body: localization, exogenous effects and changes in content in response to arterial pO2. Brain Res. 1989 Mar 6;481(2):205–214. doi: 10.1016/0006-8993(89)90795-6. [DOI] [PubMed] [Google Scholar]
  8. Prabhakar N. R., Mitra J., Cherniack N. S. Role of substance P in hypercapnic excitation of carotid chemoreceptors. J Appl Physiol (1985) 1987 Dec;63(6):2418–2425. doi: 10.1152/jappl.1987.63.6.2418. [DOI] [PubMed] [Google Scholar]
  9. Regoli D., Drapeau G., Dion S., Couture R. New selective agonists for neurokinin receptors: pharmacological tools for receptor characterization. Trends Pharmacol Sci. 1988 Aug;9(8):290–295. doi: 10.1016/0165-6147(88)90013-2. [DOI] [PubMed] [Google Scholar]
  10. Schmidt A. W., McLean S., Heym J. The substance P receptor antagonist CP-96,345 interacts with Ca2+ channels. Eur J Pharmacol. 1992 Sep 4;219(3):491–492. doi: 10.1016/0014-2999(92)90498-s. [DOI] [PubMed] [Google Scholar]
  11. Snider R. M., Constantine J. W., Lowe J. A., 3rd, Longo K. P., Lebel W. S., Woody H. A., Drozda S. E., Desai M. C., Vinick F. J., Spencer R. W. A potent nonpeptide antagonist of the substance P (NK1) receptor. Science. 1991 Jan 25;251(4992):435–437. doi: 10.1126/science.1703323. [DOI] [PubMed] [Google Scholar]
  12. Wang Z. Z., He L., Stensaas L. J., Dinger B. G., Fidone S. J. Localization and in vitro actions of atrial natriuretic peptide in the cat carotid body. J Appl Physiol (1985) 1991 Feb;70(2):942–946. doi: 10.1152/jappl.1991.70.2.942. [DOI] [PubMed] [Google Scholar]
  13. Wharton J., Polak J. M., Pearse A. G., McGregor G. P., Bryant M. G., Bloom S. R., Emson P. C., Bisgard G. E., Will J. A. Enkephalin-, VIP- and substance P-like immunoreactivity in the carotid body. Nature. 1980 Mar 20;284(5753):269–271. doi: 10.1038/284269a0. [DOI] [PubMed] [Google Scholar]

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