The primary function of the arterial chemoreceptors, i.e., the carotid and aortic bodies, is to transduce changes in arterial PO2, PCO2 and/or H+ ions, and possibly changes in temperature and osmolarity into nerve signals. There is no general agreement on how these physiological stimuli are changed into nerve impulses, nor is it known whether all stimuli act through a common mechanism. It is generally believed that one or more neuroactive substance(s) are involved in the transduction process. The long-term goal of the proposal is to evaluate the importance of the neuropeptide substance P (SP) in the process of chemoreception of the arterial chemoreceptors. It originates from data by ourselves and others showing that substance P and other related tachykinins stimulate the carotid body, and that substance P antagonists block the carotid body response to hypoxia. This project addresses the following issues: 1) Does substance P act similarly in the carotid and aortic bodies; 2) does it have the same effect in different species; and 3) how does it interact with other peptides found in the carotid body, such as vasoactive intestinal polypeptide and enkephalins, as well as with the known neurotransmitters like acetycholine, dopamine and norepinephrine. In addition, a major objective of the proposal is to determine where Substance P is localized in the carotid body and whether it is released by hypoxia and/or hypercapnia. In order to achieve the proposed goals, experiments will be carried out in anesthetized cats and rabbits. The general methods that will be employed are 1) neural recording of the in vivo and in vitro chemoreceptor discharge using single or paucifiber recording techniques; 2) immunocytochemical methods for histochemical localization of peptides in the chemoreceptors, and 3) biochemical techniques for characterizing the chemical nature and quantitative estimation for the release of peptides from the carotid bodies. These studies examine the basic transduction mechanisms of the carotid and aortic bodies. It could provide clues as to the transduction process at other visceral sensory receptors and may aid in the understanding of the role of peptides in the nervous system as well as other tissues. This proposal may also yield information of potential use in the treatment of hypoxemia and hypercarbia which are major problems in chronic obstructive lung diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL038986-03
Application #
3471476
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1988-04-01
Project End
1993-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Prabhakar, N R; Gouda, E; Kumar, G K et al. (1995) Analysis of carotid chemoreceptor responses to substance P analogue in anaesthetized cats. J Auton Nerv Syst 52:43-50
Prabhakar, N R (1994) Neurotransmitters in the carotid body. Adv Exp Med Biol 360:57-69
Cragg, P A; Runold, M; Kou, Y R et al. (1994) Tachykinin antagonists in carotid body responses to hypoxia and substance P in the rat. Respir Physiol 95:295-310
Prabhakar, N R; Kou, Y R; Cragg, P A et al. (1993) Effect of arterial chemoreceptor stimulation: role of norepinephrine in hypoxic chemotransmission. Adv Exp Med Biol 337:301-6
Prabhakar, N R; Cao, H; Lowe 3rd, J A et al. (1993) Selective inhibition of the carotid body sensory response to hypoxia by the substance P receptor antagonist CP-96,345. Proc Natl Acad Sci U S A 90:10041-5
Prabhakar, N R; Kumar, G K; Chang, C H et al. (1993) Nitric oxide in the sensory function of the carotid body. Brain Res 625:16-22
Cragg, P A; Kou, Y R; Prabhakar, N R (1993) Role of substance P in rat carotid body responses to hypoxia and capsaicin. Adv Exp Med Biol 337:265-70
Kou, Y R; Ernsberger, P; Cragg, P A et al. (1991) Role of alpha 2-adrenergic receptors in the carotid body response to isocapnic hypoxia. Respir Physiol 83:353-64
Prabhakar, N R; Kou YuR; Runold, M (1990) Chemoreceptor responses to substance P, physalaemin and eledoisin: evidence for neurokinin-1 receptors in the cat carotid body. Neurosci Lett 120:183-6
Runold, M; Cherniack, N S; Prabhakar, N R (1990) Effect of adenosine on isolated and superfused cat carotid body activity. Neurosci Lett 113:111-4

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