The long-range goal is to identify the cellular and molecular mechanisms of O2 chemoreception specifically in the carotid body (CB) which may be applicable to other known O2 sensing systems. The consensus model is that the glomus cell in the CB is the chemoreceptor which upon stimulation mobilizes Ca2+, activates neurotransmitter release and the sensory discharge.
The specific aims are designed to test the hypothesis that PO2-dependent mitochondrial energy metabolism is the primary sensor. We plan to use CO to reversibly block cytochrome a2+3 in the perfused- superfused CB and in the separated glomus cell. On the other hand, by binding with the putative membrane home CO would block the A+ conductance decrease due to hypoxia. Thus CO would have opposite effects with respect to cytochrome a2+3 and the membrane heme -- the former being excitatory and the latter inhibitory. There is no other explanation for the excitatory response by CO than by it, intracellular complex formation unless acid is formed. This acid formation could explain a part of the CO effect. Using the sensory discharges we plan to measure the following effects of CO on CB: titrate the O2 up take and sensory activity with and without light; response to CO2 -H+ with and without light, on the blockade of energy-state and membrane sulphydryls; response to different wavelengths of light; pHi response; dependence on extracellular [Ca2+] and on vascular PO2 distribution. We also plan to measure the effects of Co on pHi and [Ca2+]1 of separated glomus cells. The experimental measurements are: chemosensory discharge, CB PO2 by the phosphorescence imaging and microelectrode techniques and intracellular pH by the fluorescence imaging and intracellular [Ca2+] and pH of dissociated and cultured glomus cell by spectrofluorimetry. Broad significance of the study concerns principle of O2 chemoreception, and its lobs and disorder and its alleviation. The second level of significance involves reflex functions (e.g., control of ventilation, airway and vascular smooth muscles, sleep apneas, etc.). Carotid bodies provide the major gateway for the organism to receive signals due to low PO2 in the lung and blood, and to generate life-saving reflex responses against hypoxia and asphyxia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL043413-07
Application #
3569182
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1989-07-01
Project End
2000-05-31
Budget Start
1996-06-01
Budget End
1997-05-31
Support Year
7
Fiscal Year
1996
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lahiri, S; Mitchell, C H; Reigada, D et al. (2007) Purines, the carotid body and respiration. Respir Physiol Neurobiol 157:123-9
Wilson, David F (2004) Identifying oxygen sensors by their photochemical action spectra. Methods Enzymol 381:690-704
Di Giulio, C; Huang, W; Waters, V et al. (2003) Atrial natriuretic peptide stimulates cat carotid body chemoreceptors in vivo. Comp Biochem Physiol A Mol Integr Physiol 134:27-31
Wilson, D F; Mokashi, A; Lahiri, S et al. (2000) Tissue PO2 and mitochondrial enzymes. Cytochrome C oxidase as O2 sensor. Adv Exp Med Biol 475:259-64
Buerk, D G; Lahiri, S (2000) Evidence that nitric oxide plays a role in O2 sensing from tissue NO and PO2 measurements in cat carotid body. Adv Exp Med Biol 475:337-47
Roy, A; Rozanov, C; Mokashi, A et al. (2000) Redox-based inhibition of K+ channel/current is not related to hypoxic chemosensory responses in rat carotid body. Adv Exp Med Biol 475:645-53
Mokashi, A; Roy, A; Rozanov, C et al. (2000) Effect of barium on rat carotid body glomus cell [Ca2+]i and carotid chemosensory response. Adv Exp Med Biol 475:715-22
Rozanov, C; Roy, A; Mokashi, A et al. (1999) Chemosensory response to high pCO is blocked by cadmium, a voltage-sensitive calcium channel blocker. Brain Res 833:101-7
Lahiri, S; Buerk, D G (1998) Vascular and metabolic effects of nitric oxide synthase inhibition evaluated by tissue PO2 measurements in carotid body. Adv Exp Med Biol 454:455-60
Mokashi, A; Roy, A; Rozanov, C et al. (1998) High PCO does not alter pHi, but raises [Ca2+]i in cultured rat carotid body glomus cells in the absence and presence of CdC12. Brain Res 803:194-7

Showing the most recent 10 out of 59 publications