The long-term objective is to understand the cellular and subcellular mechanisms of oxygen chemoreception in the carotid body. The working models is that glomus cell metabolism senses oxygen and the resultant metabolic changes lead to an alteration of the electric activity of the sensory fiber which innervates it. Multiple pathways may be involved in oxygen sensing. Accordingly, the specific aims are to measure the cellular oxygen stimulus and to measure its effect on the chemosensory discharge, intracellular (glomus cell) pH, Ca2+, plasma membrane ionic currents (K+, Na+ and Ca2+), glomus cell volume regulation and secretory activity of the glomus cells. In order to understand the mechanisms of coupling between the stimulus and chemosensory response in the carotid body at the cellular level, studies will be made with the whole carotid body and with single glomus cells in primary culture. Fluorescence and phosphorescence probes will be combined with quantitative imaging techniques to measure extra- and intracellular PO2 as well as intracellular pH and Ca2+; patch clamp techniques will be used to measure the various pathways for ion flux across the membrane and to measure increases in membrane capacitance reflecting exocytosis and secretory activity in single glomus cells. This multidiscplinary approach is made possible by bringing together investigators with expertise from different fields. Understanding of the mechanisms of oxygen detection and signalling in the carotid body are important for many health related questions. The mechanisms may be a prototype of oxygen sensing in other tissues (i.e. renal erythropoietin synthesis and release; regulation of coronary and pulmonary vascular resistance). The carotid body is the primary organ which elicits protective reflex ventilatory, autonomic and cardiovascular responses against oxygen deprivation in health (e.g. high altitude) and disease (pulmonary and cardiovascular).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL043413-01
Application #
3362087
Study Section
(SRC)
Project Start
1989-07-01
Project End
1994-04-30
Budget Start
1989-07-01
Budget End
1990-04-30
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
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

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