Protein kinase C modulation of ventilatory response to hypoxia in nucleus tractus solitarii of conscious rats.
This study aimed to determine the role of protein kinase C (PKC) in signal transduction mechanisms underlying ventilatory regulation in the nucleus tractus solitarii (NTS). Microinjection of phorbol 12-myristate 13-acetate into the commissural NTS of nine chronically instrumented, unrestrained rats elicited significant cardiorespiratory enhancements that lasted for at least 4 h, whereas administration of vehicle (n = 15) or the inactive phorbol ester 4alpha-phorbol 12,13-didecanoate (n = 7) did not elicit minute ventilation (VE) changes. Peak hypoxic VE responses (10% O2-balance N2) were measured in 19 additional animals after NTS microinjection of bisindolylmaleimide (BIM) I, a selective PKC inhibitor (n = 12), BIM V (inactive analog; n = 7), or vehicle (Con; n = 19). In Con, VE increased from 139 +/- 9 to 285 +/- 26 ml/min in room air and hypoxia, respectively, and similar responses occurred after BIM V. BIM I did not affect room air VE but markedly attenuated hypoxia-induced VE increases (128 +/- 12 to 167 +/- 18 ml/min; P < 0. 02 vs. Con and BIM V). When BIM I was microinjected into the cerebellum (n = 4), cortex (n = 4), or spinal cord (n = 4), VE responses were similar to Con. Western blots of subcellular fractions of dorsocaudal brain stem lysates revealed translocation of PKCalpha, beta, gamma, delta, epsilon, and iota isoenzymes during acute hypoxia, and enhanced overall PKC activity was confirmed in the particulate fraction of dorsocaudal brain stem lysates harvested after acute hypoxia. These studies suggest that, in the adult rat, PKC activation in the NTS mediates essential components of the acute hypoxic ventilatory response.
Gozal
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Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA. dgozal@tmcpop.tmc.tulane.edu
Roussel
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Holt
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Gozal
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Gozal
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Torres
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Gozal
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D000818:Animals; D001784:Blood Gas Analysis; D015153:Blotting, Western; D006439:Hemodynamics / Q000187:drug effects; D000860:Hypoxia / Q000201:enzymology / Q000503:physiopathology*; D007527:Isoenzymes / Q000502:physiology*; D008297:Male; D008845:Microinjections; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015656:Respiratory Mechanics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D017552:Solitary Nucleus / Q000502:physiology*
D007527:Isoenzymes; D010703:Phorbol Esters; D011493:Protein Kinase C