In vitro activation of cyclo-oxygenase in the rabbit carotid body: effect of its blockade on [3H]catecholamine release.
The release of prostaglandin E2 (PGE2) from rabbit carotid bodies (CBs) incubated in basal conditions (PO2 approximately 132 mmHg; PCO2 approximately 33 mmHg; pH = 7.42) amounts to 94.4 +/- 10.1 pg (mg protein)-1 (10 min)-1 (mean +/- S.E.M.). Incubation of the CB in a hypoxic solution (PO2 approximately 46 mmHg) produced a significant 40% increase (P < 0.05) in the release of PGE2. Indomethacin (2 microM) prevented the hypoxia-induced release of PGE2. Sensory plus sympathetic denervation of the CB 4 days prior to the experiments did not modify either basal or low PO2-induced PGE2 release, indicating that intraglomic nerve endings are not significant sources for the PGE2 released. Incubation of the CB in an acidic-hypercapnic solution (PO2 approximately 132 mmHg; PCO2 approximately 132 mmHg; pH = 6.60) or in a high K(+)-containing solution (35 mM) was also effective in promoting an increase in the outflow of PGE2 from the organs. The release of [3H]catecholamines ([3H]CA) from the CB elicited by incubating the organs in low PO2 solutions (PO2 ranged between 66 and 13 mmHg) was potentiated by two inhibitors of cyclo-oxygenase, acetylsalicylic acid (ASA, 100 microM) and indomethacin (2 microM). The effect persisted after chronic denervation of the organ. The secretory response elicited by acidic stimuli was also augmented by cyclo-oxygenase inhibitors. Thus, [3H]CA release elicited by incubating the CBs in the acidic-hypercapnic solution increased by 300% in the presence of indomethacin (2 microM), and ASA (100 microM) more than doubled the release induced by dinitrophenol (100 microM), a protonophore that mimics an acidic stimulus. Indomethacin, but not ASA, moderately increased the high K(+)-evoked [3H]CA release. The effect of indomethacin on the release of [3H]CA elicited by acidic and hypoxic stimuli was reversed by PGE2 in a dose-dependent manner (0.3-300 nM). These results show that low PO2 and high PCO2-low pH, the natural stimuli to the CB, as well as high extracellular [K+], activate the cyclo-oxygenase pathway in the CB, promoting an increase in the outflow of PGE2. The data also show that the blockade of this pathway activates the stimulus-induced [3H]CA release from the CB, indicating that naturally released prostanoids exert an inhibitory control on chemoreceptor cells. The data lend support to the notion that the hyper-reactivity of the ventilatory response to hypoxia in subjects under anti-inflammatory drug treatment results from CB cycloxygenase inhibition.
Gómez-Niño
A
A
Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, Spain.
Almaraz
L
L
González
C
C
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D002245:Carbon Dioxide / Q000494:pharmacology; D002344:Carotid Body / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011817:Rabbits
D002395:Catecholamines; D016861:Cyclooxygenase Inhibitors; D002245:Carbon Dioxide; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001241:Aspirin; D007213:Indomethacin