Effects of COX-1 and COX-2 inhibitors on eicosanoid biosynthesis and the release of substance P from the guinea-pig isolated perfused lung.
OBJECTIVE
In the guinea-pig isolated perfused lung, co-administration of bradykinin (BK) and histamine causes the release of pro-inflammatory neuropeptides, an effect that is largely dependent on BK-induced formation of prostaglandins. Since it is known that at least two isoenzymes, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) catalyse the conversion of arachidonic acid to prostaglandins (PGs) and thromboxanes, the present study aimed at investigating the effect of selective COX-1 and COX-2 inhibitors on the evoked release of substance P (SP).


METHODS
Lungs were vascularly perfused with oxygenated physiological salt solution containing peptidase inhibitors. BK (0.1 microM) and histamine (100 microM) were added to the perfusate for 10 min and 5 min, respectively. The concentrations of 6-keto-PGF1alpha, cysteinyl-leukotriene (LT), and SP were determined in the outflow by radioimmunoassay.


RESULTS
In non-stimulated preparations, indomethacin (2 microM) and the selective COX-1 inhibitor SC-560 (0.03-1 microM) reduced basal release of 6-keto-PGF1alpha, without significantly affecting the release of cysteinyl-LT and SP. The selective COX-2 inhibitors NS-398 (1 microM) or DFU (10 microM) had no significant effect on the basal release of eicosanoids or SP. Co-administration of BK and histamine caused a pronounced increase in the concentration of 6-keto-PGF1alpha and cysteinyl-LT, and SP in the effluate. Under these conditions, indomethacin as well as SC-560 reduced the release of 6-keto-PGF1alpha, enhanced cysteinyl-LT release, and attenuated the release of SP. In contrast, the selective COX-2 inhibitors NS 398 and DFU had no significant effect on the stimulated release of eicosanoids or SP.


CONCLUSIONS
These results suggest that in the isolated guinea-pig lung, basal prostanoid biosynthesis as well as BK-induced stimulation of prostanoid formation and subsequent facilitation of histamine-induced SP release is primarily mediated by COX-1 without detectable involvement of COX-2.
Amann
R
R
Institute of Experimental and Clinical Pharmacology, University of Graz, Austria. rainer.amann@kfunigraz.ac.at
Schuligoi
R
R
Peskar
B A
BA
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003545:Cysteine / Q000378:metabolism; D015777:Eicosanoids / Q000096:biosynthesis*; D005260:Female; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D017997:Leukotriene C4 / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles / Q000494:pharmacology; D013373:Substance P / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D018836:Inflammation Mediators; D007527:Isoenzymes; D015289:Leukotrienes; D009578:Nitrobenzenes; D011720:Pyrazoles; C115461:SC 560; D013449:Sulfonamides; C112381:cysteinyl-leukotriene; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D017997:Leukotriene C4; D013373:Substance P; D015121:6-Ketoprostaglandin F1 alpha; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D003545:Cysteine; D001920:Bradykinin; D007213:Indomethacin