Disturbance of peristalsis in the guinea-pig isolated small intestine by indomethacin, but not cyclo-oxygenase isoform-selective inhibitors.
1. Since the cyclo-oxygenase (COX) isoform-nonselective inhibitor indomethacin is known to modify intestinal motility, we analysed the effects of COX-1 and COX-2 inhibition on intestinal peristalsis. 2. Peristalsis in isolated segments of the guinea-pig small intestine was triggered by a rise of the intraluminal pressure and recorded via the pressure changes associated with peristalsis. 3. The COX-1 inhibitor SC-560, the COX-2 inhibitor NS-398 (both at 0.1 -- 1 microM) and the isoform-nonselective inhibitors flurbiprofen (0.01 - 10 microM) and piroxicam (0.1 - 50 microM) were without major influence on peristalsis, whereas indomethacin and etodolac (0.1 -- 10 microM) disturbed the regularity of peristalsis by causing nonpropulsive circular muscle contractions. 4. Radioimmunoassay measurements showed that SC-560, NS-398, indomethacin and etodolac (each at 1 microM) suppressed the release of 6-keto-prostaglandin F(1 alpha) (6-keto-PGF(1 alpha)) from the intestinal segments. 5. Reverse transcription - polymerase chain reaction tests revealed that, relative to glyceraldehyde-3 phosphate dehydrogenase ribonucleic acid, the expression of COX-1 mRNA increased by a factor of 2.0 whereas that of COX-2 mRNA rose by a factor of 7.9 during the 2 h experimental period. 6. Pharmacological experiments indicated that the action of indomethacin to disturb intestinal peristalsis was unrelated to inhibition of L-type calcium channels, adenosine triphosphate-sensitive potassium channels or phosphodiesterase type IV. 7. These results show that selective inhibition of COX-1 and COX-2 does not grossly alter peristaltic motor activity in the guinea-pig isolated small intestine and that the effect of indomethacin to disturb the regular pattern of propulsive motility in this species is unrelated to COX inhibition.
Department of Experimental and Clinical Pharmacology, University of Graz, Universitätsplatz 4, A-8010 Graz, Austria.
A
A
Shahbazian
R
R
Schuligoi
A
A
Heinemann
B A
BA
Peskar
P
P
Holzer
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005769:Gastrointestinal Motility / Q000502:physiology; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects* / Q000502:physiology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D016859:Lipoxygenase Inhibitors; D008297:Male; D010528:Peristalsis / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002120:Calcium Channel Agonists; D015220:Calcium Channels; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D015221:Potassium Channels; D012333:RNA, Messenger; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D015121:6-Ketoprostaglandin F1 alpha; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000527:Alprostadil; D007213:Indomethacin