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.
Shahbazian
A
A
Department of Experimental and Clinical Pharmacology, University of Graz, Universitätsplatz 4, A-8010 Graz, Austria.
Schuligoi
R
R
Heinemann
A
A
Peskar
B A
BA
Holzer
P
P
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