Differential salutary effects of nonselective and selective COX-2 inhibitors in postoperative ileus in rats.
BACKGROUND
Postoperative ileus (PI) is a common surgical complication, the treatment of which consists of supportive measures.


OBJECTIVE
The effects of several cyclooxygenase (COX) inhibitors and their interaction with L-arginine/nitric oxide synthase (NOS) pathway were tested in a rat PI model.


METHODS
Intestinal transit was measured as Evans blue migration after skin incision, laparotomy, or laparotomy followed by evisceration and gut handling.


RESULTS
In contrast to a selective inducible NOS (iNOS) blocker, L-N(6)-(1-iminoethyl)lysine hydrochloride (L-NIL), N(omega)-nitro-L-arginine methyl ester (L-NAME) reversed the additional inhibitory effects of gut manipulation after laparotomy on the gastrointestinal transit (GI) in a dose-dependent, L-arginine-sensitive manner. Laparotomy and manipulations of small intestine increased blood plasma nitrites and nitrates level (NOx), an effect preventable by L-NAME. Indomethacin, resveratrol (selective COX-1 blocker), and COX-2 antagonists, nimesulide, NS-398, DuP-697, and L-752860, attenuated the additional inhibitory effects of gut manipulation following laparotomy in a dose-dependent manner. In contrast, only nimesulide, NS-398, DuP-697, and L-752860 partly, but significantly, reversed the effects of laparotomy on the intestinal transit. Administration of L-NAME subsequent to COX inhibitors abolished the salutary effects of the latter, implying that at least the synthesis of either NO or prostanoids must remain unaffected to enable a return of GI transit during the postoperative period.


CONCLUSIONS
In addition to NO synthesized by constitutive NOS (cNOS), prostaglandins produced by both COX-1 and COX-2 participate in the pathogenesis of PI, albeit in different pathological mechanisms. Thus laparotomy stimulated COX-2 activity, whereas gut manipulation led to an excessive cNOS activity and prostaglandin synthesis by COX-1.
Korolkiewicz
Roman P
RP
Department of Pharmacology, Medical University of Gdańsk, Poland. rokor@amedec.amg.gda.pl
Ujda
Marek
M
Dabkowski
Jarosław
J
Ruczyński
Jarosław
J
Rekowski
Piotr
P
Petrusewicz
Jacek
J
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007418:Intestinal Pseudo-Obstruction / Q000188:drug therapy*; D007422:Intestines / Q000187:drug effects* / Q000601:surgery*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007813:Laparotomy / Q000009:adverse effects; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D011183:Postoperative Complications; D011451:Prostaglandin-Endoperoxide Synthases; D011453:Prostaglandins / Q000096:biosynthesis / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C090663:N(6)-(1-iminoethyl)lysine; D011453:Prostaglandins; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D008239:Lysine; D019331:NG-Nitroarginine Methyl Ester