title: Effects of Diclofenac, L-NAME, L-Arginine, and Pentadecapeptide BPC 157 on Gastrointestinal, Liver, and Brain Lesions, Failed Anastomosis, and Intestinal Adaptation Deterioration in 24 Hour-Short-Bowel Rats.
abstract: Stable gastric pentadecapeptide BPC 157 was previously used to ameliorate wound healing following major surgery and counteract diclofenac toxicity. To resolve the increasing early risks following major massive small bowel resectioning surgery, diclofenac combined with nitric oxide (NO) system blockade was used, suggesting therapy with BPC 157 and the nitric oxide synthase (NOS substrate) L-arginine, is efficacious. Immediately after anastomosis creation, short-bowel rats were untreated or administered intraperitoneal diclofenac (12 mg/kg), BPC 157 (10 μg/kg or 10 ng/kg), L-NG-nitroarginine methyl ester (L-NAME, 5 mg/kg), L-arginine (100 mg/kg) alone or combined, and assessed 24 h later. Short-bowel rats exhibited poor anastomosis healing, failed intestine adaptation, and gastrointestinal, liver, and brain lesions, which worsened with diclofenac. This was gradually ameliorated by immediate therapy with BPC 157 and L-arginine. Contrastingly, NOS-blocker L-NAME induced further aggravation and lesions gradually worsened. Specifically, rats with surgery alone exhibited mild stomach/duodenum lesions, considerable liver lesions, and severe cerebral/hippocampal lesions while those also administered diclofenac showed widespread severe lesions in the gastrointestinal tract, liver, cerebellar nuclear/Purkinje cells, and cerebrum/hippocampus. Rats subjected to surgery, diclofenac, and L-NAME exhibited the mentioned lesions, worsening anastomosis, and macro/microscopical necrosis. Thus, rats subjected to surgery alone showed evidence of deterioration. Furtheremore, rats subjected to surgery and administered diclofenac showed worse symptoms, than the rats subjected to surgery alone did. Rats subjected to surgery combined with diclofenac and L-NAME showed the worst deterioration. Rats subjected to surgery exhibited habitual adaptation of the remaining small intestine, which was markedly reversed in rats subjected to surgery and diclofenac, and those with surgery, diclofenac, and L-NAME. BPC 157 completely ameliorated symptoms in massive intestinal resection-, massive intestinal resection plus diclofenac-, and massive intestinal resection plus diclofenac plus L-NAME-treated short bowel rats that presented with cyclooxygenase (COX)-NO-system inhibition. L-arginine ameliorated only L-NAME-induced aggravation of symptoms in rats subjected to massive intestinal resection and administered diclofenac plus L-NAME.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia.
authors.forename: Nermin
authors.initials: N
authors.lastname: Lojo
authors.affiliation: Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia.
authors.forename: Zarko
authors.initials: Z
authors.lastname: Rasic
authors.affiliation: Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia.
authors.forename: Anita
authors.initials: A
authors.lastname: Zenko Sever
authors.affiliation: Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia.
authors.forename: Danijela
authors.initials: D
authors.lastname: Kolenc
authors.affiliation: Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia.
authors.forename: Darko
authors.initials: D
authors.lastname: Vukusic
authors.affiliation: Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia.
authors.forename: Domagoj
authors.initials: D
authors.lastname: Drmic
authors.affiliation: Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Zoricic
authors.affiliation: Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia.
authors.forename: Marko
authors.initials: M
authors.lastname: Sever
authors.affiliation: Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia.
authors.forename: Sven
authors.initials: S
authors.lastname: Seiwerth
authors.affiliation: Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia.
authors.forename: Predrag
authors.initials: P
authors.lastname: Sikiric
mesh_terms: D000714:Anastomosis, Surgical / Q000009:adverse effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D004008:Diclofenac / Q000009:adverse effects / Q000494:pharmacology*; D041981:Gastrointestinal Tract / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects / Q000601:surgery*; D008099:Liver / Q000187:drug effects*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; D011506:Proteins; D004008:Diclofenac; C083833:BPC 157; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester