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©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
Bypassing major venous occlusion and duodenal lesions in rats, and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine
Fedor Amic, Domagoj Drmic, Zdenko Bilic, Ivan Krezic, Helena Zizek, Marina Peklic, Robert Klicek, Alen Pajtak, Enio Amic, Tinka Vidovic, Mislav Rakic, Marija Milkovic Perisa, Katarina Horvat Pavlov, Antonio Kokot, Ante Tvrdeic, Alenka Boban Blagaic, Mario Zovak, Sven Seiwerth, Predrag Sikiric
Fedor Amic, Domagoj Drmic, Zdenko Bilic, Ivan Krezic, Helena Zizek, Marina Peklic, Robert Klicek, Alen Pajtak, Enio Amic, Tinka Vidovic, Mislav Rakic, Marija Milkovic Perisa, Katarina Horvat Pavlov, Antonio Kokot, Ante Tvrdeic, Alenka Boban Blagaic, Mario Zovak, Sven Seiwerth, Predrag Sikiric, Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
Fedor Amic, Domagoj Drmic, Zdenko Bilic, Ivan Krezic, Helena Zizek, Marina Peklic, Robert Klicek, Alen Pajtak, Enio Amic, Tinka Vidovic, Mislav Rakic, Marija Milkovic Perisa, Katarina Horvat Pavlov, Antonio Kokot, Ante Tvrdeic, Alenka Boban Blagaic, Mario Zovak, Sven Seiwerth, Predrag Sikiric, Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
Author contributions: Amic F, Drmic D, Bilic Z, Krezic I, Zizek H, Peklic M, Klicek R, Pajtak A, Amic E, Vidovic T, Rakic M, Milkovic Perisa M, Horvat Pavlov K, Kokot A, Tvrdeic A and Boban Blagaic A performed experiments; Amic F, Drmic D, Bilic Z, Krezic I, Zizek H, Peklic M, Klicek R, Pajtak A, Amic E, Vidovic T, Rakic M, Milkovic Perisa M, Horvat Pavlov K, Kokot A, Tvrdeic A, Boban Blagaic A, Zovak M, Seiwerth S and Sikiric P analyzed data; Seiwerth S and Sikiric P contributed reagents and analytic tools; Amic F, Tvrdeic A, Seiwerth S and Sikiric P wrote the manuscript.
Institutional review board statement: The study was reviewed and approved by the Department of Veterinary, Ministry of Agriculture, Republic of Croatia, No: UP/I 322-01/07-01/210.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Uprava Za Veterinarstvo (NN 135/06).
Conflict-of-interest statement: The authors state that they have no conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have checked the manuscript according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author to: Predrag Sikiric, MD, PhD, Professor, Department of Pharmacology, Medical Faculty, University of Zagreb, Salata 11, POB 916, Zagreb 10000, Croatia.
sikiric@mef.hr
Telephone: +385-1-4566833 Fax: +385-1-4920050
Received: August 8, 2018
Peer-review started: August 9, 2018
First decision: October 5, 2018
Revised: November 26, 2018
Accepted: November 30, 2018
Article in press: November 30, 2018
Published online: December 21, 2018
Processing time: 136 Days and 15 Hours
AIM
To investigate whether duodenal lesions induced by major venous occlusions can be attenuated by BPC 157 regardless nitric oxide (NO) system involvement.
METHODS
Male Wistar rats underwent superior anterior pancreaticoduodenal vein (SAPDV)-ligation and were treated with a bath at the ligated SAPDV site (BPC 157 10 μg, 10 ng/kg per 1 mL bath/rat; L-NAME 5 mg/kg per 1 mL bath/rat; L-arginine 100 mg/kg per 1 mL bath/rat, alone and/or together; or BPC 157 10 μg/kg instilled into the rat stomach, at 1 min ligation-time). We recorded the vessel presentation (filled/appearance or emptied/disappearance) between the 5 arcade vessels arising from the SAPDV on the ventral duodenum side, the inferior anterior pancreaticoduodenal vein (IAPDV) and superior mesenteric vein (SMV) as bypassing vascular pathway to document the duodenal lesions presentation; increased NO- and oxidative stress [malondialdehyde (MDA)]-levels in duodenum.
RESULTS
Unlike the severe course in the SAPDV-ligated controls, after BPC 157 application, the rats exhibited strong attenuation of the mucosal lesions and serosal congestion, improved vessel presentation, increased interconnections, increased branching by more than 60% from the initial value, the IAPDV and SMV were not congested. Interestingly, after 5 min and 30 min of L-NAME and L-arginine treatment alone, decreased mucosal and serosal duodenal lesions were observed; their effect was worsened at 24 h, and no effect on the collateral vessels and branching was seen. Together, L-NAME+L-arginine antagonized each other’s response, and thus, there was an NO-related effect. With BPC 157, all SAPDV-ligated rats receiving L-NAME and/or L-arginine appeared similar to the rats treated with BPC 157 alone. Also, BPC 157 in SAPDV-ligated rats normalized levels of NO and MDA, two oxidative stress markers, in duodenal tissues.
CONCLUSION
BPC 157, rapidly bypassing occlusion, rescued the original duodenal flow through IAPDV to SMV flow, an effect related to the NO system and reduction of free radical formation.
Core tip: Up to now, application of prototype cytoprotective agent BPC 157 induced bypassing of occlusion, in rats underwent vessels occlusions, through rapid collaterals presentation, and lesions and whole consequent syndrome (ischemic colitis; deep vein thrombosis, Virchow triad) were attenuated. In rats underwent superior anterior pancreaticoduodenal vein-ligation, medication was with BPC 157, L-NAME; L-arginine, saline given alone and/or together at 1 min ligation time. Unlike severe course in controls, BPC 157 rats commonly exhibited strong attenuation of mucosal lesion and serosal congestion, since BPC 157 rescued original duodenal flow through inferior anterior pancreaticoduodenal vein to superior mesenteric vein flow.
