title: Esophagogastric anastomosis in rats: Improved healing by BPC 157 and L-arginine, aggravated by L-NAME.
abstract: OBJECTIVE
  To cure typically life-threatening esophagogastric anastomosis in rats, lacking anastomosis healing and sphincter function rescue, in particular.
  
  
  METHODS
  Because we assume esophagogastric fistulas represent a particular NO-system disability, we attempt to identify the benefits of anti-ulcer stable gastric pentadecapeptide BPC 157, which was in trials for ulcerative colitis and currently for multiple sclerosis, in rats with esophagocutaneous fistulas. Previously, BPC 157 therapies have promoted the healing of intestinal anastomosis and fistulas, and esophagitis and gastric lesions, along with rescued sphincter function. Additionally, BPC 157 particularly interacts with the NO-system. In the 4 d after esophagogastric anastomosis creation, rats received medication (/kg intraperitoneally once daily: BPC 157 (10 μg, 10 ng), L-NAME (5 mg), or L-arginine (100 mg) alone and/or combined or BPC 157 (10 μg, 10 ng) in drinking water). For rats underwent esophagogastric anastomosis, daily assessment included progressive stomach damage (sum of the longest diameters, mm), esophagitis (scored 0-5), weak anastomosis (mL H2O before leak), low pressure in esophagus at anastomosis and in the pyloric sphincter (cm H2O), progressive weight loss (g) and mortality. Immediate effect assessed blood vessels disappearance (scored 0-5) at the stomach surface immediately after anastomosis creation.
  
  
  RESULTS
  BPC 157 (all regimens) fully counteracted the perilous disease course from the very beginning (i.e., with the BPC 157 bath, blood vessels remained present at the gastric surface after anastomosis creation) and eliminated mortality. Additionally, BPC 157 treatment in combination with L-NAME nullified any effect of L-NAME that otherwise intensified the regular course. Consistently, with worsening (with L-NAME administration) and amelioration (with L-arginine), either L-arginine amelioration prevails (attenuated esophageal and gastric lesions) or they counteract each other (L-NAME + L-arginine); with the addition of BPC 157 (L-NAME + L-arginine + BPC 157), there was a marked beneficial effect. BPC 157 treatment for esophagogastric anastomosis, along with NOS-blocker L-NAME and/or NOS substrate L-arginine, demonstrated an innate NO-system disability (as observed with L-arginine effectiveness). BPC 157 distinctively affected corresponding events: worsening (obtained with L-NAME administration that was counteracted); or amelioration (L-arginine + BPC 157-rats correspond to BPC 157-rats).
  
  
  CONCLUSIONS
  Innate NO-system disability for esophagogastric anastomoses, including L-NAME-worsening, suggests that these effects could be corrected by L-arginine and almost completely eliminated by BPC 157 therapy.
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Djakovic
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Ivka
authors.initials: I
authors.lastname: Djakovic
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Vedran
authors.initials: V
authors.lastname: Cesarec
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Goran
authors.initials: G
authors.lastname: Madzarac
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Tomislav
authors.initials: T
authors.lastname: Becejac
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Goran
authors.initials: G
authors.lastname: Zukanovic
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Domagoj
authors.initials: D
authors.lastname: Drmic
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Lovorka
authors.initials: L
authors.lastname: Batelja
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Anita
authors.initials: A
authors.lastname: Zenko Sever
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Danijela
authors.initials: D
authors.lastname: Kolenc
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Alen
authors.initials: A
authors.lastname: Pajtak
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Nikica
authors.initials: N
authors.lastname: Knez
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Mladen
authors.initials: M
authors.lastname: Japjec
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Kresimir
authors.initials: K
authors.lastname: Luetic
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Dinko
authors.initials: D
authors.lastname: Stancic-Rokotov
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Sven
authors.initials: S
authors.lastname: Seiwerth
authors.affiliation: Zeljko Djakovic, Ivka Djakovic, Vedran Cesarec, Goran Madzarac, Tomislav Becejac, Goran Zukanovic, Domagoj Drmic, Lovorka Batelja, Anita Zenko Sever, Danijela Kolenc, Alen Pajtak, Nikica Knez, Mladen Japjec, Kresimir Luetic, Dinko Stancic-Rokotov, Sven Seiwerth, Predrag Sikiric, Departments of Pharmacology and Pathology Medical Faculty University of Zagreb, 10000 Zagreb, Croatia.
authors.forename: Predrag
authors.initials: P
authors.lastname: Sikiric
mesh_terms: D000714:Anastomosis, Surgical / Q000009:adverse effects; D057868:Anastomotic Leak / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D049630:Esophageal Sphincter, Lower / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004941:Esophagitis / Q000209:etiology / Q000517:prevention & control; D004947:Esophagus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D005753:Gastric Mucosa / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D011312:Pressure; D011506:Proteins / Q000494:pharmacology*; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects* / Q000473:pathology / Q000601:surgery; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D010446:Peptide Fragments; D011506:Proteins; D009569:Nitric Oxide; C083833:BPC 157; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
keywords: Aggravation; BPC 157; Curative treatment; Esophagogastric anastomosis; L-NAME; L-arginine; Rats