Published online Dec 21, 2018. doi: 10.3748/wjg.v24.i47.5366
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
The research background was our recent claim that treatment with the prototype cytoprotective agent, stable gastric pentadecapeptide BPC 157, induced bypassing of occlusions in rats that underwent vessel occlusions through the rapid presentation of collaterals. In this study, we focused on the resolving of the duodenal lesions induced by major venous occlusions. These lesions can be counteracted by BPC 157 regardless of the involvement of the nitric oxide (NO) system while recruitment of blood vessels to bypass obstruction may occur quickly.
Research motivation was to resolve the major venous occlusions and duodenal lesions in the rat with the use of the stable gastric pentadecapeptide BPC 157 and/or NO-agents, L-NAME (NOS-blocker) and L-arginine (NOS-substrate). BPC 157 is a prototype cytoprotective agent used in ulcerative colitis and multiple sclerosis trials (LD1 not achieved) and is known to counteract duodenal lesions. Rat duodenal lesion research is mostly based on cysteamine and acetic acid models. Investigations are sparse on the impact of major venous obstruction and whether recruitment of blood vessels to bypass obstruction may occur quickly, and if so, whether it may be facilitated by a suitable therapy.
Research objectives were the occluded superior anterior pancreaticoduodenal vein (SAPDV) and duodenal lesions (congestion) and the recovering effect (rapidly activated collaterals bypassing vascular occlusion, absent lesions), the therapy effect of stable gastric pentadecapeptide BPC 157 vs harmful effect of NO-agents [L-NAME (NO-system-blockade), L-arginine (NO-system over-stimulation); L-NAME+L-arginine (NO-system immobilization)]. 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), superior mesenteric vein (SMV) as bypassing vascular pathway to document the duodenal lesions presentation. In duodenum, BPC 157 normalizes NO-levels and counteracts increased oxidative stress [malondialdehyde (MDA)]-levels.
For research methods, we used rats with the occluded SAPDV and duodenal lesions (congestion) to reveal the recovering effect (rapidly activated collaterals bypassing vascular occlusion, absent lesions), at 5 min, 30 min and 24 h ligation time. Therapy effect of the stable gastric pentadecapeptide BPC 157 was achieved with two regimens (10 μg, 10 ng/kg per 1 mL bath/rat or 10 μg/kg instilled into the rat stomach), at 1 min ligation-time. Harmful effect of NO-agents [L-NAME (NO-system-blockade), L-arginine (NO-system over-stimulation); L-NAME+L-arginine (NO-system immobilization)] goes with L-NAME 5 mg/kg per 1 mL bath/rat; L-arginine 100 mg/kg per 1 mL bath/rat, alone and/or together. Considering the point immediately before therapy (as 100%), we scored the vessel presentation [recorded filled/appearance or emptied/disappearance (camera attached to a USB microscope)] between the 5 arcade vessels arising from the SAPDV on the ventral duodenum side, the IAPDV, SMV as bypassing vascular pathway. Upon the duodenum opening and after sacrifice, we assessed the congested hemorrhagic areas as the sum of the largest lesion diameters. In the collected duodenal tissue samples, we assessed NO-levels (Griess reaction) and oxidative stress [by quantifying thiobarbituric acid-reactive species (TBARS) as MDA equivalents].
For research results, we attempted to alleviate major venous obstruction and duodenal lesions in rats with stable gastric pentadecapeptide BPC 157 treatment and to investigate its relation to the NO system. In duodenal lesion development, the occlusion of the SAPDV appears as the key failure (before other vessel occlusions: i.e., left colic artery and vein ligation, and inferior caval vein ligation) that could never be spontaneously alleviated, even though well-placed vessels or additional therapy with NO agents [NOS-over-activation (L-arginine) and/or NOS-blockade (L-NAME)]. On the other hand, BPC 157 therapy resulted in promptly alleviated vascular presentation and then alleviated a perilous course of duodenal lesions in rats with SAPDV occlusions. We documented again “running” toward the bypassing vessel occlusion(s) and that BPC 157 after SAPDV occlusion quickly restores the blood supply to the ischemically injured area. BPC 157 rapidly activates collaterals much like a fundamental treatment that and counteracted the injurious course (ischemic colitis; the syndrome resulting from inferior caval vein infrarenal-ligation) and this effect involves the NO system and reduction of free radical formation.
The new phenomena that were found through experiments in this study of the duodenal lesions with an obstructed major vein (SAPDV) offered is the early positive outcome (“bypassing” effect) of BPC 157. The hypotheses that were confirmed through experiments in this study are related to the cytoprotective agents, to the effects originally noted in the stomach, which is the rapid endothelial protection. Using BPC 157 as a prototype cytoprotective agent, these mechanisms can prevent and resolve adjacent ischemic mucosal lesions providing activation of the collateral circulation. This activation is specific and can circumvent obstructions. That effect may be crucial for its persisting beneficial effect, even with continuous occlusions. The effect of BPC 157 in rats with SAPDV-ligation and previously, in rats with left colic artery and vein ligations may indicate that the action of BPC 157 overlaps in the duodenum and colon. BPC 157 plays an important role in with respect to the “bypassing” effect that maintains duodenum and colon mucosal integrity and interacts with the NO system [L-NAME and L-arginine exhibited parallel effects (lesion worsening), which mitigated each other] in SAPDV, left colic artery and vein circulation, and duodenal and colon lesions. Thus, these findings can be regarded as an implementation of the original cytoprotection concept in vascular occlusion therapy.
For research perspectives, we attempted to alleviate major venous obstruction and duodenal lesions in rats with stable gastric pentadecapeptide BPC 157 treatment and to investigate its relation to the NO system. In duodenal lesion development, the SAPDV occlusion appears as the key failure that could never be spontaneously alleviated, even though well-placed vessels or additional therapy with NO agents [NOS-overactivation (L-arginine) and/or NOS-blockade (L-NAME)]. Finally, BPC 157 therapy results in “bypassing” effect combined with mucosal integrity, or major vessel obstruction made harmless. These BPC 157 effects can be an implementation of the original cytoprotection concept in vascular occlusion therapy.