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Int. J. Mol. Sci. 2014, 15(3), 4946-4964; doi:10.3390/ijms15034946
Article

Exogenous Asymmetric Dimethylarginine (ADMA) in Pathogenesis of Ischemia-Reperfusion-Induced Gastric Lesions: Interaction with Protective Nitric Oxide (NO) and Calcitonin Gene-Related Peptide (CGRP)

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Department of Physiology, Jagiellonian University Medical College, Grzegorzecka Street 16, Cracow 31-531, Poland These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 27 December 2013 / Revised: 3 March 2014 / Accepted: 4 March 2014 / Published: 20 March 2014
(This article belongs to the Special Issue ADMA and Nitrergic System)
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Abstract

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthesis inhibitor and pro-inflammatory factor. We investigated the role of ADMA in rat gastric mucosa compromised through 30 min of gastric ischemia (I) and 3 h of reperfusion (R). These I/R animals were pretreated with ADMA with or without the combination of l-arginine, calcitonin gene-related peptide (CGRP) or a small dose of capsaicin, all of which are known to afford protection against gastric lesions, or with a farnesoid X receptor (FXR) agonist, GW 4064, to increase the metabolism of ADMA. In the second series, ADMA was administered to capsaicin-denervated rats. The area of gastric damage was measured with planimetry, gastric blood flow (GBF) was determined by H2-gas clearance, and plasma ADMA and CGRP levels were determined using ELISA and RIA. ADMA significantly increased I/R-induced gastric injury while significantly decreasing GBF, the luminal NO content, and the plasma level of CGRP. This effect of ADMA was significantly attenuated by pretreatment with CGRP, l-arginine, capsaicin, or a PGE2 analogue. In GW4064 pretreated animals, the I/R injury was significantly reduced and this effect was abolished by co-treatment with ADMA. I/R damage potentiated by ADMA was exacerbated in capsaicin-denervated animals with a further reduction of CGRP. Plasma levels of IL-10 were significantly decreased while malonylodialdehyde (MDA) and plasma TNF-α contents were significantly increased by ADMA. In conclusion, ADMA aggravates I/R-induced gastric lesions due to a decrease of GBF, which is mediated by a fall in NO and CGRP release, and the enhancement of lipid peroxidation and its pro-inflammatory properties.
Keywords: asymmetric dimethyl arginine; gastric mucosa; ischemia/reperfusion; farnesoid X receptor; gastric damage; sensory neurons; calcitonin gene-related peptide; capsaicin asymmetric dimethyl arginine; gastric mucosa; ischemia/reperfusion; farnesoid X receptor; gastric damage; sensory neurons; calcitonin gene-related peptide; capsaicin
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Magierowski, M.; Jasnos, K.; Sliwowski, Z.; Surmiak, M.; Krzysiek-Maczka, G.; Ptak-Belowska, A.; Kwiecien, S.; Brzozowski, T. Exogenous Asymmetric Dimethylarginine (ADMA) in Pathogenesis of Ischemia-Reperfusion-Induced Gastric Lesions: Interaction with Protective Nitric Oxide (NO) and Calcitonin Gene-Related Peptide (CGRP). Int. J. Mol. Sci. 2014, 15, 4946-4964.

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