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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Therapeutic Potential of 1-Methylnicotinamide against Acute Gastric Lesions Induced by Stress: Role of Endogenous Prostacyclin and Sensory Nerves

Tomasz Brzozowski, Peter C. Konturek, Stefan Chlopicki, Zbigniew Sliwowski, Michal Pawlik, Agata Ptak-Belowska, Slawomir Kwiecie, Danuta Drozdowicz, Robert Pajdo, Ewa Slonimska, Stanislaw J. Konturek, and Wieslaw W. Pawlik

Departments of Physiology (T.B., Z.S., M.P., A.P.-B., D.D., S.K., R.P., S.J.K., W.W.P.) and Experimental Pharmacology (S.C.), Jagiellonian University Medical College, Cracow, Poland; Department of Biochemistry, Medical Academy, Gdansk, Poland (E.S.); and Department of Medicine I, University of Erlangen-Nuremberg, Erlangen, Germany (P.C.K.)

1-Methylnicotinamide (MNA) is one of the major derivatives of nicotinamide, which was recently shown to exhibit antithrombotic and antiinflammatory actions. However, it is not yet known whether MNA affects gastric mucosal defense. The effects of exogenous MNA were studied on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and water restraint stress (WRS) or in rats administered 75% ethanol. MNA [6.25–100 mg/kg intragastrically (i.g.)] led to a dose-dependent rise in the plasma MNA level, inhibited gastric acid secretion, and attenuated these gastric lesions induced by WRS or ethanol. The gastroprotective effect of MNA was accompanied by an increase in the gastric mucosal blood flow and plasma calcitonin gene-related peptide (CGRP) levels, the preservation of prostacyclin (PGI₂) generation (measured as 6-keto-PGF1), and an overexpression of mRNAs for cyclooxygenase (COX)-2 and CGRP in the gastric mucosa. R-3-(4-Fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO 324479), which is the selective antagonist of IP/PGI₂ receptors, reversed the effects of MNA on gastric lesions and GBF. MNA-induced gastroprotection was attenuated by suppression of COX-1 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; SC-560] and COX-2 [4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one; rofecoxib] activity, capsaicin denervation, and by the pretreatment with CGRP_8-37 or capsazepine. Addition of exogenous PGI₂ or CGRP restored the MNA-induced gastroprotection in rats treated with COX-1 and COX-2 inhibitors or in those with capsaicin denervation. WRS enhanced MDA content while decreasing superoxide dismutase (SOD) activity in the gastric mucosa, but pretreatment with MNA reversed these changes. MNA exerts potent gastroprotection against WRS damage via mechanisms involving cooperative action of PGI₂ and CGRP in preservation of microvascular flow, antioxidizing enzyme SOD activity, and reduction in lipid peroxidation.

Address correspondence to: Dr. Tomasz Brzozowski, Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka St., 31-531 Cracow, Poland. E-mail: mpbrzozo{at}cyf-kr.edu.pl