Brzozowski Tomasz, Konturek Peter C, Chlopicki Stefan, Sliwowski Zbigniew, Pawlik Michal, Ptak-Belowska Agata, Kwiecien Slawomir, Drozdowicz Danuta, Pajdo Robert, Slonimska Ewa, Konturek Stanislaw J, Pawlik Wieslaw W
Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka St., 31-531 Cracow, Poland.
J Pharmacol Exp Ther. 2008 Jul;326(1):105-16. doi: 10.1124/jpet.108.136457. Epub 2008 Apr 2.
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 (PGI(2)) generation (measured as 6-keto-PGF1alpha), 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/PGI(2) 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 PGI(2) 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 PGI(2) and CGRP in preservation of microvascular flow, antioxidizing enzyme SOD activity, and reduction in lipid peroxidation.
1-甲基烟酰胺（MNA）是烟酰胺的主要衍生物之一，最近研究表明其具有抗血栓形成和抗炎作用。然而，MNA是否影响胃黏膜防御尚不清楚。本研究观察了外源性MNA对水浸束缚应激（WRS）3.5小时或给予75%乙醇诱导的大鼠胃分泌及胃损伤的影响。MNA[6.25 - 100mg/kg灌胃（i.g.）]可使血浆MNA水平呈剂量依赖性升高，抑制胃酸分泌，并减轻WRS或乙醇诱导的胃损伤。MNA的胃保护作用伴随着胃黏膜血流量及血浆降钙素基因相关肽（CGRP）水平升高、前列环素（PGI₂）生成（以6 - 酮 - PGF₁α衡量）的维持以及胃黏膜中环氧化酶（COX）-2和CGRP的mRNA过表达。R - 3 -（4 - 氟苯基）-2 - [5 -（4 - 氟苯基）-苯并呋喃 - 2 - 基甲氧基羰基氨基] - 丙酸（RO 324479），即IP/PGI₂受体的选择性拮抗剂，可逆转MNA对胃损伤和胃血流量的影响。抑制COX - 1[5 -（4 - 氯苯基）-1 -（4 - 甲氧基苯基）-3 -（三氟甲基）-1H - 吡唑；SC - 560]和COX - 2[4 -（4 - 甲基磺酰基苯基）-3 - 苯基 - 5H - 呋喃 - 2 - 酮；罗非昔布]活性、辣椒素去神经支配以及用CGRP（8 - 37）或辣椒素受体拮抗剂预处理均可减弱MNA诱导的胃保护作用。添加外源性PGI₂或CGRP可恢复用COX - 1和COX - 2抑制剂处理的大鼠或辣椒素去神经支配大鼠中MNA诱导的胃保护作用。WRS可增加胃黏膜丙二醛（MDA）含量，同时降低超氧化物歧化酶（SOD）活性，但MNA预处理可逆转这些变化。MNA通过涉及PGI₂和CGRP协同作用以维持微血管血流、抗氧化酶SOD活性及减少脂质过氧化的机制，对WRS损伤发挥强大的胃保护作用。
