The preferential iNOS inhibitors

• Main Authors: Hsiao-Ching Hsu, 許筱晴
• Other Authors: Tony J.F. Lee
• Format: Others
• Language: en_US
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/19773450985500973727

碩士 === 慈濟大學 === 藥理暨毒理學研究所 === 94 === Synthesis of Nitric oxide (NO), a gas molecule with a half-life of few seconds, is catalyzed by three NOS isoforms: eNOS, nNOS and iNOS. The neuronal (nNOS) and endothelial (eNOS) isoforms are constitutively expressed. The physiological concentration of NO is important in regulating normal vascular function. In contrast, iNOS, which is induced following infection, generates large amount of NO with severe hypotension. In patients with sepsis, specific inhibition of iNOS activity is therefore an alternative strategy in treating septic shock. The purpose of this study is to search for preferential iNOS inhibitors derived from nitro-L-arginine (NLA). We examined the inhibitory effects of these synthetic NLA derivatives on iNOS activity in activated RAW264.7 macrophages. One group of derivative with modification made on hydroxyl moiety of NLA (Nω-nitro-L-arginine alkyl ester, NEx) and the second group with modification made on hydroxyl and nitro moieties of NLA (Nω-amino-L-arginine alkyl ester, NH2Ex). The results indicated that these compounds inhibited NO synthesis. The IC50 values of NE2 and NE4 were 12.37 and 19.37 �慆icroM, respectively. This NEx group of inhibitors also blocked transmural nerve stimulation (TNS)-induced relaxation of isolated porcine basilar arterial rings with IC50 values of 0.93~2.12 �慆icroM. The NH2Ex group, NH2E7~10, was more potent inhibitors than NEx group for iNOS activity with IC50 value of 9.18~25.21 �慆icroM. The NH2Ex inhibitor, however, was rather insensitive in blocking TNS-induced relaxation of the porcine basilar arteries with the IC50 values of greater than 100 �慆icroM, suggesting that the derivatives of the NH2Ex have significantly less effect than the NEx derivatives on nNOS activity. We further observed that NE4, NH2E7, and NH2E10 did not affect endothelium-dependent, eNOS-mediated relaxation, suggesting that these inhibitors did not affect eNOS activity. These results indicate that the NEx derivatives are nonspecific NOS inhibitors, while NH2E7~10 are preferential iNOS inhibitors.