一氧化氮释放参与新型呋咱衍生物CHF 2363的药理活性。

The involvement of the release of nitric oxide in the pharmacological activity of the new furoxan derivative CHF 2363.

作者信息

Civelli M, Giossi M, Caruso P, Razzetti R, Bergamaschi M, Bongrani S, Gasco A

机构信息

Department of Pharmacology, Chiesi Farmaceutici S.p.A., Parma, Italy.

出版信息

Br J Pharmacol. 1996 Jun;118(4):923-8. doi: 10.1111/j.1476-5381.1996.tb15487.x.

DOI:10.1111/j.1476-5381.1996.tb15487.x

PMID:8799563

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1909539/

Abstract

The mechanism of action and the pharmacological effects of the new furoxan derivative, CHF 2363 (4-ethoxy-3-phenylsulphonylfuroxan), were investigated. 2. Pre-incubation of CHF 2363 with human platelet-rich plasma produced a concentration-dependent inhibition of the platelet aggregation induced by collagen, adenosine diphosphate (ADP) and platelet activating factor (PAF). The test compound was about 5 times more potent than sodium nitroprusside. 3-Isobutyl-1-methyl-xanthine (IBMX) potentiated the antiaggregating effect of CHF 2363. 3. CHF 2363 was a potent inhibitor of rubbed endothelium rabbit aortic ring contraction induced by noradrenaline. Comparison of IC50 values showed that CHF 2363 was as potent as glyceryl trinitrate (GTN). 4. Increasing concentrations of CHF 2363 elevated platelet guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were unaffected. 5. Oxyhaemoglobin reduced all the pharmacological actions of the test compound. Moreover, CHF 2363 concentration-dependently released nitric oxide (NO) in platelet-rich plasma. The NO release was correlated to its ability to increase platelet cyclic GMP levels. 6. After exposure of rat aortic strips to supramaximal concentrations of GTN (550 microM), the vasorelaxant activity of CHF 2363 did not change, although that of GTN decreased about 55 fold. 7. It has been concluded that the new furoxan derivative CHF 2363 exerts a potent antiaggregating and vasorelaxant activity via NO release and increase of cyclic GMP levels. No in vitro cross tolerance between GTN and CHF 2363 was observed.

摘要

对新型呋咱衍生物CHF 2363（4-乙氧基-3-苯基磺酰基呋咱）的作用机制和药理作用进行了研究。2. 将CHF 2363与人富含血小板血浆预孵育，可产生浓度依赖性地抑制由胶原、二磷酸腺苷（ADP）和血小板活化因子（PAF）诱导的血小板聚集。受试化合物的效力比硝普钠约强5倍。3-异丁基-1-甲基黄嘌呤（IBMX）增强了CHF 2363的抗聚集作用。3. CHF 2363是去甲肾上腺素诱导的兔主动脉环收缩的强效抑制剂。IC50值比较表明，CHF 2363与硝酸甘油（GTN）效力相当。4. CHF 2363浓度增加可提高血小板鸟苷3':5'-环一磷酸（环鸟苷酸）水平。腺苷3':5'-环一磷酸（环腺苷酸）水平未受影响。5. 氧合血红蛋白降低了受试化合物的所有药理作用。此外，CHF 2363在富含血小板血浆中浓度依赖性地释放一氧化氮（NO）。NO释放与其增加血小板环鸟苷酸水平的能力相关。6. 将大鼠主动脉条暴露于超最大浓度的GTN（550微摩尔）后，CHF 2363的血管舒张活性未改变，而GTN的血管舒张活性降低了约55倍。7. 得出结论，新型呋咱衍生物CHF 2363通过释放NO和增加环鸟苷酸水平发挥强效抗聚集和血管舒张活性。未观察到GTN与CHF 2363之间的体外交叉耐受性。