Ryman T, Petersson J, Högestätt E D
Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University Hospital, Sweden.
Pharmacol Toxicol. 1999 Aug;85(2):80-4. doi: 10.1111/j.1600-0773.1999.tb00070.x.
KRN2391 is a cyanoamidine derivative with a pyridine ring and a nitroxyl group. This gives the molecule a dual pharmacological action as both an ATP-sensitive K channel (K(ATP)) opener and an organic nitrate. In cerebrovascular disease with endothelial dysfunction, such a compound could be advantageous to prevent the negative consequences of a reduced synthesis of endogenous nitric oxide and endothelium-derived hyperpolarizing factor. The objective of this study was to characterise the vasodilator action of KRN2391 in a cerebral artery. As shown in the rabbit basilar artery contracted by endothelin-1 KRN2391 elicited a concentration-dependent relaxation. KRN2391 was unable to relax arteries contracted by a 60 mM K solution. The KRN2391-induced relaxation of endothelin-1-contracted arteries was unaffected by N(G)-nitro-L-arginine (0.1 mM), indomethacin (10 microM) or removal of the endothelium. The guanylate cyclase inhibitors ODQ (10 microM) and LY53583 (10 microM), and the cGMP phosphodiesterase inhibitor zaprinast (10 microM) each had no effect on the KRN2391-induced relaxation. Glibenclamide (1 microM), a blocker of K(ATP), caused a rightward shift of the concentration-response curve for KRN2391. The relaxation induced by the prototype K(ATP) opener levcromakalim was inhibited to a similar extent by glibenclamide. Addition of ODQ or LY53583, or the calcium-sensitive K channel blockers apamin (0.1 microM) and charybdotoxin (0.1 microM) in the presence of glibenclamide did not produce a significant further inhibition of the KRN-induced relaxation. KRN2391 (10 microM) did not influence the content of cGMP in the basilar artery, whereas the nitric oxide donor 3-morpholino-sydnonimine (0.1 mM) increased the cGMP level three-fold. Thus, KRN2391 is an effective vasodilator of the rabbit basilar artery, acting mainly through opening of KATP . The nitro-moiety of the molecule does not seem to contribute to the relaxant effect in this artery.
KRN2391是一种带有吡啶环和硝酰基的氰脒衍生物。这赋予该分子双重药理作用，既是一种ATP敏感性钾通道（K(ATP)）开放剂，又是一种有机硝酸盐。在伴有内皮功能障碍的脑血管疾病中，这样一种化合物可能有利于预防内源性一氧化氮和内皮源性超极化因子合成减少所带来的负面后果。本研究的目的是表征KRN2391在脑动脉中的血管舒张作用。如在由内皮素-1收缩的兔基底动脉中所示，KRN2391引起浓度依赖性舒张。KRN2391无法舒张由60 mM钾溶液收缩的动脉。KRN2391诱导的内皮素-1收缩动脉的舒张不受N(G)-硝基-L-精氨酸（0.1 mM）、吲哚美辛（10 microM）或去除内皮的影响。鸟苷酸环化酶抑制剂ODQ（10 microM）和LY53583（10 microM）以及cGMP磷酸二酯酶抑制剂扎普司特（10 microM）对KRN2391诱导的舒张均无影响。格列本脲（1 microM），一种K(ATP)阻滞剂，使KRN2391的浓度-反应曲线向右移动。原型K(ATP)开放剂左卡尼汀诱导的舒张被格列本脲抑制到相似程度。在格列本脲存在的情况下添加ODQ或LY53583，或钙敏感性钾通道阻滞剂蜂毒明肽（0.1 microM）和大蝎毒素（0.1 microM），并未对KRN诱导的舒张产生显著的进一步抑制。KRN2391（10 microM）不影响基底动脉中cGMP的含量，而一氧化氮供体3-吗啉代-西多胺（0.1 mM）使cGMP水平增加了三倍。因此，KRN2391是兔基底动脉的一种有效血管舒张剂，主要通过开放KATP起作用。该分子的硝基部分似乎对该动脉的舒张作用没有贡献。
