Norman N R, Toombs C F, Khan S A, Buchanan L V, Cimini M G, Gibson J K, Meisheri K D, Shebuski R J
Upjohn Laboratories, Upjohn Company, Kalamazoo, Mich. 49001.
Pharmacology. 1994 Aug;49(2):86-95. doi: 10.1159/000139220.
ATP-sensitive potassium (K+ATP) channel openers such as cromakalim and pinacidil exhibit both potent vasodilatory and anti-ischemic properties. U-89232, a cyanoguanidine analog of cromakalim, has recently been found to exhibit myocardial protection during ischemia without altering in vivo hemodynamics. We examined the effects of U-89232, cromakalim and pinacidil in isolated vascular and cardiac tissue and tested whether glyburide, a KATP channel blocker, could antagonize their effects. All three compounds produced concentration-dependent relaxation in isolated vascular segments, with cromakalim being approximately 100-fold more potent than either pinacidil or U-89232. Glyburide completely antagonized the effects of pinacidil but merely blunted the effects of cromakalim and U-89232. In an isolated rabbit cardiac tissue preparation, U-89232 had little effect on maximum tension in cardiac muscle, whereas cromakalim and pinacidil significantly decreased maximum developed tension in a concentration-dependent manner. Glyburide effectively antagonized the effects of cromakalim and pinacidil in cardiac tissue. These data suggest that U-89232, although chemically related to cromakalim, possesses activity which is not common to known potassium channel openers.
ATP敏感性钾（K+ATP）通道开放剂，如色满卡林和吡那地尔，具有强大的血管舒张和抗缺血特性。U - 89232是色满卡林的氰基胍类似物，最近发现其在缺血期间具有心肌保护作用，且不改变体内血流动力学。我们研究了U - 89232、色满卡林和吡那地尔对离体血管和心脏组织的影响，并测试了KATP通道阻滞剂格列本脲是否能拮抗它们的作用。这三种化合物在离体血管段均产生浓度依赖性舒张，其中色满卡林的效力比吡那地尔或U - 89232强约100倍。格列本脲完全拮抗了吡那地尔的作用，但仅减弱了色满卡林和U - 89232的作用。在离体兔心脏组织制备中，U - 89232对心肌最大张力影响很小，而色满卡林和吡那地尔则以浓度依赖性方式显著降低最大舒张张力。格列本脲有效拮抗了色满卡林和吡那地尔在心脏组织中的作用。这些数据表明，U - 89232虽然在化学上与色满卡林相关，但其具有已知钾通道开放剂所不具备的活性。
