Steinberg M I, Wiest S A, Zimmerman K M, Ertel P J, Bemis K G, Robertson D W
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
J Pharmacol Exp Ther. 1991 Jan;256(1):222-9.
Pinacidil, a potassium channel opener (PCO), relaxes vascular smooth muscle by increasing potassium ion membrane conductance, thereby causing membrane hyperpolarization. PCOs also act on cardiac muscle to decrease action potential duration (APD) selectively. To examine the enantiomeric selectivity of pinacidil, the stereoisomers of pinacidil (a 4-pyridylcyanoguanidine) and its 3-pyridyl isomer (LY222675) were synthesized and studied in canine Purkinje fibers and cephalic veins. The (-)-enantiomers of both pinacidil and LY222675 were more potent in relaxing phenylephrine-contracted cephalic veins and decreasing APD than were their corresponding (+)-enantiomers. The EC50 values for (-)-pinacidil and (-)-LY222675 in relaxing cephalic veins were 0.44 and 0.09 microM, respectively. In decreasing APD, the EC50 values were 3.2 microM for (-)-pinacidil and 0.43 microM for (-)-LY222675. The eudismic ratio was greater for the 3-pyridyl isomer than for pinacidil in both cardiac (71 vs. 22) and vascular (53 vs. 17) tissues. (-)-LY222675 and (-)-pinacidil (0.1-30 microM) also increased 86Rb efflux from cephalic veins to a greater extent than did their respective optical antipodes. The antidiabetic sulfonylurea, glyburide (1-30 microM), shifted the vascular concentration-response curve of (-)-pinacidil to the right by a similar extent at each inhibitor concentration. Glipizide also antagonized the response to (-)-pinacidil, but was about 1/10 as potent with a maximal shift occurring at 10 and 30 microM. Glyburide antagonized the vascular relaxant effects of 0.3 microM (-)-LY222675 (EC50, 2.3 microM) and reversed the decrease in APD caused by 3 microM (-)-LY222675 (EC50, 1.9 microM). Nitroprusside did not alter 86Rb efflux, and vascular relaxation induced by sodium nitroprusside was unaffected by sulfonylureas. Thus, the enantiomers of the 3-pyridyl isomer of pinacidil demonstrate enhanced stereospecificity in both canine cardiac and vascular tissues compared to the enantiomers of pinacidil. However, the relative selectivity of pinacidil and its 3-pyridyl isomer for cardiac and vascular smooth muscle remains unaltered. Sulfonylureas antagonize the more potent enantiomers in both tissues, supporting the involvement of an ATP-sensitive potassium channel in the action of PCOs; however, antagonism in canine vascular smooth muscle by sulfonylureas does not resemble classical competitive antagonism.
吡那地尔是一种钾通道开放剂（PCO），它通过增加钾离子膜电导来舒张血管平滑肌，从而引起膜超极化。PCOs还作用于心肌，选择性地缩短动作电位时程（APD）。为了研究吡那地尔的对映体选择性，合成了吡那地尔（一种4-吡啶基氰基胍）及其3-吡啶基异构体（LY222675）的立体异构体，并在犬浦肯野纤维和头静脉中进行了研究。吡那地尔和LY222675的（-）-对映体在舒张去氧肾上腺素收缩的头静脉和缩短APD方面比其相应的（+）-对映体更有效。（-）-吡那地尔和（-）-LY222675舒张头静脉的EC50值分别为0.44和0.09微摩尔。在缩短APD方面，（-）-吡那地尔的EC50值为3.2微摩尔，（-）-LY222675的EC50值为0.43微摩尔。在心脏（71对22）和血管（53对17）组织中，3-吡啶基异构体的优映体比例均高于吡那地尔。（-）-LY222675和（-）-吡那地尔（0.1 - 30微摩尔）也比它们各自的旋光对映体更大程度地增加了86Rb从头静脉的流出。抗糖尿病磺脲类药物格列本脲（1 - 30微摩尔）在每个抑制剂浓度下都使（-）-吡那地尔的血管浓度 - 反应曲线向右移动相似的程度。格列吡嗪也拮抗对（-）-吡那地尔的反应，但效力约为其1/10，最大移位发生在10和30微摩尔时。格列本脲拮抗0.3微摩尔（-）-LY222675的血管舒张作用（EC50，2.3微摩尔），并逆转了3微摩尔（-）-LY222675引起的APD缩短（EC50，1.9微摩尔）。硝普钠不改变86Rb流出，硝普钠诱导的血管舒张不受磺脲类药物影响。因此，与吡那地尔的对映体相比，吡那地尔的3-吡啶基异构体的对映体在犬心脏和血管组织中表现出增强的立体特异性。然而，吡那地尔及其3-吡啶基异构体对心脏和血管平滑肌的相对选择性保持不变。磺脲类药物拮抗两种组织中更有效的对映体，支持ATP敏感性钾通道参与PCOs的作用；然而，磺脲类药物对犬血管平滑肌的拮抗作用并不类似于经典的竞争性拮抗作用。
