Davie C S, Standen N B
Department of Cell Physiology and Pharmacology, University of Leicester, UK.
Cardiovasc Res. 1998 Mar;37(3):791-8. doi: 10.1016/s0008-6363(97)00262-9.
Nicorandil is used clinically to treat angina and acts in part by opening ATP-sensitive K+ channels whose opening is also enhanced by metabolic compromise. We have therefore investigated whether treatments that mimic conditions in ischaemia can increase the potency of nicorandil to dilate coronary arteries.
Ring segments from pig small coronary arteries were mounted on a myograph, contracted with 20 mM K+ Krebs solution containing 200 nM BAYK 6844, and relaxations to cumulative doses of nicorandil were measured.
Nicorandil produced a dose-dependent relaxation with a mean pEC50 (-log EC50, M) of 4.76 +/- 0.02. Inhibition of metabolism with carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 100 nM) or by removal of extracellular glucose significantly increased the potency of nicorandil (pEC50s of 5.11 +/- 0.08 and 5.08 +/- 0.06, p < 0.05 in each case). The adenosine analogue 2-chloroadenosine (2-CA, 300 nM) had a similar effect (pEC50 = 5.17 +/- 0.06, p < 0.05). Reducing extracellular pH to 6.8 also significantly increased the potency of nicorandil, but to a smaller extent. Glibenclamide reduced the potency of nicorandil (pEC50 = 3.81 +/- 0.01, n = 7), and abolished its enhancement by CCCP, zero glucose, 2-CA or pH 6.8 solution. 2-CA did not affect the potency of nicorandil in relaxing contractions to 80 mM K+ or the potency of glyceryl trinitrate. We conclude that the potency of nicorandil to cause coronary vasorelaxation is increased under conditions of metabolic inhibition. This effect appears to result from the K+ channel opening action of the drug, and may have significant consequences for its therapeutic effectiveness.
尼可地尔临床上用于治疗心绞痛，其部分作用机制是通过开放ATP敏感性钾通道，而代谢受损也会增强该通道的开放。因此，我们研究了模拟缺血条件的处理方法是否能增强尼可地尔扩张冠状动脉的效力。
取猪小冠状动脉的环段，安装在肌张力测定仪上，用含200 nM BAYK 6844的20 mM K⁺ Krebs溶液使其收缩，然后测量对累积剂量尼可地尔的舒张反应。
尼可地尔产生剂量依赖性舒张作用，平均pEC50（-log EC50，M）为4.76±0.02。用羰基氰化物间氯苯腙（CCCP，100 nM）抑制代谢或去除细胞外葡萄糖可显著增强尼可地尔的效力（pEC50分别为5.11±0.08和5.08±0.06，每种情况p<0.05）。腺苷类似物2-氯腺苷（2-CA，300 nM）有类似作用（pEC50 = 5.17±0.06，p<0.05）。将细胞外pH降至6.8也显著增强了尼可地尔的效力，但程度较小。格列本脲降低了尼可地尔的效力（pEC50 = 3.81±0.01，n = 7），并消除了CCCP、无糖、2-CA或pH 6.8溶液对其效力的增强作用。2-CA不影响尼可地尔对80 mM K⁺ 收缩的舒张效力，也不影响硝酸甘油的效力。我们得出结论，在代谢抑制条件下，尼可地尔引起冠状动脉血管舒张的效力会增强。这种效应似乎源于药物的钾通道开放作用，可能对其治疗效果有重要影响。
