Evidence that pinacidil may promote the opening of ATP-sensitive K+ channels yet inhibit the opening of Ca2(+)-activated K+ channels in K(+)-contracted canine mesenteric artery.
作者信息
Masuzawa K, Matsuda T, Asano M
机构信息
Department of Pharmacology, Nagoya City University Medical School, Japan.
The effects of cromakalim and pinacidil on contraction and 86Rb efflux were investigated in strips of canine mesenteric artery. 2. Cromakalim and pinacidil relaxed arterial strips precontracted with 20.9 mM K+ with pD2 values of 6.56 and 5.88, respectively. 3. High (above 10 microM) concentrations of pinacidil, but not cromakalim, relaxed arterial strips bathed by a medium containing 65.9 mM K+, and inhibited Ca2(+)-induced contractions in strips bathed by a medium containing 80 mM K+. These findings suggested that pinacidil may act as an inhibitor of Ca2+ influx. 4. In arterial strips preloaded with 86Rb, cromakalim and pinacidil increased the basal 86Rb efflux. 5. When the effects of cromakalim and pinacidil on 86Rb efflux were determined in arterial strips contracted with 65.9 mM K+, both drugs increased 86Rb efflux. The increase in 86Rb efflux induced by pinacidil was much smaller than that induced by cromakalim. Under the same conditions, nifedipine decreased 86Rb efflux. 6. After the addition of nifedipine to arterial strips contracted with 65.9 mM K+, pinacidil produced a greater increase in 86Rb efflux than in the absence of nifedipine, whereas the effects of cromakalim were the same for the two conditions. Therefore, the effects of pinacidil on 86Rb efflux may be the resultant of two opposing effects: an increased 86Rb efflux due to the opening of ATP-sensitive K+ channels, and a decreased efflux due to the closing of Ca2(+)-activated K+ channels. 7. In causing relaxation, cromakalim was competitively antagonized by glibenclamide with a pA2 value of 7.16. However, glibenclamide antagonism of pinacidil was not of the simple competitive type, suggesting that inhibition of Ca2 + influx may contribute to the relaxant action of pinacidil. 8. It may be concluded that although the ability of pinacidil to increase 86Rb efflux via ATP-sensitive K+ channel opening was similar to that of cromakalim, the inhibition of Ca2 + influx by pinacidil may reduce the opening of Ca2 +-activated K+ channels in K+-contracted arterial strips.
摘要
研究了克罗卡林和吡那地尔对犬肠系膜动脉条收缩和⁸⁶Rb外流的影响。2. 克罗卡林和吡那地尔使由20.9 mM K⁺预收缩的动脉条舒张，其pD2值分别为6.56和5.88。3. 高浓度（高于10 μM）的吡那地尔而非克罗卡林，可使浸浴于含65.9 mM K⁺培养基中的动脉条舒张，并抑制浸浴于含80 mM K⁺培养基中的动脉条的Ca²⁺诱导收缩。这些发现提示吡那地尔可能作为Ca²⁺内流的抑制剂。4. 在预先加载⁸⁶Rb的动脉条中，克罗卡林和吡那地尔增加基础⁸⁶Rb外流。5. 当在由65.9 mM K⁺收缩的动脉条中测定克罗卡林和吡那地尔对⁸⁶Rb外流的影响时，两种药物均增加⁸⁶Rb外流。吡那地尔诱导的⁸⁶Rb外流增加远小于克罗卡林诱导的增加。在相同条件下，硝苯地平降低⁸⁶Rb外流。6. 在向由65.9 mM K⁺收缩的动脉条中加入硝苯地平后，吡那地尔使⁸⁶Rb外流增加幅度大于未加硝苯地平时，而克罗卡林在两种情况下的作用相同。因此，吡那地尔对⁸⁶Rb外流的影响可能是两种相反作用的结果：因ATP敏感性钾通道开放导致⁸⁶Rb外流增加，以及因Ca²⁺激活钾通道关闭导致外流减少。7. 在引起舒张方面，克罗卡林被格列本脲竞争性拮抗，pA2值为7.16。然而，格列本脲对吡那地尔的拮抗并非简单的竞争类型，提示抑制Ca²⁺内流可能有助于吡那地尔的舒张作用。8. 可以得出结论，尽管吡那地尔通过开放ATP敏感性钾通道增加⁸⁶Rb外流的能力与克罗卡林相似，但吡那地尔对Ca²⁺内流的抑制可能会减少钾离子收缩的动脉条中Ca²⁺激活钾通道的开放。
