Buchheit K H, Hofmann A
Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
Naunyn Schmiedebergs Arch Pharmacol. 1996 Aug-Sep;354(3):355-61. doi: 10.1007/BF00171068.
Many openers of ATP-dependent potassium channels (KATP channel openers) cause bronchorelaxation, whereas only a few of them have been claimed to reverse airways hyperreactivity. We investigated whether the antihyperreactive effect is a general feature of KATP channel openers and whether this property is linked to their ability to relax airways smooth muscle. For this purpose, the potency of the four KATP channel openers, bimakalim, rilmakalim, levcromakalim and SDZ PCO 400 ((-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-cyclopent -1 -enyloxy)-2H-1-benzopyran-6-carbonitrile), to inhibit bombesin- or histamine-induced bronchoconstriction and to reverse immune complex-induced airways hyperreactivity to histamine in guinea pigs, was compared to salbutamol, following intratracheal administration to minimize pharmacokinetic differences. Total lung resistance (RL) was determined in anaesthetized, ventilated guinea pigs. Bronchoconstriction, measured as increase in RL, was elicited in normoreactive animals by i.v. infusion of bombesin (100 ng/kg/min) or by i.v. injection of histamine (1.8-10 micrograms/kg). Airways hyper-reactivity was induced by acute i.v. administration of preformed immune complexes. I.v. bolus injections of histamine were used to define the sensitivity of the airways prior to and after the exposure to immune complex. Levcromakalim (ED50 = 150 micrograms/kg), bimakalim (ED50 = 4 micrograms/kg), rilmakalim (ED50 = 40 micrograms/kg) and SDZ PCO 400 (ED50 = 280 micrograms/kg) reverse bombesin-induced bronchoconstriction with lower potency than salbutamol (ED50 = 1 microgram/kg). The four KATP channel openers and salbutamol also reversed immune complex-induced airways hyperreactivity to histamine with ED50 values which were markedly lower than those for reversal of bombesin-induced bronchoconstriction; the rank order of potency was rilmakalim (ED50 = 0.2 microgram/kg) > bimakalim (ED50 = 0.5 microgram/kg) > SDZ PCO 400 (ED50 = 3.2 micrograms/kg) > levcromakalim (ED50 = 22 micrograms/kg). Salbutamol (ED50 = 0.008 microgram/kg) was the most potent compound in this test. Bimakalim, levcromakalim and SDZ PCO 400 did not inhibit histamine-induced bronchoconstriction in normoreactive guinea pigs at doses which completely reversed immune complex-induced airways hyperreactivity to histamine. For rilmakalim and salbutamol, 60-130 times higher doses were needed for protection against histamine-induced bronchoconstriction in normoreactive guinea pigs than for reversal of airways hyperreactivity. There was a poor correlation between the ED50 values for inhibition of histamine- or bombesin-induced bronchoconstriction in normoreactive guinea pigs and the reversal of immune complex-induced airways hyperreactivity. It is thus concluded that the ability of KATP channel openers to reverse immune complex-induced airways hyperreactivity is independent of their ability to reverse or prevent bronchoconstriction and thus from their ability relax airway smooth muscle.
许多ATP依赖性钾通道开放剂（KATP通道开放剂）可引起支气管舒张，然而其中只有少数几种被认为能逆转气道高反应性。我们研究了抗高反应性效应是否是KATP通道开放剂的普遍特性，以及这种特性是否与其舒张气道平滑肌的能力相关。为此，将四种KATP通道开放剂，即比马卡林、利马卡林、左沙丁胺醇和SDZ PCO 400（（-）-（3S，4R）-3，4-二氢-3-羟基-2，2-二甲基-4-（3-氧代-环戊-1-烯氧基）-2H-1-苯并吡喃-6-腈），与沙丁胺醇进行比较，在豚鼠气管内给药以尽量减少药代动力学差异后，观察它们抑制蛙皮素或组胺诱导的支气管收缩以及逆转免疫复合物诱导的豚鼠气道对组胺的高反应性的效力。在麻醉、通气状态下的豚鼠中测定总肺阻力（RL）。在正常反应性动物中，通过静脉输注蛙皮素（100 ng/kg/min）或静脉注射组胺（1.8 - 10 μg/kg）来诱发以RL增加来衡量的支气管收缩。通过静脉内急性给予预先形成的免疫复合物来诱导气道高反应性。静脉推注组胺用于确定暴露于免疫复合物之前和之后气道的敏感性。左沙丁胺醇（ED50 = 150 μg/kg）、比马卡林（ED50 = 4 μg/kg）、利马卡林（ED50 = 40 μg/kg）和SDZ PCO 400（ED50 = 280 μg/kg）逆转蛙皮素诱导的支气管收缩的效力低于沙丁胺醇（ED50 = 1 μg/kg）。这四种KATP通道开放剂和沙丁胺醇也能逆转免疫复合物诱导的气道对组胺的高反应性，其ED50值明显低于逆转蛙皮素诱导的支气管收缩的ED50值；效力顺序为利马卡林（ED50 = 0.2 μg/kg）＞比马卡林（ED50 = 0.5 μg/kg）＞SDZ PCO 400（ED50 = 3.2 μg/kg）＞左沙丁胺醇（ED50 = 22 μg/kg）。沙丁胺醇（ED50 = 0.008 μg/kg）在该试验中是最有效的化合物。比马卡林、左沙丁胺醇和SDZ PCO 400在能完全逆转免疫复合物诱导的气道对组胺的高反应性的剂量下，并不抑制正常反应性豚鼠中组胺诱导的支气管收缩。对于利马卡林和沙丁胺醇，在正常反应性豚鼠中预防组胺诱导的支气管收缩所需的剂量比逆转气道高反应性所需的剂量高60 - 130倍。在正常反应性豚鼠中，抑制组胺或蛙皮素诱导的支气管收缩的ED50值与逆转免疫复合物诱导的气道高反应性之间的相关性很差。因此得出结论，KATP通道开放剂逆转免疫复合物诱导的气道高反应性的能力与其逆转或预防支气管收缩的能力无关，因此也与其舒张气道平滑肌的能力无关。
