Smith S N, Middleton P G, Chadwick S, Jaffe A, Bush K A, Rolleston S, Farley R, Delaney S J, Wainwright B, Geddes D M, Alton E W
Ion Transport Unit, National Heart and Lung Institute at Imperial College, London, United Kingdom.
Am J Respir Cell Mol Biol. 1999 Jan;20(1):129-34. doi: 10.1165/ajrcmb.20.1.3278.
Previous studies have indicated that milrinone, a specific type III phosphodiesterase inhibitor, may be able to induce chloride secretion in cystic fibrosis (CF) tissues. We have now assessed the effect of this agent in vivo on the nasal epithelium of CF mutant mice and also in the nose and lungs of human subjects with CF. Wild-type mice showed a small hyperpolarization of the nasal potential difference (PD) in response to milrinone (100 microM, 1.6 +/- 0.6 mV, n = 8, P < 0.05). In contrast, CF mice carrying either the most common human mutation of the gene for the CF transmembrane regulator (CFTR), DeltaF508 (protein mislocalized), or the G551D mutation (protein normally localized) failed to demonstrate this response. Milrinone perfused alone had no significant effect on the baseline nasal PD of human subjects without CF (14.7 +/- 4.0 mV preperfusion; 15.3 +/- 4.6 mV postperfusion), but significantly (P < 0.05) augmented the hyperpolarization induced by a subsequently perfused low-chloride solution (with milrinone, 36.8 +/- 3.0 mV, n = 6; without milrinone, 18.1 +/- 2.2 mV, n = 19). In contrast, in human subjects with CF (n = 6), milrinone alone significantly (P < 0. 05) altered the nasal baseline PD (52.2 +/- 3.3 mV preperfusion; 57. 4 +/- 4.2 mV, postperfusion) but not the subsequent responses to the low-chloride solution (with milrinone, 1.1 +/- 2.2 mV, n = 4; without milrinone, 0.6 +/- 0.5 mV, n = 28) or to isoproterenol (100 microM). In a separate study in subjects (n = 6) with the DeltaF508 mutation, nasal coadministration of milrinone with isoproterenol produced no effect in the presence of amiloride and a low-chloride solution (-0.8 +/- 0.5 mV). This was also the case in the nasal epithelium of CF subjects (n = 4) carrying at least one G551D allele (-0.3 +/- 0.8 mV). Similarly, milrinone did not hyperpolarize the PD of either the tracheal (n = 6) or segmental (n = 6) airways of CF subjects (DeltaF508) when applied topically in vivo in the presence of amiloride, isoproterenol, or adenosine triphosphate (all 100 microM) in a low-chloride solution. These data do not support the use of milrinone to induce chloride secretion in CF airways in vivo.
以往的研究表明，米力农作为一种特定的III型磷酸二酯酶抑制剂，可能能够在囊性纤维化（CF）组织中诱导氯化物分泌。我们现在评估了该药物在体内对CF突变小鼠鼻上皮以及CF人类受试者的鼻和肺的影响。野生型小鼠对米力农（100 microM）有轻微的鼻电位差（PD）超极化反应（1.6±0.6 mV，n = 8，P < 0.05）。相比之下，携带CF跨膜调节因子（CFTR）基因最常见人类突变的CF小鼠，即ΔF508（蛋白质定位错误）或G551D突变（蛋白质正常定位），未能表现出这种反应。单独灌注米力农对非CF人类受试者的基线鼻PD无显著影响（灌注前14.7±4.0 mV；灌注后15.3±4.6 mV），但显著（P < 0.05）增强了随后灌注的低氯溶液诱导的超极化（使用米力农时为36.8±3.0 mV，n = 6；不使用米力农时为18.1±2.2 mV，n = 19）。相比之下，在CF人类受试者（n = 6）中，单独使用米力农显著（P < 0.05）改变了鼻基线PD（灌注前52.2±3.3 mV；灌注后57.4±4.2 mV），但对随后对低氯溶液（使用米力农时为1.1±2.2 mV，n = 4；不使用米力农时为0.6±0.5 mV，n = 28）或异丙肾上腺素（100 microM）的反应无影响。在另一项针对携带ΔF508突变的受试者（n = 6）的研究中，在存在氨氯吡咪和低氯溶液的情况下，米力农与异丙肾上腺素联合鼻内给药无效果（-0.8±0.5 mV）。携带至少一个G551D等位基因的CF受试者（n = 4）的鼻上皮情况也是如此（-0.3±0.8 mV）。同样，当在低氯溶液中在存在氨氯吡咪、异丙肾上腺素或三磷酸腺苷（均为100 microM）的情况下在体内局部应用时，米力农并未使CF受试者（ΔF508）的气管（n = 6）或节段性（n = 6）气道的PD超极化。这些数据不支持在体内使用米力农诱导CF气道中的氯化物分泌。
