长效支气管扩张剂作用机制探讨

目的 旨在比较长效支气管扩张剂福莫均（ＦＯＲ）沙美特罗（ＳＬＭ）与短效支气管扩张剂芬诺均（ＦＥＮ）、少丁胺醇（ＳＡＬ０及异丙肾上腺素（ＩＳＯ）的内在活性，受体亲和力及其在细胞的信号放大作用。方法 采用酶解法制备扣支气管骨肌细胞，以＾３２Ｐ－ＡＴＰ为底物，测定各激动剂作用于β２受体，激活腺苷酸环化酶生成ｃＤＮＡ的ＩＡ及其生成半数最大量ｃＡＭＰ所需浓度（ＥＣ５０），并计算出各激动剂的相对效应ｐＥＣ５０

Inquiry into the mechanism of long-acting bronchodilators

OBJECTIVE: To compare the intrinsic activity and the affinity of long-(formoterol and salmeterol) and short-acting (fenoterol and salbutamol) bronchodilators with isoproterenol in membranes of calf tracheal smooth muscle. METHODS: Membranes were prepared after isolation of intact cells using a mixture of collagenase and pronase. Affinities were measured with radioligand binding. Intrinsic activities (IA) of agonists and effective concentrations of agonists used for half maximum stimulation of adenylate cyclase (AC) (EC50) were determined as stimulants of beta 2-adrenoceptor coupled AC activity using alpha-22P-ATP as substrate. RESULTS: The results showed that IA estimated as fraction of the maximum effect by isoproterenol (1.00) were 1.00, 0.76, 0.81 and 0.83 for formoterol, salmeterol, fenoterol and salbutamol respectively. Affinities measured as dissociation constants (pKD) exhibited higher affinities for long-acting (formoterol: 8.02, salmeterol: 8.43) than for short-acting agonists (fenoterol: 5.84, salbutamol: 5.84). Relative effects of agonists (pEC50) were much higher for formoterol (9.10) and salmeterol (8.70) than for fenoterol (6.69) and salbutamol (6.78). CONCLUSIONS: The results indicated that formoterol was characterized as a full agonist with a 20-fold higher affinity than isoproterenol whereas the other agonists acted as partial agonists. Significant amplifications of receptor signalling quantified as difference of values between pEC50 and pKD was found for the agonists in the tested receptor membranes. It is suggested that high IA, affinity and the signal amplification of formoterol might play a role in its long-acting effect.