Anderson P, Lötvall J, Lindén A
Department of Respiratory Medicine and Allergology, University of Gothenburg, Sahlgrenska Hospital, Sweden.
Lung. 1996;174(3):159-70. doi: 10.1007/BF00173308.
The mechanisms producing long duration of action for formoterol and salmeterol are not fully understood. The aim of the current study was to examine how the concentration of long and short acting beta 2-adrenoceptor agonists affects their relaxation kinetics in airway smooth muscle. Onset (time to peak relaxation) and offset of action (reassertion of reversible relaxation followed repeated beta-adrenoceptor blockade and washout) were measured in the guinea pig trachea precontracted postjunctionally by carbachol 0.3 microM in vitro. At 10-1,000% (C10-C1,000) of the maximally effective concentration (C100: 150 nM formoterol, 10 microM salbutamol, 30 microM salmeterol), salbutamol had a shorter time to peak relaxation than did salmeterol. Formoterol and salmeterol had a similar time to peak relaxation at C10, but, in contrast to salmeterol, formoterol's time to peak relaxation became markedly shorter and similar to that of salbutamol as the concentration was increased up to C1,000. Significant reversible reasserted relaxation was demonstrated for salmeterol alone at C10. At C30-C1,000, however, salmeterol produced irreversible relaxation only, in spite of repeated beta-adrenoceptor blockade by sotalol 10 microM followed by washout. In contrast, formoterol produced an increasing reversible reasserted relaxation at C30-C1,000. Salbutamol produced significant, reversible reasserted relaxation at C1,000 only. In conclusion, the concentration determines the onset and offset of action for formoterol and to a lesser extent for salbutamol, but not for salmeterol. To cause sustained action, a submaximally effective concentration is sufficient for salmeterol, whereas formoterol requires a maximally effective concentration. The rank order of concentration dependence for the relaxation kinetics is not paralleled by the rank order of lipophilicity for formoterol, salbutamol, and salmeterol. Therefore, factors other than lipophilicity may also play a role in determining the relationship between concentration and relaxation kinetics for the investigated beta 2-agonists.
福莫特罗和沙美特罗产生长效作用的机制尚未完全明确。本研究旨在探讨长效和短效β2肾上腺素能受体激动剂的浓度如何影响其在气道平滑肌中的舒张动力学。在体外，通过0.3微摩尔卡巴胆碱使豚鼠气管节后预收缩，测量起效时间（达到最大舒张的时间）和作用消退时间（在反复β肾上腺素能受体阻断和冲洗后可逆性舒张的恢复）。在最大有效浓度（C100：150纳摩尔福莫特罗、10微摩尔沙丁胺醇、30微摩尔沙美特罗）的10%-1000%（C10-C1000）下，沙丁胺醇达到最大舒张的时间比沙美特罗短。在C10时，福莫特罗和沙美特罗达到最大舒张的时间相似，但与沙美特罗不同的是，随着浓度增加至C1000，福莫特罗达到最大舒张的时间明显缩短，与沙丁胺醇相似。仅在C10时，沙美特罗出现了显著的可逆性舒张恢复。然而，在C30-C1000时，尽管用10微摩尔索他洛尔反复进行β肾上腺素能受体阻断并冲洗，沙美特罗仅产生不可逆性舒张。相比之下，福莫特罗在C30-C1000时产生的可逆性舒张恢复增加。沙丁胺醇仅在C1000时产生显著的、可逆性舒张恢复。总之，浓度决定了福莫特罗的起效和作用消退时间，对沙丁胺醇的影响较小，但对沙美特罗无影响。要产生持续作用，低于最大有效浓度对沙美特罗就足够了，而福莫特罗需要最大有效浓度。福莫特罗、沙丁胺醇和沙美特罗的舒张动力学浓度依赖性顺序与亲脂性顺序并不平行。因此，除亲脂性外的其他因素也可能在决定所研究的β2激动剂浓度与舒张动力学之间的关系中起作用。
