Ruff F, Zander J F, Edoute Y, Santais M C, Flavahan N A, Verbeuren T J, Vanhoutte P M
Department of Physiology and Biophysics, Mayo Clinic, Rochester, Minnesota.
J Pharmacol Exp Ther. 1988 Jan;244(1):173-80.
Experiments were designed to determine the mechanism of action of the bronchodilator drug tulobuterol. Tissues were suspended in organ chambers for isometric tension recording. Tulobuterol caused concentration-dependent relaxations of guinea pig tracheae, canine saphenous veins and canine bronchi; the compound relaxed canine coronary arteries only at high concentrations and did not affect spontaneously beating guinea pig atria. A metabolite of tulobuterol, 4-hydroxytulobuterol, was more potent in relaxing guinea pig tracheae than tulobuterol, salbutamol and isoproterenol. Other metabolites (3-hydroxy-, 5-hydroxy- and 4,5-dihydroxytulobuterol) were less efficacious than 4-hydroxytulobuterol. Both tulobuterol and 4-hydroxytulobuterol acted as partial agonists. The effects of tulobuterol in the saphenous vein (but not in the coronary artery) were antagonized by the selective beta-2 adrenergic blocker ICI 118,551 but were not affected by the selective beta-1 adrenergic inhibitor metoprolol. In bronchi, removal of the epithelium reduced the relaxations caused by tulobuterol. The drug did not inhibit responses of canine bronchi to electrical stimulation of the cholinergic nerves more than those to exogenous acetylcholine. Tulobuterol caused a moderate augmentation of the evoked release of [3H]norepinephrine in canine saphenous veins previously incubated with the labeled transmitter. Thus, tulobuterol is a selective beta-2 adrenergic agonist with minimal nonselective inhibitory effect on airway and vascular smooth muscle. It also facilitates adrenergic neurotransmission, which may help to explain its bronchodilator effect in the intact organism. Tulobuterol does not activate beta-1 adrenoceptors and has no direct positive chronotropic effect. A metabolite of tulobuterol, 4-hydroxytulobuterol, is more active than the parent compound.
设计实验以确定支气管扩张药妥布特罗的作用机制。将组织悬于器官浴槽中进行等长张力记录。妥布特罗可引起豚鼠气管、犬隐静脉和犬支气管浓度依赖性舒张；该化合物仅在高浓度时使犬冠状动脉舒张，对豚鼠自发搏动的心房无影响。妥布特罗的一种代谢产物4-羟基妥布特罗，在舒张豚鼠气管方面比妥布特罗、沙丁胺醇和异丙肾上腺素更有效。其他代谢产物（3-羟基-、5-羟基-和4,5-二羟基妥布特罗）的效力低于4-羟基妥布特罗。妥布特罗和4-羟基妥布特罗均作为部分激动剂起作用。妥布特罗在隐静脉（而非冠状动脉）中的作用被选择性β2肾上腺素能阻滞剂ICI 118,551拮抗，但不受选择性β1肾上腺素能抑制剂美托洛尔影响。在支气管中，去除上皮可减少妥布特罗引起的舒张。该药物对犬支气管对胆碱能神经电刺激的反应的抑制作用，并不比对外源性乙酰胆碱的反应抑制作用更强。妥布特罗使预先用标记递质孵育的犬隐静脉中诱发的[3H]去甲肾上腺素释放适度增加。因此，妥布特罗是一种选择性β2肾上腺素能激动剂，对气道和血管平滑肌的非选择性抑制作用最小。它还促进肾上腺素能神经传递，这可能有助于解释其在完整机体中的支气管扩张作用。妥布特罗不激活β1肾上腺素受体，也无直接的正性变时作用。妥布特罗的一种代谢产物4-羟基妥布特罗比母体化合物更具活性。
