Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria, 3010, Australia.
Eur J Pharmacol. 2020 Sep 5;882:173304. doi: 10.1016/j.ejphar.2020.173304. Epub 2020 Jun 24.
Recently, the β-adrenoceptor agonist terbutaline was shown to have α-adrenolytic activity in mouse isolated pulmonary arteries in vitro and to lower pulmonary artery pressure in anaesthetised mice. The aim of our study was to determine the α-adrenoceptor antagonist activity of terbutaline and its structurally close resorcinol, orciprenaline, in rat isolated small mesenteric arteries set up for myography. Their α-adrenoceptor antagonist potency was then compared with their potency as β-adrenoceptor agonists. Concentration-response curves to methoxamine were competitively antagonised by terbutaline (30-300 μM) or orciprenaline (30-300 μM) with a pK of 4.70 ± 0.09 or 4.79 ± 0.17, respectively. Both terbutaline and orciprenaline fulfilled the criteria for simple, silent competitive antagonism. Terbutaline (30-300 μM) had no effect on endothelin-1 concentration-contraction curves. Our findings suggest that after oral dosing of terbutaline, the maximum plasma levels would NOT reach levels to show α-adrenoceptor antagonist activity. In conclusion, our work has provided additional quantitative evidence that terbutaline and orciprenaline are weak competitive α-adrenoceptor antagonists, but this additional property is probably not therapeutically important in the clinical treatment of asthma or pulmonary artery hypertension with these more potent β-adrenoceptor agonists.
最近，β-肾上腺素受体激动剂特布他林在体外的小鼠离体肺血管中显示出α-肾上腺素能拮抗剂活性，并降低麻醉小鼠的肺动脉压。我们的研究目的是确定特布他林及其结构上相近的间羟异丙肾上腺素（奥西那林）在用于肌动描记术的大鼠离体小肠系膜动脉中的α-肾上腺素受体拮抗剂活性。然后，将它们作为β-肾上腺素受体激动剂的效力与其进行比较。甲氧胺的浓度-反应曲线被特布他林（30-300μM）或奥西那林（30-300μM）竞争性拮抗，pK 值分别为 4.70±0.09 或 4.79±0.17。特布他林和奥西那林均满足简单、沉默的竞争性拮抗的标准。特布他林（30-300μM）对内皮素-1浓度-收缩曲线没有影响。我们的发现表明，口服特布他林后，最大血浆水平不会达到显示α-肾上腺素受体拮抗剂活性的水平。总之，我们的工作提供了额外的定量证据，表明特布他林和奥西那林是弱的竞争性α-肾上腺素受体拮抗剂，但这种额外的特性在这些更有效的β-肾上腺素受体激动剂治疗哮喘或肺动脉高压的临床治疗中可能不重要。
