Monopoli A, Forlani A, Bevilacqua M, Vago T, Norbiato G, Bertora P, Biglioli P, Alamanni F, Ongini E
Research Laboratories, Essex Italia, Subsidiary of Schering-Plough, Milan.
J Cardiovasc Pharmacol. 1989 Jul;14(1):114-20. doi: 10.1097/00005344-198907000-00020.
beta- And alpha 1-adrenoceptor antagonist properties of bufuralol, carvedilol, celiprolol, dilevalol, labetalol, and pindolol were investigated in human myocardium and mammary artery using binding techniques and functional studies. In myocardial membranes, beta-adrenoceptor antagonists showed monophasic competition isotherms for [125I]pindolol binding with high affinity (Ki from 1-100 nM), except for celiprolol which displayed a biphasic competition isotherm (pKi = 6.4 +/- 0.06 for beta 1- and 4.8 +/- 0.07 for beta 2-adrenoceptors). Drug interactions with alpha 1-adrenoceptors were evaluated in human mammary artery by [3H]prazosin binding and by measuring contractile responses to norepinephrine (NE). Labetalol and carvedilol showed a moderate affinity for alpha 1-adrenoceptors (pKi = 6.2 +/- 0.01 and 6.1 +/- 0.06, respectively), and inhibited NE-induced contractions (pA2 = 6.93 +/- 0.23 and 8.64 +/- 0.24, respectively). Dilevalol, bufuralol, and pindolol displayed weak effect both in binding (Ki in micromolar range) and functional experiments (pA2 = 5.98, 5.54, and 6.23, respectively). Celiprolol did not show antagonist properties up to 100 microM in functional studies, but displayed a slight affinity for alpha 1-adrenoceptors in binding studies. The data indicate that the vasodilating activity of these beta-adrenoceptor antagonists is caused in some instances by an alpha 1-adrenoceptor antagonism (labetalol, carvedilol), whereas for the others alternative mechanisms should be considered.
使用结合技术和功能研究，在人心肌和乳腺动脉中研究了布呋洛尔、卡维地洛、塞利洛尔、地来洛尔、拉贝洛尔和吲哚洛尔的β及α1肾上腺素能受体拮抗特性。在心肌膜中，除塞利洛尔显示双相竞争等温线外（β1肾上腺素能受体的pKi = 6.4±0.06，β2肾上腺素能受体的pKi = 4.8±0.07），β肾上腺素能受体拮抗剂对[125I]吲哚洛尔结合呈现单相竞争等温线，具有高亲和力（Ki为1 - 100 nM）。通过[3H]哌唑嗪结合以及测量对去甲肾上腺素（NE）的收缩反应，在人乳腺动脉中评估药物与α1肾上腺素能受体的相互作用。拉贝洛尔和卡维地洛对α1肾上腺素能受体显示出中等亲和力（pKi分别为6.2±0.01和6.1±0.06），并抑制NE诱导的收缩（pA2分别为6.93±0.23和8.64±0.24）。地来洛尔、布呋洛尔和吲哚洛尔在结合（Ki在微摩尔范围内）和功能实验中均显示出较弱的作用（pA2分别为5.98、5.54和6.23）。在功能研究中，塞利洛尔在高达100μM时未显示拮抗剂特性，但在结合研究中对α1肾上腺素能受体显示出轻微亲和力。数据表明，这些β肾上腺素能受体拮抗剂的血管舒张活性在某些情况下是由α1肾上腺素能受体拮抗作用引起的（拉贝洛尔、卡维地洛），而对于其他药物，则应考虑其他机制。
