Aoki K, Asano M, Matsuda T
Second Department of Internal Medicine, Nagoya City University Medical School, Japan.
J Cardiovasc Pharmacol. 1988 Aug;12(2):167-78. doi: 10.1097/00005344-198808000-00007.
Antagonism of alpha 1-adrenoceptor-mediated vascular contraction by urapidil was examined in helical strips of femoral and mesenteric arteries isolated from 13-week-old Aoki spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto (WKY) rats, since this agent has antihypertensive effect through antagonizing peripheral alpha-adrenoceptors. Schild plot analyses clearly demonstrated the existence of only alpha 1-adrenoceptors in these arteries from both strains. Therefore, it is possible to demonstrate alpha 1-adrenoceptor blocking effects of nonselective alpha-adrenoceptor antagonists as well as selective alpha 1-adrenoceptor antagonists. Urapidil antagonized the alpha 1-adrenoceptor-mediated vascular contraction in a competitive fashion. The pA2 value for urapidil against alpha 1-adrenoceptors was not significantly different between SHR and WKY rats. The addition of 10(-5) M norepinephrine (NE) produced a sustained contraction in a SHR femoral artery, whereas in a WKY rat femoral artery this agonist produced a transient contraction followed by a sustained relaxation. Urapidil elicited a dose-dependent relaxation with a IC50 value of 6.50 in the SHR femoral artery precontracted with NE. In the presence of 3 x 10(-7) M timolol, a beta-adrenoceptor antagonist, femoral arteries from both strains exhibited similar magnitude of contraction in response to the stimulation with 10(-5) M NE. Under these conditions, urapidil elicited a similar extent of relaxation between SHR and WKY rats. On the other hand, the addition of 10(-5) M NE produced a sustained contraction in mesenteric arteries from both SHR and WKY rats. The contraction expressed as a ratio to the maximum developed by KCl depolarization was significantly greater in SHR than in WKY rats. In these arteries, the relaxing effect of urapidil was more evident in SHR than in WKY rats. Contractile responses to NE and relaxing effects of urapidil were not affected by timolol. These results suggest that urapidil effectively antagonized enhanced alpha 1-adrenoceptor responses seen in SHR arteries.
由于乌拉地尔通过拮抗外周α-肾上腺素能受体发挥降压作用，因此我们在从13周龄青木自发性高血压大鼠（SHR）和年龄匹配的正常血压Wistar-Kyoto（WKY）大鼠分离的股动脉和肠系膜动脉螺旋条中研究了乌拉地尔对α1-肾上腺素能受体介导的血管收缩的拮抗作用。Schild图分析清楚地表明，这两种品系的这些动脉中仅存在α1-肾上腺素能受体。因此，有可能证明非选择性α-肾上腺素能受体拮抗剂以及选择性α1-肾上腺素能受体拮抗剂的α1-肾上腺素能受体阻断作用。乌拉地尔以竞争性方式拮抗α1-肾上腺素能受体介导的血管收缩。乌拉地尔对α1-肾上腺素能受体的pA2值在SHR和WKY大鼠之间没有显著差异。加入10（-5）M去甲肾上腺素（NE）可使SHR股动脉产生持续收缩，而在WKY大鼠股动脉中，该激动剂产生短暂收缩，随后是持续舒张。乌拉地尔在预先用NE预收缩的SHR股动脉中引起剂量依赖性舒张，IC50值为6.50。在存在3×10（-7）M噻吗洛尔（一种β-肾上腺素能受体拮抗剂）的情况下，两种品系的股动脉对10（-5）M NE刺激的收缩幅度相似。在这些条件下，乌拉地尔在SHR和WKY大鼠之间引起相似程度的舒张。另一方面，加入10（-5）M NE可使SHR和WKY大鼠的肠系膜动脉产生持续收缩。以KCl去极化产生的最大收缩比例表示的收缩在SHR中比在WKY大鼠中显著更大。在这些动脉中，乌拉地尔的舒张作用在SHR中比在WKY大鼠中更明显。对NE的收缩反应和乌拉地尔的舒张作用不受噻吗洛尔的影响。这些结果表明，乌拉地尔有效地拮抗了SHR动脉中增强的α1-肾上腺素能受体反应。
