Buisson-Defferier S, Van den Buuse M
Marion Merrell Dow Research Institute, Strasbourg, France.
Eur J Pharmacol. 1992 Nov 17;223(2-3):133-41. doi: 10.1016/0014-2999(92)94831-f.
The effects of pretreatment with the potent and selective 5-HT1A receptor ligand, MDL 73005EF, on the cardiovascular responses to administration of the 5-HT1A receptor agonists, 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT), flesinoxan and 5-methylurapidil were studied in conscious spontaneously hypertensive rats (SHR) and compared with those of putative 5-HT1A receptor antagonists. MDL 7300EF (0.1-3 mg/kg) induced a dose-dependent but transient decrease in mean arterial pressure (MAP). Pretreatment with doses of 1 or 3 mg/kg MDL 73005EF significantly inhibited the hypotensive and bradycardiac effects of 8-OH-DPAT (0.03-1 mg/kg). Pretreatment with 1 mg/kg MDL 73005EF similarly reduced the hypotensive actions of flesinoxan (0.3-1 mg/kg) and 5-methylurapidil (0.1 mg/kg). In contrast, MDL 73005EF did not significantly affect the decrease in blood pressure induced by administration of 0.01 mg/kg clonidine, 0.3 mg/kg hydralazine or 0.2 mg/kg nifedipine. The effect of 8-OH-DPAT (0.1 mg/kg) on MAP was also reduced by pretreatment with 1 mg/kg BMY 7378, buspirone or pindolol, but not NAN 190 or spiperone. BMY 7378, NAN 190, pindolol and spiperone induced a significant decrease in blood pressure. To rule out the possibility that the reduced baseline may have influenced responses to 8-OH-DPAT, we showed that pretreatment with the vasodilator, hydralazine (0.3 mg/kg), had no effect on the MAP response to 8-OH-DPAT although it significantly reduced MAP. We conclude that MDL 73005EF acts as a mixed agonist/antagonist at 5-HT1A receptors since it caused a decrease in blood pressure, but also reduced the cardiovascular responses to the 5-HT1A receptor agonists, 8-OH-DPAT, flesinoxan and 5-methylurapidil.
在清醒的自发性高血压大鼠（SHR）中，研究了强效选择性5-羟色胺1A（5-HT1A）受体配体MDL 73005EF预处理对给予5-HT1A受体激动剂8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）、氟司立坦和5-甲基尿嘧啶引起的心血管反应的影响，并与推定的5-HT1A受体拮抗剂的影响进行比较。MDL 7300EF（0.1 - 3mg/kg）引起平均动脉压（MAP）剂量依赖性但短暂的降低。用1或3mg/kg MDL 73005EF剂量预处理可显著抑制8-OH-DPAT（0.03 - 1mg/kg）的降压和减慢心率作用。用1mg/kg MDL 73005EF预处理同样可降低氟司立坦（0.3 - 1mg/kg）和5-甲基尿嘧啶（0.1mg/kg）的降压作用。相比之下，MDL 73005EF对给予0.01mg/kg可乐定、0.3mg/kg肼屈嗪或0.2mg/kg硝苯地平引起的血压降低没有显著影响。用1mg/kg BMY 7378、丁螺环酮或吲哚洛尔预处理也可降低8-OH-DPAT（0.1mg/kg）对MAP的作用，但NAN 190或螺哌隆则无此作用。BMY 7378、NAN 190、吲哚洛尔和螺哌隆可引起血压显著降低。为排除基线降低可能影响对8-OH-DPAT反应的可能性，我们发现用血管扩张剂肼屈嗪（0.3mg/kg）预处理对8-OH-DPAT的MAP反应没有影响，尽管它显著降低了MAP。我们得出结论，MDL 73005EF在5-HT1A受体上起混合激动剂/拮抗剂的作用，因为它引起血压降低，但也降低了对5-HT1A受体激动剂8-OH-DPAT、氟司立坦和5-甲基尿嘧啶的心血管反应。
