Hamilton C A, Reid J L, Vincent J
Br J Pharmacol. 1985 Sep;86(1):79-87. doi: 10.1111/j.1476-5381.1985.tb09437.x.
The cardiovascular effects of doxazosin, a quinazoline derivative related to prasozin were investigated and compared to prazosin in the rabbit. Radioligand binding studies using rabbit cerebral membranes showed that both doxazosin and prazosin were roughly equipotent at displacing [3H]-prazosin from specific binding sites. However, the lower pA2 value for doxazosin at alpha 1-adrenoceptors in isolated thoracic aorta preparations suggests a lower potency compared to prazosin. The dose-related pressor effects of intravenous phenylephrine were used to assess vascular alpha 1-adrenoceptor antagonism in vivo. There was a close agreement between alpha 1-adrenoceptor antagonist potency and maximum hypotensive effects with both doxazosin and prazosin. The alpha 1-adrenoceptor antagonist effects of doxazosin were more prolonged than those of prazosin. Studies using either radioligand binding or pressor responses to B-HT 920 showed that doxazosin did not show any significant affinity for the alpha 2-adrenoceptor. Similarly, no direct vasodilator effects were observed either in animals administered angiotensin II or in isolated thoracic aorta spiral strip preparations contracted with potassium. Doxazosin has a longer terminal elimination half-life than prazosin. The pharmacokinetics of doxazosin were linear over the dose range examined. Following pharmacological 'autonomic blockade' and treatment with prazosin, doxazosin did not cause any further fall in blood pressure. These observations suggest that doxazosin, like prazosin, appears to exert its hypotensive action through alpha 1-adrenoceptor antagonism. The prolonged fall in blood pressure and well sustained alpha 1-adrenoceptor antagonism after doxazosin raise the possibility of an active metabolite which also has alpha 1-adrenoceptor blocking properties.
研究了喹唑啉衍生物多沙唑嗪（与哌唑嗪相关）对心血管的影响，并在兔身上与哌唑嗪进行了比较。使用兔脑膜进行的放射性配体结合研究表明，多沙唑嗪和哌唑嗪在从特定结合位点置换[3H] - 哌唑嗪方面大致等效。然而，在离体胸主动脉制剂中，多沙唑嗪在α1 - 肾上腺素受体处的pA2值较低，表明其效力低于哌唑嗪。静脉注射去氧肾上腺素的剂量相关升压作用用于评估体内血管α1 - 肾上腺素受体拮抗作用。多沙唑嗪和哌唑嗪的α1 - 肾上腺素受体拮抗效力与最大降压作用之间密切相关。多沙唑嗪的α1 - 肾上腺素受体拮抗作用比哌唑嗪更持久。使用放射性配体结合或对B - HT 920的升压反应进行的研究表明，多沙唑嗪对α2 - 肾上腺素受体没有任何显著亲和力。同样，在给予血管紧张素II的动物或用钾收缩的离体胸主动脉螺旋条制剂中均未观察到直接血管舒张作用。多沙唑嗪的终末消除半衰期比哌唑嗪长。在所研究的剂量范围内，多沙唑嗪的药代动力学呈线性。在进行药理学“自主神经阻滞”并用哌唑嗪治疗后，多沙唑嗪不会导致血压进一步下降。这些观察结果表明，多沙唑嗪与哌唑嗪一样，似乎通过α1 - 肾上腺素受体拮抗作用发挥其降压作用。多沙唑嗪后血压的持续下降和α1 - 肾上腺素受体拮抗作用的良好维持增加了存在具有α1 - 肾上腺素受体阻断特性的活性代谢物的可能性。
