Davey M
Am J Cardiol. 1987 May 29;59(14):18G-28G. doi: 10.1016/0002-9149(87)90153-6.
The realization that a generalized increase in peripheral vascular resistance was the fundamental hemodynamic abnormality in essential hypertension and that the maintenance of arteriolar tone depended on the continuity of the adrenergic nervous system led to the alpha-adrenoceptor inhibitors being the first substances to receive serious consideration as antihypertensive agents. An agent that inhibited the effect of the adrenergic transmitter at the neuroeffector junction was anticipated to be ideal in inhibiting adrenergic vasoconductor tone. The clinical expectations for these compounds in the treatment of arterial hypertension, however, were not fulfilled. Although they lowered blood pressure, the effect was accompanied by unacceptable side effects such as tachycardia, and tolerance rapidly developed. The realization that transmitter norepinephrine modulates its own release through a prejunctionally located, alpha-adrenoceptor operated control mechanism explained several paradoxical phenomena and suggested exciting therapeutic possibilities. Most important, it provided a plausible if not compelling explanation for the clinical failure of the classic alpha-adrenoceptor inhibitors as antihypertensive agents. Characterization of the prejunctional and postjunctional effects of alpha agonists and antagonists led to the conclusion that prejunctional and postjunctional alpha adrenoceptors differed in receptor structure and led to the identification of prazosin as the first virtually specific alpha-adrenoceptor inhibitor. This was a crucially important step in the development of specific agents to combat adrenergic predominance in essential hypertension. Antihypertensive drugs like prazosin and doxazosin preserve feedback control of transmitter norepinephrine release, and consequently cause minimal reflex activation. They represent an alternative choice for therapy in all grades of hypertension with virtually no contra indicatons to their use.
认识到外周血管阻力普遍增加是原发性高血压的基本血流动力学异常，且小动脉张力的维持依赖于肾上腺素能神经系统的连续性，这使得α-肾上腺素能受体抑制剂成为首批被认真考虑作为抗高血压药物的物质。一种能在神经效应器连接处抑制肾上腺素能递质作用的药物被认为是抑制肾上腺素能血管收缩张力的理想药物。然而，这些化合物在治疗动脉高血压方面的临床预期并未实现。尽管它们能降低血压，但这种作用伴随着诸如心动过速等不可接受的副作用，而且很快就会产生耐受性。认识到递质去甲肾上腺素通过位于节前的、由α-肾上腺素能受体操纵的控制机制调节其自身释放，这解释了几个矛盾现象，并暗示了令人兴奋的治疗可能性。最重要的是，它为经典α-肾上腺素能受体抑制剂作为抗高血压药物的临床失败提供了一个合理的（即使不是令人信服的）解释。对α激动剂和拮抗剂的节前和节后效应的表征得出结论，节前和节后α肾上腺素能受体在受体结构上存在差异，并导致哌唑嗪被确定为第一种几乎特异性的α-肾上腺素能受体抑制剂。这是开发对抗原发性高血压中肾上腺素能优势的特异性药物的关键重要一步。像哌唑嗪和多沙唑嗪这样的抗高血压药物保留了对递质去甲肾上腺素释放的反馈控制，因此引起的反射激活最小。它们是治疗各级高血压的替代选择，实际上没有使用禁忌。
