Mechanism of alpha blockade for blood pressure control.

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.