Hemodynamic and neuroendocrine responses to acute and chronic alpha-adrenergic blockade with prazosin and phenoxybenzamine.

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Abstract
We investigated the relevance of the selective alpha 1-adrenergic receptor blockade produced by prazosin to its blood pressure-lowering efficacy in man. The hemodynamic and neuroendocrine responses to the acute and chronic oral administration of prazosin and phenoxybenzamine were compared in a randomized, double-blind, placebo-controlled, crossover study of 11 patients with essential hypertension. These responses were also evaluated during lower body negative pressure and dynamic bicycle exercise, which produce potent but diversified activation of the sympathetic nervous system. In the acute studies, arterial blood pressure decreased to similar levels with prazosin or phenoxybenzamine; however, hemodynamic and neuroendocrine responses differed both before and during sympathetic nervous system activation. Prazosin lowered arterial blood pressure by reducing total peripheral resistance (p less than 0.05). In contrast, phenoxybenzamine produced a modest reduction in cardiac output (8%, p less than 0.05) with little change in total peripheral resistance, forearm vascular resistance or forearm blood flow. Additionally, plasma norepinephrine concentration and heart rate rose to significantly higher levels with prazosin (p less than 0.02) than with phenoxybenzamine, a difference that was most evident with lower body negative pressure or dynamic exercise. Baroreceptor control of arterial pressure homeostasis was preserved with both agents, except during marked degrees of cardiovascular stress. With chronic therapy, the circulatory responses adapted to the alpha-adrenergic antagonists, and both drugs produced similar hemodynamic and neuroendocrine profiles. The differences with acute administration may be the result of a more rapid onset of action and a more marked degree of alpha-adrenergic blockage with prazosin than with phenoxybenzamine therapy, rather than to any difference in their alpha 1- and alpha 2-adrenergic receptor blocking properties. Moreover, the findings of the present study suggest that the prejunctional alpha 2-receptor, autoinhibitory to sympathetic neuronal norepinephrine release, is of no functional significance in patients with essential hypertension.