In vivo and in vitro studies of alpha 2-adrenoceptor responses in human vascular smooth muscle.

To assess the role of alpha 2-receptor mechanisms in the control of vascular tone in humans, the pharmacological activities of RX 781094, an alpha 2-antagonist, and UK 14304, an alpha 2-agonist, have been investigated with the additional use of an alpha 1-antagonist, doxazosin. The effects of these agents on human forearm blood flow have been studied. In addition, some preliminary observations on the effects of these alpha 2-selective agents on isolated human arterial segments have been made. The alpha 2 agonist, UK 14304, produced a dose-dependent reduction in forearm blood flow, but the antagonism of this response by both doxazosin and RX 781094 at a dose which must be regarded as nonselective casts doubt on the hypothesis that alpha 2-receptors may be located postsynaptically in human vascular smooth muscle. These observations may be explained by UK 14304 having partial alpha 1-agonist activity. RX 781094 infused at low doses produced a dose-dependent reduction in forearm blood flow, which is interpreted as evidence for a presynaptic alpha 2 autoregulatory mechanism in the vasculature. Observations on isolated arterial segments (mesenteric, renal, splenic, gastric, and brachial) obtained during surgical procedures and mounted under tension in tissue baths did not provide evidence for a postsynaptic alpha 2-receptor mediating vasoconstriction. In contrast, the potentiation of the adrenaline response in the presence of the alpha 2 antagonist, RX 781094, supports the possibility that, in humans, an extrajunctional alpha 2-receptor may serve as the adrenergic mechanism for the release of an endothelial derived relaxing factor.