Maintenance of vascular tone occurs at the junctional synapse between the sympathetic nerve terminal and the blood vessel wall. The α1-receptors are located postsynaptically in the vascular smooth muscle within the region of the synapse; α2-receptors are located presynaptically at the nerve terminal, postsynaptically in the vascular smooth muscle outside the direct region of the synapse and within the endothelial wall.
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These anatomic differences may correlate with variations in individual drug activity under certain clinical circumstances (e.g., heating, cooling, differences in relative receptor expressions and locations).
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In most mammalian species, arterial vasoconstriction via directly innervated stimulation of vascular smooth muscle is mediated predominantly by α1-adrenoreceptors, though other receptors also play a role in vasoregulation; both α1 and α2 receptors appear to contribute significantly to venous vasoconstriction.
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The presence of presynaptic α2-receptors appears to inhibit norepinephrine release, which might contribute to vasodilation via a negative feedback loop mechanism.
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It is not clear when this mechanism would dominate in the clinical setting; however, this activity could potentially emerge in selected clinical situations where postsynaptic α2 adrenoreceptor activity and/or density are diminished in rosacea-affected skin.
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More data are needed to further clarify the potential role of this mechanism in the clinical setting where worsening of erythema develops after topical α2 agonist application.
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The presence of α2 receptors on endothelial cells has been shown to mediate release of nitric oxide (NO), which induces vasodilation. Hence, stimulation of endothelial cell α2 receptors might invoke a vasodilatory response.
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α1 receptor stimulation on vascular smooth muscle is able to override the NO-induced vascular relaxation response.
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The potential triggers that may induce release of endothelium-derived NO are increased levels of shear stress, neurotransmitters, autacoids, and hormonal stimuli.
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In any given patient, the extent of α2 receptor-induced vasoconstriction or vasodilation may reflect the net effect of α2 invoked vascular smooth muscle stimulation (which causes vasoconstriction) versus α2-mediated endothelial NO release (which causes vasodilation). When the latter response dominates, vasodilation occurs.
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