| Maintenance of vascular tone occurs at the junctional synapse between the sympathetic nerve terminal and the blood vessel wall. The α-1 receptors are located postsynaptically in the vascular smooth muscle within the region of the synapse; α-2 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.23–25,27,28
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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 α-1 adrenoreceptors, though other receptors also play a role in vasoregulation; both α-1 and α-2 receptors appear to contribute significantly to venous vasoconstriction.23
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| The presence of presynaptic a-2 receptors appear to inhibit norepinephrine release, which may contribute to vasodilation via a negative feedback loop mechanism.2.23,28
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It is not clear when this mechanism would dominate in the clinical setting; however, this activity may potentially emerge in selected clinical situations where postsynaptic α-2 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 α-2 agonist application.
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| The presence of α-2 receptors on endothelial cells has been shown to mediate release of nitric oxide (NO), which induces vasodilation.24–26 Hence, stimulation of endothelial cell a-2 receptors may invoke a vasodilatory response. |
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α-1 receptor stimulation on vascular smooth muscle is able to override the NO-induced vascular relaxation response.24–26
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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.24
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In any given patient, the extent of α-2 receptor-induced vasoconstriction or vasodilation may reflect the net effect of α-2-invoked vascular smooth muscle stimulation (which causes vasoconstriction) versus α-2-mediated endothelial NO release (which causes vasodilation).24–26 When the latter response dominates, vasodilation occurs.
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