Silent alpha(2C)-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries

Cold constricts cutaneous blood vessels by increasing the reactivity of smooth muscle Alpha(2)-adrenergic receptors (Alpha(2)-ARs). Experiments were performed to determine the role of Alpha(2)-AR subtypes (Alpha(2A)-, Alpha(2B)-, Alpha(2C)-ARs) in this response. Stimulation of Alpha(1)-ARs by phenylephrine or Alpha(2)-ARs by UK-14,304 caused constriction of isolated mouse tail arteries mounted in a pressurized myograph system. Compared with proximal arteries, distal arteries were more responsive to Alpha(2)-AR activation but less responsive to activation of Alpha(1)-ARs. Cold augmented constriction to Alpha(2)-AR activation in distal arteries but did not affect the response to Alpha(1)-AR stimulation or the level of myogenic tone. Western blot analysis demonstrated expression of Alpha(2A)- and Alpha(2C)-ARs in tail arteries: expression of Alpha(2C)-ARs decreased in distal compared with proximal arteries, whereas expression of the glycosylated form of the Alpha(2A)-AR increased in distal arteries. At 37 degrees C, Alpha(2)-AR-induced vasoconstriction in distal arteries was inhibited by selective blockade of Alpha(2A)-ARs (BRL-44408) but not by selective inhibition of Alpha(2B)-ARs (ARC-239) or Alpha(2C)-ARs (MK-912). In contrast, during cold exposure (28 degrees C), the augmented response to UK-14,304 was inhibited by the Alpha(2C)-AR antagonist MK-912, which selectively abolished cold-induced amplification of the response. These experiments indicate that cold-induced amplification of Alpha(2)-ARs is mediated by Alpha(2C)-ARs that are normally silent in these cutaneous arteries. Blockade of Alpha(2C)-ARs may prove an effective treatment for Raynaud's Phenomenon.