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

Cold constricts cutaneous blood vessels by increasing the reactivity of smo oth muscle alpha(2)-adrenergic receptors (alpha(2)-ARs). Experiments were p erformed to determine the role of alpha(2)-AR subtypes (alpha(2A-), alpha(2 B-), alpha(2C-)ARS) in this response. Stimulation of alpha(1)-ARs by phenyl ephrine or alpha(2)-ARs by UK-14,304 caused constriction of isolated mouse tail arteries mounted in a pressurized myograph system. Compared with proxi mal arteries, distal arteries were more responsive to aa-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 respons e to al-AR stimulation or the level of myogenic tone. Western blot analysis demonstrated expression of a(2A-) and alpha(2C-)ARs in tail arteries: expr ession 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 (BR L-44408) but not by selective inhibition of alpha(2B)-ARs (ARC-239) or alph a(2C)-ARs (MK-912). In contrast, during cold exposure (28 degrees C), the a ugmented response to UK-14,304 was inhibited by the alpha(2C)-AR antagonist MK-912, which selectively abolished cold-induced amplification of the resp onse. These experiments indicate that cold-induced amplification of alpha(2 )-ARs is mediated by alpha(2C)-ARs that are normally silent in these cutane ous arteries. Blockade of alpha(2C)-ARs may prove an effective treatment fo r Raynaud's Phenomenon.