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

Cold constricts cutaneous blood vessels by increasing the reactivity of smooth muscle α₂-adrenergic receptors (α₂-ARs). Experiments were performed to determine the role of α₂-AR subtypes (α(2A)-, α(2B)-, α(2C)-ARs) in this response. Stimulation of α₁-ARs by phenylephrine or α₂-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 α₁-AR activation but less responsive to activation of α₁-ARs. Cold augmented constriction to α₂-AR activation in distal arteries but did not affect the response to α₁-AR stimulation or the level of myogenic tone. Western blot analysis demonstrated expression of α(2A)- and α(2C)-ARs in tail arteries: expression of α(2C)- ARs decreased in distal compared with proximal arteries, whereas expression of the glycosylated form of the α(2A)-AR increased in distal arteries. At 37°C, α₂-AR-induced vasoconstriction in distal arteries was inhibited by selective blockade of α(2A)-ARs (BRL-44408) but not by selective inhibition of α(2B)-ARs (ARC-239) or α(2C)-ARs (MK-912). In contrast, during cold exposure (28°C), the augmented response to UK-14,304 was inhibited by the α(2C)-ARs antagonist MK-912, which selectively abolished cold-induced amplification of the response. These experiments indicate that cold-induced amplification of α₂-ARs is mediated by α(2C)-ARs that are normally silent in these cutaneous arteries. Blockade of α(2C)-ARs may prove an effective treatment for Raynaud's Phenomenon.