Silent α2C-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries

Abstract

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 α₂-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-AR 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.