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

Abstract

Cold constricts cutaneous blood vessels by increasing the reactivity of smooth muscle α 2-adrenergic receptors (α 2-ARs). Experiments were performed to determine the role of α 2-AR subtypes (α 2A-, α 2B-, α 2C-ARs) in this response. Stimulation of α 1-ARs by phenylephrine or α 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 α 2-AR activation but less responsive to activation of α 1-ARs. Cold augmented constriction to α 2-AR activation in distal arteries but did not affect the response to α 1-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, α 2-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 α 2-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.