title: Silent alpha(2C)-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries.
abstract: 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.
authors.affiliation: Heart and Lung Institute, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Chotani
authors.forename: S
authors.initials: S
authors.lastname: Flavahan
authors.forename: S
authors.initials: S
authors.lastname: Mitra
authors.forename: D
authors.initials: D
authors.lastname: Daunt
authors.forename: N A
authors.initials: NA
authors.lastname: Flavahan
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000737:chemistry / Q000502:physiology; D001833:Body Temperature Regulation / Q000502:physiology; D000068438:Brimonidine Tartrate; D019556:COS Cells; D003080:Cold Temperature; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000378:metabolism; D009924:Organ Culture Techniques; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011807:Quinolizines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011928:Raynaud Disease / Q000503:physiopathology; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000503:physiopathology; D012867:Skin / Q000098:blood supply*; D013623:Tail / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: C547775:Adra2c protein, mouse; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D007211:Indoles; D054833:Isoindoles; D007546:Isoquinolines; D010879:Piperazines; D011807:Quinolizines; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; C054290:L 657743; D010656:Phenylephrine; D000068438:Brimonidine Tartrate; C032994:AR-C239; C072125:BRL 44408