Silent α_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.

Effect of Oral OPC-28326, a Selective Femoral Arterial Vasodilator, on Hindlimb Subcutaneous Tissue Temperature in Conscious Dogs Under Buprenorphine Sedation

“…It was reported that cooling augmented vasoconstriction induced by a2-adrenoceoptor activation and that postjunctional a2-adrenoceptors are important for thermoregulation in this vascular bed (8,9). More recently, it was demonstrated that vasoconstriction induced by the cold was augmented preferentially via a 2C-adrenoceptors, which were silent in a warm environment (10). Taken together, the effects of OPC-28326 shown in this study might be responsible for its a2C-adrenoceptor-blocking action.…”

Sympathetic, sensory, and nonneuronal contributions to the cutaneous vasoconstrictor response to local cooling

“…With respect to direct local cooling, several lines of evidence point to an involvement of the sympathetic vasoconstrictor system in the reduction of skin blood flow. Postsynaptic ␣ 2 -adrenergic receptors have an enhanced affinity for norepinephrine, perhaps mediated through translocation of ␣ 2C -receptors to the membrane through a Rho kinase mechanism, and there is an increased ␣ 1 -receptor reserve, these effects countering negative effects of cooling on norepinephrine synthesis and release and on contractile function (2,4,6,29,41). Previous studies in our laboratory show that presynaptic blockade of sympathetic vasoconstrictor nerves with bretylium, applied to the intact skin iontophoretically, reverses the initial vasoconstrictor response to local cooling to one of vasodilation (31) and reverses the inhibition by local cooling of reflex cutaneous vasodilation (30).…”

Radiofrequency upper thoracic sympathectomy in the treatment of critical upper limb ischemia - a case series

“…11 ). Neurogenic causes include stress, increased activity of sympathetic nerves, increased number and activation of silent α2 receptors 12 , depletion of neurokinin A, substance P and CGRP (calcitonin gene-related peptide) (ref. 13 ).…”