Role of α_2C‐adrenoceptors in the reduction of skin blood flow induced by local cooling in mice

Abstract

Background and purpose: The reduction of skin blood flow induced by local cooling results from a reflex increase in sympathetic output and an enhanced vasoconstrictor activity of cutaneous vessels. The present study investigated the latter local response in vivo in tetrodotoxin-treated mice, in which the sympathetic nerve tone was abolished. Experimental approach: Male ddY mice, anaesthetized with pentobarbitone, were treated with tetrodotoxin and artificially ventilated. The plantar skin blood flow (PSBF) was measured by laser Doppler flowmetry. Key results: Cooling the air temperature around the left foot from 25 to 101C decreased the PSBF of the left foot. Bunazosin, an a 1 -adrenoceptor antagonist, RS79948, an a 2 -adrenoceptor antagonist, and MK-912, an a 2C -adrenoceptor antagonist, all significantly inhibited the cooling-induced reduction of PSBF; the inhibition by bunazosin was relatively small compared with that by RS79948 and MK-912. The response was not affected by guanethidine or bretylium, but was diminished in adrenalectomized mice. An intra-arterial injection of clonidine, an a 2 -adrenoceptor agonist, to the left iliac artery of adrenalectomized mice caused a transient decrease in PSBF, which was significantly augmented at 101C. MK-912 suppressed only the augmented portion at 101C. Y-27632, H-1152 and fasudil, Rho kinase inhibitors, also inhibited the cooling-induced reduction of PSBF. RS79948 caused no further reduction of the cooling-induced response after the inhibition by Y-27632. Conclusions and implications: Local cooling-induced reduction of skin blood flow in mice primarily results from increased reactivity of a 2C -adrenoceptors to circulating catecholamines, in which the Rho/Rho kinase pathway is involved.

Differential involvement of .ALPHA.1-adrenoceptors in vasoconstrictor responses to cooling in mouse plantar arteries in vitro and in vivo

“…We have recently demonstrated that this model is also involved in the in vivo cutaneous response to local cooling: MK-912, an α2C-adrenoceptor antagonist, inhibited coolinginduced reduction of PSBF in tetrodotoxin-treated mice in vivo (Honda et al, 2007). In addition, we found that a part of the cooling-induced response was also inhibited by bunazosin, an α1-adrenoceptor antagonist (Honda et al, 2007). This is apparently different from the results of earlier in vitro studies.…”

“…Thus, cooling seems to lead to the translocation of α2C-adrenoceptors to the plasma membrane, thereby augmenting vasoconstriction. We have recently demonstrated that this model is also involved in the in vivo cutaneous response to local cooling: MK-912, an α2C-adrenoceptor antagonist, inhibited coolinginduced reduction of PSBF in tetrodotoxin-treated mice in vivo (Honda et al, 2007). In addition, we found that a part of the cooling-induced response was also inhibited by bunazosin, an α1-adrenoceptor antagonist (Honda et al, 2007).…”

“…; 75 mg/kg), and placed on a heating pad in the dorsal position. Changes in PSBF in mice were measured with a non-contact laser Doppler flow meter (ALF 2100; Advance, Tokyo, Japan), as described previously (Honda et al, 2007). In brief, polyethylene tubes were inserted in the right femoral vein to administer drugs and in the right carotid artery to measure the mean arterial blood pressure (MAP) and heart rate (HR).…”

Regulation of Vascular Reactivity in Scleroderma: New Insights into Raynaud's Phenomenon

“…The role of the Rho/ROCK pathway in mediating cold-induced vasoconstriction in the cutaneous circulation has been confirmed in several studies [26][27][28] . In vivo analysis of the cutaneous circulation of mice and humans demonstrated an important role of ROCK activity in mediating the cold-induced increase in adrenergic and α 2C -AR vasoconstrictor activity 26-28 .…”

Cyclic AMP-Rap1A signaling mediates cell surface translocation of microvascular smooth muscle α2C-adrenoceptors through the actin-binding protein filamin-2

“…Divergent signaling pathways may C842 FILAMIN-2 AND MICROVASCULAR ␣2C-ADRENOCEPTORS converge on Rho-ROCK-filamin-2 to mediate receptor translocation and function. For example, the ␣ 2C -ARs have a known physiological role in human and murine cutaneous circulation response to cold temperatures (7,17,38). Moderate cooling to 28°C leads to increased biological activity of arteriolar ␣ 2C -ARs and to vasoconstriction.…”