Involvement of nitric oxide production in the impairment of skin blood flow response to local cooling in diabetic db/db mice

Abstract

An enhanced vasoconstrictor activity of cutaneous vessels participates in the reduction of skin blood flow induced by cooling. The present study investigated changes in the local response to cooling in hyperglycemic conditions. Male diabetic db/db and control C57BL/6J mice, anaesthetized with pentobarbitone, were treated with tetrodotoxin for eliminating the sympathetic nerve tone and artificially ventilated. The plantar skin blood flow (PSBF) was measured by laser Doppler flowmetry. Cooling the air temperature around the foot reduced PSBF in a temperature-dependent manner in control and db/db mice. The PSBF reduction was significantly smaller in db/db mice than in control mice. Phentolamine, a non-selective α-antagonist, bunazosin, a selective α1-antagonist, MK-912, a selective α2C-antagonist, and Y-27632, a Rho-kinase inhibitor, significantly inhibited the PSBF reduction induced by cooling to 15°C in both mice and the inhibitory effects were comparable between these mice. The cooling-induced PSBF reduction was also significantly inhibited by Nω-nitro-l-arginine, an inhibitor of nitric oxide synthase, in control mice; however, the inhibitory effect of Nω-nitro-l-arginine was not observed in db/db mice. The reduction of PSBF induced by the intraarterial administration of adrenaline was comparable between control and db/db mice both before and after the treatment with Nω-nitro-l-arginine. It is thus likely that the reduction of skin blood flow induced by local cooling might be partly mediated by a decrease in endothelium-derived nitric oxide production, and that an impairment of the nitric oxide production might be related to reduced vasoconstrictor response to cooling in db/db mice.