Reactive oxygen species (ROS) from NADPH and xanthine oxidase modulate the cutaneous local heating response in healthy humans

Abstract

Local cutaneous heating produces vasodilation that is largely nitric oxide (NO) dependent. We showed that angiotensin II (ANG II) attenuates this by an ANG II receptor, type 1 (AT1R)-dependent mechanism that is reversible with the antioxidant ascorbate, indicating oxidative stress. Reactive oxygen species (ROS) produced by ANG II employ NADPH and xanthine oxidase pathways. To determine whether these mechanisms pertain to skin, we measured cutaneous local heating with 10 μM ANG II, using apocynin to inhibit NADPH oxidase and allopurinol to inhibit xanthine oxidase. We also inhibited superoxide with tempol, and H(2)O(2) with ebselen. We heated the skin of the calf in 8 healthy volunteers (24.5-29.9 yr old) to 42°C and measured local blood flow to assess the percentage of maximum cutaneous vascular conductance. We remeasured while perfusing allopurinol, apocynin, ebselen, and tempol through individual microdialysis catheters. This was then repeated with ANG II combined with antioxidant drugs. tempol and apocynin alone had no effect on the heat response. Allopurinol enhanced the entire response (125% of heat alone), while ebselen suppressed the heat plateau (76% of heat alone). ANG II alone caused significant attenuation of the entire heat response (52%). When added to ANG II, Allopurinol partially reversed the ANG II attenuation. Heat with ebselen and ANG II were similar to heat and ANG II; ebselen only partially reversed the ANG II attenuation. Apocynin and tempol each partially reversed the attenuation caused by ANG II. This suggests that ROS, produced by ANG II via NADPH and xanthine oxidase pathways, modulates the response of skin to the application of heat, and thus contributes to the control of local cutaneous blood flow.

Fig. 1.

Sequence of events for experimental maneuvers. SNP, sodium nitroprusside; Apo, apocynin; Allo, allopurinol; Ebs, ebselen; Temp, tempol.

Fig. 2.

The response of skin to local heating alone and after administration of ANG II, or ANG II plus apocynin (left) or ANG II plus allopurinol (right). Data are expressed as percentage of maximum cutaneous vascular conductance (%CVCmax) and are averaged over all subjects. In this figure averaged data ± SE are shown at baseline, first thermal peak, nadir, and heat plateau. *Significantly different from heat alone, P < 0.05. ‡Significantly different from heat + ANG II, P < 0.05.

Fig. 3.

The response of skin to local heating alone and after administration of ANG II, or ANG II plus ebselen. Data are expressed as %CVCmax and are averaged over all subjects. In this figure averaged data ± SE are shown at baseline, first thermal peak, nadir, and heat plateau. *Significantly different from heat alone, P < 0.05. ‡Significantly different from heat + ANG II, P < 0.05.

Fig. 4.

The response of skin to local heating alone and after administration of ANG II, or ANG II plus Tempol. Data are expressed as %CVCmax, and are averaged over all subjects. In this figure averaged data ± SE are shown at baseline, first thermal peak, nadir, and heat plateau. *Significantly different from heat alone, P < 0.05. ‡Significantly different from heat + ANG II, P < 0.05.