Ketorolac alters blood flow during normothermia but not during hyperthermia in middle-aged human skin

In young healthy humans full expression of reflex cutaneous vasodilation is dependent on cyclooxygenase (COX)- and nitric oxide synthase (NOS)-dependent mechanisms. Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation potentially through both platelet and vascular COX-dependent mechanisms. We hypothesized the contribution of COX-dependent vasodilators to reflex cutaneous vasodilation during localized acute COX inhibition would be attenuated in healthy middle-aged humans due to a shift toward COX-dependent vasoconstrictors. Four microdialysis fibers were placed in forearm skin of 13 middle-aged (53 ± 2 yr) normotensive healthy humans, serving as control (Ringer), COX-inhibited (10 mM ketorolac), NOS-inhibited (10 mM N ^G-nitro-L-arginine methyl ester), and combined NOS- and COX-inhibited sites. Red blood cell flux was measured over each site by laser-Doppler flowmetry as reflex vasodilation was induced by increasing oral temperature (T_or) 1.0°C using a water-perfused suit. Cutaneous vascular conductance was calculated (CVC = flux/mean arterial pressure) and normalized to maximal CVC (CVC_max; 28 mM sodium nitroprusside). CVC_max was not affected by localized microdialysis drug treatment (P > 0.05). Localized COX inhibition increased baseline (18 ± 3%CVC_max; P < 0.001) compared with control (9 ± 1%CVC_max), NOS-inhibited (7 ± 1%CVC_max), and combined sites (10 ± 1%CVC_max). %CVC_max in the COX-inhibited site remained greater than the control site with ΔT_or ≤ 0.3°C; however, there was no difference between these sites with ΔT_or ≥ 0.4°C. NOS inhibition and combined COX and NOS inhibition attenuated reflex vasodilation compared with control (P < 0.001), but there was no difference between these sites. Localized COX inhibition with ketorolac significantly augments baseline CVC but does not alter the subsequent skin blood flow response to hyperthermia, suggesting a limited role for COX-derived vasodilator prostanoids in reflex cutaneous vasodilation and a shift toward COX-derived vasoconstrictors in middle-aged human skin.