Impaired acetylcholine-induced cutaneous vasodilation in young smokers: roles of nitric oxide and prostanoids

<jats:p>Cigarette smoking attenuates acetylcholine (ACh)-induced cutaneous vasodilation in humans, but the underlying mechanisms are unknown. We tested the hypothesis that smokers have impaired nitric oxide (NO)- and cyclooxygenase (COX)-dependent cutaneous vasodilation to ACh infusion. Twelve young smokers, who have smoked more than 5.2 ± 0.7 yr with an average daily consumption of 11.4 ± 1.2 cigarettes, and 12 nonsmokers were tested. Age, body mass index, and resting mean arterial pressure were similar between the groups. Cutaneous vascular conductance (CVC) was evaluated as laser-Doppler flux divided by mean arterial pressure, normalized to maximal CVC (local heating to 43.0°C plus sodium nitroprusside administration). We evaluated the increase in CVC from baseline to peak (CVC<jats:sub>Δpeak</jats:sub>) and area under the curve of CVC (CVC<jats:sub>AUC</jats:sub>) during a bolus infusion (1 min) of 137.5 μM ACh at four intradermal microdialysis sites: 1) Ringer (control), 2) 10 mM N<jats:sup>G</jats:sup>-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor), 3) 10 mM ketorolac (COX inhibitor), and 4) combination of l-NAME + ketorolac. CVC<jats:sub>Δpeak</jats:sub>and CVC<jats:sub>AUC</jats:sub>at the Ringer site in nonsmokers were greater than in smokers (CVC<jats:sub>Δpeak</jats:sub>, 42.9 ± 5.1 vs. 22.3 ± 3.5%<jats:sub>max</jats:sub>, P < 0.05; and CVC<jats:sub>AUC</jats:sub>, 8,085 ± 1,055 vs. 3,145 ± 539%<jats:sub>max</jats:sub>·s, P < 0.05). In nonsmokers, CVC<jats:sub>Δpeak</jats:sub>and CVC<jats:sub>AUC</jats:sub>at the l-NAME site were lower than the Ringer site (CVC<jats:sub>Δpeak</jats:sub>, 29.5 ± 6.2%<jats:sub>max</jats:sub>, P < 0.05; and CVC<jats:sub>AUC</jats:sub>, 5,377 ± 1,109%<jats:sub>max</jats:sub>·s, P < 0.05), but in smokers, there were no differences between the Ringer and l-NAME sites (CVC<jats:sub>Δpeak</jats:sub>, 16.8 ± 4.3%<jats:sub>max</jats:sub>, P = 0.11; and CVC<jats:sub>AUC</jats:sub>, 2,679 ± 785%<jats:sub>max</jats:sub>·s, P = 0.30). CVC<jats:sub>Δpeak</jats:sub>and CVC<jats:sub>AUC</jats:sub>were reduced with ketorolac in nonsmokers (CVC<jats:sub>Δpeak</jats:sub>, 13.3 ± 3.6%<jats:sub>max</jats:sub>, P < 0.05; and CVC<jats:sub>AUC</jats:sub>, 1,967 ± 527%<jats:sub>max</jats:sub>·s, P < 0.05) and smokers (CVC<jats:sub>Δpeak</jats:sub>, 7.8 ± 1.8%<jats:sub>max</jats:sub>, P < 0.05; and CVC<jats:sub>AUC</jats:sub>, 1,246 ± 305%<jats:sub>max</jats:sub>·s, P < 0.05) and at the combination site in nonsmokers (CVC<jats:sub>Δpeak</jats:sub>, 15.9 ± 3.1%<jats:sub>max</jats:sub>, P < 0.05; and CVC<jats:sub>AUC</jats:sub>, 2,660 ± 512%<jats:sub>max</jats:sub>·s, P < 0.05) and smokers (CVC<jats:sub>Δpeak</jats:sub>, 11.5 ± 2.6%<jats:sub>max</jats:sub>, P < 0.05; and CVC<jats:sub>AUC</jats:sub>, 1,693 ± 409%<jats:sub>max</jats:sub>·s, P < 0.05), but the magnitudes were greater in nonsmokers ( P < 0.05). These results suggest that impaired ACh-induced skin vasodilation in young smokers is related to diminished NO- and COX-dependent vasodilation.</jats:p>