Cholinergic nerve contribution to cutaneous active vasodilation in response to exercise heat‐loading is similar to passive whole‐body heat‐loading

Abstract

Introduction Twenty-five years ago, Dean Kellogg and colleagues established the sympathetic cholinergic nerve co-transmitter theory for cutaneous active vasodilation (CAVD) during passive heating in humans. In this seminal study, pretreatment of the skin with botulinum toxin type-A (BOTOX), a presynaptic cholinergic nerve blocker, abolished CAVD during passive whole-body heat stress in six subjects. To date, these findings have not been confirmed. More recently, a clear role for NO in CAVD has been established, where NO accounts for up to 50% of CAVD. The specific isoform of NO-synthase has been reported to differ between CAVD in response to different thermal loading modalities (passive heating vs. exercise). These findings suggest that there may be mechanistic differences in the skin blood flow responses (SkBF) to hyperthermic challenge that are dependent on how thermal loading is accomplished. With this in mind, it is unknown if the cholinergic co-transmitter theory of CAVD applies to other thermal loading modalities such as exercise heat-loading. Therefore, this study sought to confirm the role of cholinergic nerve activation in CAVD during passive whole-body heat-loading and expand these findings to exercise heat-loading using a cross-over study design. It was hypothesized that CAVD during exercise and passive whole-body heating would both be abolished by BOTOX administration. Methods Eight young (18-30 years) recreationally-active individuals participated in both an exercise heat-loading study day (40% VO2peak, 1 hour; seated cycle ergometer) and a passive whole-body heat-loading study day (mean skin temperature clamp @ 39°C, ~1 hour; water-perfused suit, seated), in a randomized order. Cholinergic nerve blockade was achieved through BOTOX administration ~2 weeks prior to study days. Throughout heat-loading trials, SkBF was assessed at BOTOX treated and untreated sites using laser-doppler flowmetry. Results At rest, there were no differences in SkBF expressed as % CVCmax by site (BOTOX treated vs. untreated) or by modality (Exercise heat-loading vs. passive whole body heat-loading). The SkBF response, as a function of increasing internal temperature, was similar between heat-loading modalities at BOTOX treated and untreated sites. At the end of heat-loading (@ 0.7 °C increase in internal temperature), % CVCmax at the BOTOX treated sites (Exercise: 19 ± 2 and Passive whole-body heating: 15 ± 5 % CVCmax), were significantly less (P<0.001) than at the untreated sites (Exercise: 35 ± 4 and Passive whole-body heating: 38 ± 2 % CVCmax). Additionally, there were no differences in %CVCMax between thermal loading modalities (modality, P = 0.909; modality-by-microdialysis site interaction, P=0.230) at the end of heat-loading. Conclusions We conclude that CAVD in response to exercise heat-loading and passive whole-body heat-loading are both mediated by cholinergic nerve transmission, a critical thermoregulatory mechanism whose function appears to be independent of the thermal loading modality.