Endogenous muscarinic acetylcholine receptor signaling blunts α1-adrenergic vasoconstriction during higher-intensity handgrip exercise in humans.

Background: Muscarinic acetylcholine receptors (mAChR) are expressed ubiquitously in the human skeletal muscle vasculature. Prior studies have been unable to identify a contribution of mAChR signaling to exercise-mediated vasodilation; however, no studies have determined whether endogenous mAChR signaling regulates the ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction, a phenomenon called 'functional sympatholysis.' We tested the hypothesis that endogenous mAChR signaling contributes to functional sympatholysis in humans.

Methods: In healthy volunteers (8 F, 8 M; 26 ± 5 yrs), changes in forearm vascular conductance (ΔFVC) were calculated in response to intra-arterial infusions of phenylephrine (PE; α1-agonist) during 1) infusion of a 'non-metabolic' vasodilator at rest (rest; adenosine or sodium nitroprusside), 2) dynamic handgrip exercise at 15% maximal voluntary contraction (MVC), and 3) higher-intensity exercise (25% MVC). Conditions were completed before and after intra-arterial infusion of atropine (mAChR antagonist).

Results: Under control conditions, vasoconstriction to PE was limited in parallel with exercise intensity (PE-induced %ΔFVC, rest: -40 ± 13%, 15% MVC: -20 ± 7%, 25% MVC: -12 ± 8%; P < 0.0001). There was no effect of atropine on PE vasoconstriction during rest (-38 ± 12%; P = 0.60 vs. control) or 15% MVC exercise (-23 ± 7%, P = 0.34 vs. control). However, PE-mediated vasoconstriction was ~2-fold greater during 25% MVC exercise after blockade of mAChRs (-22 ± 9%, P < 0.001 vs. control).

Conclusions: These results provide evidence of a novel physiological role of endogenous mAChR signaling as a modulator of α1-adrenergic vasoconstriction during higher-intensity handgrip exercise in humans.