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

Muscarinic acetylcholine receptors (mAChRs) 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. In healthy volunteers (8 F, 8 M; 26 ± 5 yr), changes in forearm vascular conductance (ΔFVC) were calculated in response to intra-arterial infusions of phenylephrine (PE; α₁-agonist) during <i>1</i>) infusion of a "nonmetabolic" vasodilator at rest (rest; adenosine or sodium nitroprusside), <i>2</i>) dynamic handgrip exercise at 15% maximal voluntary contraction (MVC), and <i>3</i>) higher-intensity exercise (25% MVC). Conditions were completed before and after intra-arterial infusion of atropine (mAChR antagonist). 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%; <i>P</i> < 0.0001). There was no effect of atropine on PE vasoconstriction during rest (-38 ± 12%; <i>P</i> = 0.60 vs. control) or 15% MVC exercise (-23 ± 7%, <i>P</i> = 0.34 vs. control). However, PE-mediated vasoconstriction was approximately twofold greater during 25% MVC exercise after blockade of mAChRs (-22 ± 9%, <i>P</i> < 0.001 vs. control). 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.<b>NEW & NOTEWORTHY</b> The present study demonstrates that muscarinic acetylcholine receptor (mAChR) signaling attenuates postjunctional α₁-adrenergic signaling during higher-intensity exercise specifically within contracting skeletal muscle, thereby revealing endogenous mAChR signaling as a potential mechanism of functional sympatholysis. This is the first study to identify an endogenous signaling pathway that selectively modulates α₁-adrenergic vasoconstriction specifically in contracting muscle in humans. These findings establish a novel physiological role for endogenous mAChR signaling in the regulation of muscle blood flow during exercise.