Endothelium-dependent vasodilatory signalling modulates α1-adrenergic vasoconstriction in contracting skeletal muscle of humans

Abstract

Stimulation of α-adrenoceptors elicits vasoconstriction in resting skeletal muscle that is blunted during exercise in an intensity-dependent manner. In humans, the underlying mechanisms remain unclear. We tested the hypothesis that stimulating endothelium-dependent vasodilatory signalling will enhance the ability of contracting skeletal muscle to blunt α₁-adrenergic vasoconstriction. Changes in forearm vascular conductance (FVC; Doppler Ultrasound, brachial intra-arterial pressure via catheter) to local intra-arterial infusion of phenylephrine (PE; α₁-adrenoceptor agonist) were calculated during (1) infusion of the endothelium-dependent vasodilators acetylcholine (ACh) and adenosine triphosphate (ATP), the endothelium-independent vasodilator (sodium nitroprusside, SNP), or potassium chloride (KCl) at rest; (2) mild or moderate intensity handgrip exercise; and (3) combined mild exercise + ACh, ATP, SNP, or KCl infusions in healthy adults. Robust vasoconstriction to PE was observed during vasodilator infusion alone and mild exercise, and this was blunted during moderate intensity exercise (ΔFVC:−34 ± 4 and −34 ± 3 vs. −13 ± 2% respectively, P < 0.05). Infusion of ACh or ATP during mild exercise significantly attenuated PE vasoconstriction similar to levels observed during moderate exercise (ACh:−3 ± 4; ATP:−18 ± 4%). In contrast, infusion SNP or KCl during mild exercise did not attenuate PE-mediated vasoconstriction (−32 ± 5 and −46 ± 3%). To further study the role of endothelium-dependent hyperpolarization (EDH), ACh trials were repeated with combined nitric oxide synthase and cyclooxygenase inhibition. Here, PE-mediated vasoconstriction was blunted at rest (blockade: −20 ± 5 vs. control: −31 ± 3% vs.; P < 0.05) and remained blunted during exercise (blockade: −15 ± 5 vs. control: −14 ± 5%). We conclude that stimulation of EDH-like vasodilatation can blunt α₁-adrenergic vasoconstriction in contracting skeletal muscle of humans.

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