Amplification of endothelium-dependent vasodilatation in contracting human skeletal muscle: role of K IR channels.

KEY POINTS: In humans, the vasodilatory response to skeletal muscle contraction is mediated in part by activation of inwardly rectifying potassium (KIR ) channels. Evidence from animal models suggest that KIR channels serve as electrical amplifiers of endothelium-dependent hyperpolarization (EDH). We found that skeletal muscle contraction amplifies vasodilatation to the endothelium-dependent agonist acetylcholine (ACh), whereas there was no change in the vasodilatory response to sodium nitroprusside, an endothelium-independent nitric oxide donor. Blockade of KIR channels reduced the exercise-induced amplification of ACh-mediated vasodilatation. Conversely, pharmacological activation of KIR channels in quiescent muscle via intra-arterial infusion of KCl independently amplified the vasodilatory response to ACh. This study is the first in humans to demonstrate that specific endothelium-dependent vasodilatory signalling is amplified in the vasculature of contracting skeletal muscle and that KIR channels may serve as amplifiers of EDH-like vasodilatory signalling in humans.

ABSTRACT: The local vasodilatory response to muscle contraction is due in part to the activation of inwardly rectifying potassium (KIR ) channels. Evidence from animal models suggest that KIR channels function as "amplifiers" of endothelium-dependent vasodilators. We tested the hypothesis that contracting muscle selectively amplifies endothelium-dependent vasodilatation via activation of KIR channels. We measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra-arterial infusion of ACh (endothelium-dependent dilator) during resting conditions, handgrip exercise (5% maximum voluntary contraction), or sodium nitroprusside (SNP; endothelium-independent dilator) which served as a high-flow control condition (n = 7, young healthy men and women). Trials were performed before and after blockade of KIR channels via infusion of barium chloride. Exercise augmented peak ACh-mediated vasodilatation (ΔFVC saline: 117 ± 14; exercise: 236 ± 21 ml (min)-1 (100 mmHg)-1 ; P<0.05), whereas SNP did not impact ACh-mediated vasodilatation. Blockade of KIR channels attenuated the exercise-induced augmentation of ACh. In 8 additional subjects, SNP was administered as the experimental dilator. In contrast to ACh, exercise did not alter SNP-mediated vasodilatation (ΔFVC saline: 158 ± 35; exercise: 121 ± 22 ml (min)-1 (100 mmHg)-1 ; NS). Finally, in a subset 6 subjects, direct pharmacological activation of KIR channels in quiescent muscle via infusion of KCl amplified peak ACh-mediated vasodilatation (ΔFVC saline: 97 ± 15, KCl: 142 ± 16 ml (min)-1 (100 mmHg)-1 ; respectively; P<0.05). These findings indicate that skeletal muscle contractions selectively amplify endothelium-dependent vasodilatory signalling via activation of KIR channels, and this may be an important mechanism contributing to the normal vasodilatory response to exercise in humans. This article is protected by copyright. All rights reserved.