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K_IR channel activation links local vasodilatation with muscle fibre recruitment during exercise in humans.

ABSTRACT:

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During exercise, blood flow to working skeletal muscle increases in parallel with contractile activity such that oxygen delivery is sufficient to meet metabolic demand. K⁺ released from active skeletal muscle fibres could facilitate vasodilatation in proportion to the degree of muscle fibre recruitment. Once released, K⁺ stimulates inwardly rectifying K⁺ (K_IR ) channels on the vasculature to elicit an increase in blood flow. In the present study, we demonstrate that K_IR channels mediate the rapid vasodilatory response to an increase in exercise intensity. We also show that K_IR channels augment vasodilatation during exercise which demands greater muscle fibre recruitment independent of the total amount of work performed. These results suggest that K⁺ plays a key role in coupling the magnitude of vasodilatation to the degree of contractile activity. Ultimately, the findings from this study help us understand the signalling mechanisms that regulate muscle blood flow in humans.

Abstract

Blood flow to active skeletal muscle is augmented with greater muscle fibre recruitment. We tested whether activation of inwardly rectifying potassium (K_IR ) channels underlies vasodilatation with elevated muscle fibre recruitment when work rate is increased (Protocol 1) or held constant (Protocol 2). We assessed forearm vascular conductance (FVC) during rhythmic handgrip exercise under control conditions and during local inhibition of K_IR channels (intra-arterial BaCl₂ ). In Protocol 1, healthy volunteers performed mild handgrip exercise for 3 min, then transitioned to moderate intensity for 30 s. BaCl₂ eliminated vasodilatation during the first contraction at the moderate workload (ΔFVC, BaCl₂ : -1 ± 17 vs. control: 30 ± 28 ml min^-1 100 mmHg^-1 ; n = 9; P = 0.004) and attenuated the 30 s area under the curve by 56 ± 14% (n = 9; P < 0.0001). In Protocol 2, participants performed two exercise bouts in which muscle fibre recruitment was manipulated while total contractile work was held constant via reciprocal changes in contraction frequency: (1) low fibre recruitment, with contractions at 12.5% maximal voluntary contraction once every 4 s and (2) high fibre recruitment, with contractions at 25% maximal voluntary contraction once every 8 s. Under control conditions, steady-state FVC was augmented in high vs. low fibre recruitment (211 ± 90 vs. 166 ± 73 ml min^-1 ⋅100 mmHg^-1 ; n = 10; P = 0.0006), whereas BaCl₂ abolished the difference between high and low fibre recruitment (134 ± 59 vs. 134 ± 63 ml min^-1 100 mmHg^-1 ; n = 10; P = 0.85). These findings demonstrate that K_IR channel activation is a key mechanism linking local vasodilatation with muscle fibre recruitment during exercise.

SUBMITTER: Terwoord JD

PROVIDER: S-EPMC7332407 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIncretin therapies appear to provide cardioprotection and improve cardiovascular outcomes in patients with diabetes, but the mechanism of this effect remains elusive. We have previously shown that glucagon-like peptide (GLP)-1 is a coronary vasodilator and we sought to investigate if this is an adenosine-mediated effect.MethodsWe recruited 41 patients having percutaneous coronary intervention (PCI) for stable angina and allocated them into four groups administering a specific study-related infusion following successful PCI: GLP-1 infusion (Group G) (n = 10); Placebo, normal saline infusion (Group P) (n = 11); GLP-1 + Theophylline infusion (Group GT) (n = 10); and Theophylline infusion (Group T) (n = 10). A pressure wire assessment of coronary distal pressure and flow velocity (thermodilution transit time-Tmn) at rest and hyperaemia was performed after PCI and repeated following the study infusion to derive basal and index of microvascular resistance (BMR and IMR).ResultsThere were no significant differences in the demographics of patients recruited to our study. Most of the patients were not diabetic. GLP-1 caused significant reduction of resting Tmn that was not attenuated by theophylline: mean delta Tmn (SD) group G - 0.23 s (0.27) versus group GT - 0.18 s (0.37), p = 0.65. Theophylline alone (group T) did not significantly alter resting flow velocity compared to group GT: delta Tmn in group T 0.04 s (0.15), p = 0.30. The resulting decrease in BMR observed in group G persisted in group GT: - 20.83 mmHg s (24.54 vs. - 21.20 mmHg s (30.41), p = 0.97. GLP-1 did not increase circulating adenosine levels in group GT more than group T: delta median adenosine - 2.0 ng/ml (- 117.1, 14.8) versus - 0.5 ng/ml (- 19.6, 9.4); p = 0.60.ConclusionThe vasodilatory effect of GLP-1 is not abolished by theophylline and GLP-1 does not increase adenosine levels, indicating an adenosine-independent mechanism of GLP-1 coronary vasodilatation.Trial registrationThe local research ethics committee approved the study (National Research Ethics Service-NRES Committee, East of England): REC reference 14/EE/0018. The study was performed according to institutional guidelines, was registered on http://www.clinicaltrials.gov (unique identifier: NCT03502083) and the study conformed to the principles outlined in the Declaration of Helsinki.

Project description:High-altitude (>2500 m or 8200 ft) residence reduces uterine artery blood flow during pregnancy, contributing to an increased incidence of preeclampsia and intrauterine growth restriction. However, not all pregnancies are affected by the chronic hypoxic conditions of high-altitude residence. K+ channels play important roles in the uterine vascular adaptation to pregnancy, promoting a reduction in myogenic tone and an increase in blood flow. We hypothesized that, in pregnancies with normal fetal growth at high altitude, K+ channel-dependent vasodilatation of myometrial arteries is increased compared to those from healthy pregnant women at a lower altitude (∼1700 m). Using pharmacological modulation of two K+ channels, ATP-sensitive (KATP ) and large-conductance Ca2+ -activated (BKCa ) K+ channels, we assessed the vasodilatation of myometrial arteries from appropriate for gestational age (AGA) pregnancies in women living at high or low altitudes. In addition, we evaluated the localization of these channels in the myometrial arteries using immunofluorescence. Our results showed an endothelium-dependent increase in KATP -dependent vasodilatation in myometrial arteries from high versus low altitude, whereas vasodilatation induced by BKCa activation was reduced in these vessels. Additionally, KATP channel co-localization with endothelial markers was reduced in the high-altitude myometrial arteries, which suggested that the functional increase in KATP activity may be by mechanisms other than regulation of channel localization. These observations highlight an important contribution of K+ channels to the human uterine vascular adaptation to pregnancy at high altitude serving to maintain normal fetal growth under conditions of chronic hypoxia. KEY POINTS: High-altitude (>2500 m or 8200 ft) residence reduces uterine blood flow during pregnancy and fetal growth. Animal models of high altitude/chronic hypoxia suggest that these reductions are partially due to reduced vascular K+. channel responses, such as those elicited by large conductance Ca2+ -activated (BKCa ) and ATP-sensitive (KATP ) K+ channel activation. We found that women residing at high versus low altitude during pregnancy showed diminished myometrial artery vasodilatory responses to endothelium-independent BKCa channel activation but greater responses to endothelium-dependent KATP channel activation. Our observations indicate that KATP channels play an adaptive role in maintaining myometrial artery vasodilator sensitivity under chronic hypoxic conditions during pregnancy. Thus, KATP channels represent potential therapeutic targets for augmenting uteroplacental blood flow and, in turn, preserving fetal growth in cases of uteroplacental hypoperfusion.

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K_IR channel activation links local vasodilatation with muscle fibre recruitment during exercise in humans.

Key points

Abstract

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

KIR channel activation links local vasodilatation with muscle fibre recruitment during exercise in humans.

Key points

Abstract

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

K_IR channel activation links local vasodilatation with muscle fibre recruitment during exercise in humans.