Vascular KATP channels mitigate severe muscle O2 delivery-utilization mismatch during contractions in chronic heart failure rats

Holdsworth, Clark; Ferguson, Scott K.; Colburn, Trenton D.; Fees, Alexander; Craig, Jesse C.; Hirai, Daniel M.; Poole, David C.; Musch, Timothy I.

doi:10.1016/j.resp.2017.01.009

Cited by 9 publications

(12 citation statements)

References 73 publications

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“…Thus, each rat underwent at least six GLI injections over ß7-8 weeks. During interstitial PO 2 measurements, inhibition was administered locally via GLI superfusion (5 mg kg −1 in Krebs-Hensleit solution, Holdsworth et al 2017).…”

Section: Drug Dosingmentioning

confidence: 99%

“…Importantly, it remains unknown how vascular K ATP channels contribute to O 2 transport within highly oxidative fast‐twitch muscles and their role in supporting fatiguing exercise, especially as the proportional contribution of these channels to the overall vascular response may increase in disease (Holdsworth et al . 2017).…”

Section: Introductionmentioning

confidence: 99%

“…critical speed (CS) or critical power) where oxidative metabolism meets metabolic demand below this threshold but, above this threshold, increases in fast-twitch fibre recruitment, fatigue-related metabolite production, and O 2 consumption leading toVO 2 max and task failure (Monod & Scherrer, 1965;Poole et al 1988Poole et al , 2016Jones et al 2008;Copp et al 2010). Importantly, it remains unknown how vascular K ATP channels contribute to O 2 transport within highly oxidative fast-twitch muscles and their role in supporting fatiguing exercise, especially as the proportional contribution of these channels to the overall vascular response may increase in disease (Holdsworth et al 2017).…”

Section: Introductionmentioning

confidence: 99%

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Vascular ATP‐sensitive K⁺ channels support maximal aerobic capacity and critical speed via convective and diffusive O₂ transport

Colburn

Weber

Hageman

et al. 2020

The Journal of Physiology

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Key points Oral sulphonylureas, widely prescribed for diabetes, inhibit pancreatic ATP‐sensitive K+ (KATP) channels to increase insulin release. However, KATP channels are also located within vascular (endothelium and smooth muscle) and muscle (cardiac and skeletal) tissue. We evaluated left ventricular function at rest, maximal aerobic capacity (trueV̇O2max) and submaximal exercise tolerance (i.e. speed–duration relationship) during treadmill running in rats, before and after systemic KATP channel inhibition via glibenclamide. Glibenclamide impaired critical speed proportionally more than trueV̇O2max but did not alter resting cardiac output. Vascular KATP channel function (topical glibenclamide superfused onto hindlimb skeletal muscle) resolved a decreased blood flow and interstitial PO2 during twitch contractions reflecting impaired O2 delivery‐to‐utilization matching. Our findings demonstrate that systemic KATP channel inhibition reduces trueV̇O2max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O2 delivery, and thus trueV̇O2, especially within fast‐twitch oxidative skeletal muscle. Abstract Vascular ATP‐sensitive K+ (KATP) channels support skeletal muscle blood flow and microvascular oxygen delivery‐to‐utilization matching during exercise. However, oral sulphonylurea treatment for diabetes inhibits pancreatic KATP channels to enhance insulin release. Herein we tested the hypotheses that: i) systemic KATP channel inhibition via glibenclamide (GLI; 10 mg kg−1 i.p.) would decrease cardiac output at rest (echocardiography), maximal aerobic capacity (trueV̇O2max) and the speed–duration relationship (i.e. lower critical speed (CS)) during treadmill running; and ii) local KATP channel inhibition (5 mg kg−1 GLI superfusion) would decrease blood flow (15 µm microspheres), interstitial space oxygen pressures (PO2is; phosphorescence quenching) and convective and diffusive O2 transport (trueQ̇O2 and DO2, respectively; Fick Principle and Law of Diffusion) in contracting fast‐twitch oxidative mixed gastrocnemius muscle (MG: 9% type I+IIa fibres). At rest, GLI slowed left ventricular relaxation (2.11 ± 0.59 vs. 1.70 ± 0.23 cm s−1) and decreased heart rate (321 ± 23 vs. 304 ± 22 bpm, both P < 0.05) while cardiac output remained unaltered (219 ± 64 vs. 197 ± 39 ml min−1, P > 0.05). During exercise, GLI reduced trueV̇O2max (71.5 ± 3.1 vs. 67.9 ± 4.8 ml kg−1 min−1) and CS (35.9 ± 2.4 vs. 31.9 ± 3.1 m min−1, both P < 0.05). Local KATP channel inhibition decreased MG blood flow (52 ± 25 vs. 34 ± 13 ml min−1 100 g tissue−1) and PO2isnadir (5.9 ± 0.9 vs. 4.7 ± 1.1 mmHg) during twitch contractions. Furthermore, MG trueV̇O2 was reduced via impaired trueQ̇O2 and DO2 (P < 0.05 for each). Collectively, these data support that vascular KATP channels help sustain submaximal exercise tolerance in healthy rats. For patients taking sulfonylureas, KATP channel inhibition may exacerbate exercise intolerance.

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Section: Drug Dosingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vascular ATP‐sensitive K⁺ channels support maximal aerobic capacity and critical speed via convective and diffusive O₂ transport

Colburn

Weber

Hageman

et al. 2020

The Journal of Physiology

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“…The two control groups received solvent gavaged. Doses were chosen based on former research [61][62][63][64][65]. Weight of the animals were measured once weekly for the 12 weeks of the study.…”

Section: Animals and Groupsmentioning

confidence: 99%

Retinoprotection by BGP-15, a Hydroximic Acid Derivative, in a Type II Diabetic Rat Model Compared to Glibenclamide, Metformin, and Pioglitazone

Wachal

Bombicz

Priksz

et al. 2020

IJMS

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High blood glucose and the consequential ischemia-reperfusion (I/R) injury damage vessels of the retina, deteriorating its function, which can be clearly visualized by electroretinography (ERG). The aim of the present study was to evaluate the possible retinoprotective effects of systemic BGP-15, an emerging drug candidate, in an insulin resistant animal model, the Goto-Kakizaki rat, and compare these results with well-known anti-diabetics such as glibenclamide, metformin, and pioglitazone, which even led to some novel conclusions about these well-known agents. Experiments were carried out on diseased animal model (Goto-Kakizaki rats). The used methods include weight measurement, glucose-related measurements—like fasting blood sugar analysis, oral glucose tolerance test, hyperinsulinemic euglycemic glucose clamp (HEGC), and calculations of different indices from HEGC results—electroretinography and Western Blot. Beside its apparent insulin sensitization, BGP-15 was also able to counteract the retina-damaging effect of Type II diabetes comparable to the aforementioned anti-diabetics. The mechanism of retinoprotective action may include sirtuin 1 (SIRT1) and matrix metalloproteinase 9 (MMP9) enzymes, as BGP-15 was able to elevate SIRT1 and decrease MMP9 expression in the eye. Based on our results, this emerging hydroximic acid derivative might be a future target of pharmacological developments as a potential drug against the harmful consequences of diabetes, such as diabetic retinopathy.

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“…Reports of reduced or unaltered exercising muscle blood flow in either human patients or animal models of HF may reflect differences in disease severity, exercise intensity/mode, measurement techniques, and/or pharmacological therapy. Moreover, compensatory mechanisms (e.g., endothelium-derived hyperpolarizing factors, prostaglandins; [25,32,35]) could prevent or minimize decrements in bulk muscle blood flow and potentially mask disease-induced impairments in specific vasodilatory pathways during submaximal work. Consistent with our previous findings in awake animals [24,41], moderate HF rats showed no impairments in total hindlimb blood flow during submaximal treadmill exercise compared to their healthy counterparts.…”

Section: Discussionmentioning

confidence: 99%

Neuronal nitric oxide synthase regulation of skeletal muscle functional hyperemia: exercise training and moderate compensated heart failure

et al. 2018

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Nitric oxide (NO) modulates oxygen delivery-utilization matching in resting and contracting skeletal muscle. Recent reports indicate that neuronal NO synthase (nNOS)-mediated vasoregulation during contractions is enhanced with exercise training and impaired with chronic heart failure (HF). Consequently, we tested the hypothesis that selective nNOS inhibition (S-methyl-l-thiocitrulline; SMTC, 2.1 μmol/kg) would produce attenuated reductions in muscle blood flow during moderate/heavy submaximal exercise in sedentary HF rats compared to their healthy counterparts. In addition, SMTC was expected to evoke greater reductions in exercising muscle blood flow in trained compared to sedentary healthy and HF rats. Blood flow during submaximal treadmill running (20 min/m, 5% grade) was determined via radiolabeled microspheres pre- and post-SMTC administration in healthy sedentary (Healthy + Sed, n = 8), healthy exercise trained (Healthy + ExT, n = 8), HF sedentary (HF + Sed, left ventricular end-diastolic pressure (LVEDP) = 12 ± 1 mmHg, n = 8), and HF exercise trained (HF + ExT, LVEDP = 16 ± 2 mmHg, n = 7) rats. nNOS contribution to exercising total hindlimb blood flow (ml/min/100 g) was not increased by training in either healthy or HF groups (Healthy + Sed: 105 ± 11 vs. 108 ± 16; Healthy + ExT: 96 ± 9 vs. 91 ± 7; HF + Sed: 124 ± 6 vs. 110 ± 12; HF + ExT: 107 ± 13 vs. 101 ± 8; control vs. SMTC, respectively; p > .05 for all). Similarly, SMTC did not reduce exercising blood flow in the majority of individual hindlimb muscles in any group (p > .05 for all, except for the semitendinosus and adductor longus in HF + Sed and the adductor longus in HF + ExT; p < .05). Contrary to our hypothesis, we find no support for either upregulation of nNOS function contributing to exercise hyperemia after training or its dysregulation with chronic HF.

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Vascular KATP channels mitigate severe muscle O2 delivery-utilization mismatch during contractions in chronic heart failure rats

Cited by 9 publications

References 73 publications

Vascular ATP‐sensitive K⁺ channels support maximal aerobic capacity and critical speed via convective and diffusive O₂ transport

Vascular ATP‐sensitive K⁺ channels support maximal aerobic capacity and critical speed via convective and diffusive O₂ transport

Retinoprotection by BGP-15, a Hydroximic Acid Derivative, in a Type II Diabetic Rat Model Compared to Glibenclamide, Metformin, and Pioglitazone

Neuronal nitric oxide synthase regulation of skeletal muscle functional hyperemia: exercise training and moderate compensated heart failure

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Vascular KATP channels mitigate severe muscle O2 delivery-utilization mismatch during contractions in chronic heart failure rats

Cited by 9 publications

References 73 publications

Vascular ATP‐sensitive K+ channels support maximal aerobic capacity and critical speed via convective and diffusive O2 transport

Vascular ATP‐sensitive K+ channels support maximal aerobic capacity and critical speed via convective and diffusive O2 transport

Retinoprotection by BGP-15, a Hydroximic Acid Derivative, in a Type II Diabetic Rat Model Compared to Glibenclamide, Metformin, and Pioglitazone

Neuronal nitric oxide synthase regulation of skeletal muscle functional hyperemia: exercise training and moderate compensated heart failure

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Product

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Vascular ATP‐sensitive K⁺ channels support maximal aerobic capacity and critical speed via convective and diffusive O₂ transport

Vascular ATP‐sensitive K⁺ channels support maximal aerobic capacity and critical speed via convective and diffusive O₂ transport