Vascular ATP‐sensitive K+ channels support maximal aerobic capacity and critical speed via convective and diffusive O2 transport, 2020, Colburn et al

Andy · Aug 17, 2020

In rats.

Key points

Oral sulphonylureas, widely prescribed in 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 (V̇O2max) 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 V̇O2max 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 V̇O2max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O2 delivery, and thus V̇O2, 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 in 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 (V̇O2max) 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 (Q̇O2 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 LV 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 V̇O2max (71.5 ± 1.0 vs. 68.0 ± 1.5 ml kg−1 min−1) and CS (35.9 ± 0.9 vs. 31.9 ± 1.1 m min−1, both P < 0.05). Local KATP channel inhibition decreased MG blood flow (49 ± 9 vs. 34 ± 4 ml min−1 100g tissue−1) and PO2is nadir (5.9 ± 0.3 vs. 4.7 ± 0.4 mmHg) during twitch contractions. Furthermore, MG V̇O2 was reduced via impaired Q̇O2 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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Paywall, https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP280232
Sci hub, https://sci-hub.tw/10.1113/jp280232

adambeyoncelowe · Aug 17, 2020

Interesting. I am always low on potassium and get muscle cramps for hours if I don't supplement it. I'm sure they need to do a lot more to show this applies in humans, though.

Amw66 · Aug 17, 2020

Potassium seems to be the element that tanks in refeeding syndrome. On the other place there were numerous threads on potassium deficiency after starting a new supplement. Folate (and methylated Bs) seemed to be especially problematic. V8 juice and coconut water seem to be good at bringing levels up/ checking status.

I havn't read the paper - would this feed into the hypoxia theory?

adambeyoncelowe · Aug 17, 2020

Amw66 said: ↑

Potassium seems to be the element that tanks in refeeding syndrome. On the other place there were numerous threads on potassium deficiency after starting a new supplement. Folate (and methylated Bs) seemed to be especially problematic. V8 juice and coconut water seem to be good at bringing levels up/ checking status.

I havn't read the paper - would this feed into the hypoxia theory?
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Ah, so B vitamins might deplete potassium?

adambeyoncelowe · Aug 17, 2020

Looks like B12 can do, yeah (and potassium can deplete B12 too). Which might explain a lot. That's that in the bin then!

Amw66 · Aug 17, 2020

adambeyoncelowe said: ↑

Looks like B12 can do, yeah (and potassium can deplete B12 too). Which might explain a lot. That's that in the bin then!
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Nothing is ever easy is it ? An ever moving goalposts.

Given that potassium is key for cellular pumps , how does the finding affect sodium?

Hutan · Aug 17, 2020

For what it's worth, sulphonylureas are quite widely used herbicides e.g. from a study of spray diaries of NZ cereal growers

The sulfonylurea group was the most widely used of selective herbicides by cereal growers, as 109 of the 136 fields were treated with one of these compounds.
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In a quick google, I didn't find such much evidence of, or concern about, toxicity to humans.

adambeyoncelowe · Aug 18, 2020

Amw66 said: ↑

Nothing is ever easy is it ? An ever moving goalposts.

Given that potassium is key for cellular pumps , how does the finding affect sodium?
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I know. Everything has a knock on effect.

Snow Leopard · Aug 20, 2020

The key point is that muscular capillary function is not controlled by central nerves like Arteries and veins, but regulated locally to maintain a constant-flow condition (variable pressure).

It is already known that KATP channels play a key role.

Some more discussion here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132831/

Hutan · Aug 20, 2020

KATP channels seem potentially relevant to ME/CFS - ATP signalling; vascular tone regulation; mention of sepsis, ROS.

For an example, LPS-induced vascular KATP channel upregulation may be a myocardial protective mechanism because it increases coronary blood flow and reduces myocardial depression during sepsis. However, an excessively up-regulated vascular KATP channel will cause severe peripheral vasodilation leading to lethal hypotension and organ failure.
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I don't have time/capacity right now to dig into that paper that @Snow Leopard posted. I'd have to draw some diagrams to work out what is making what go up or down. But @Snow Leopard, or anyone else, if you have the time and interest to translate and summarise, I'd appreciate an easy way into understanding a bit more about this.

Snow Leopard · Aug 21, 2020

Hutan said: ↑

I don't have time/capacity right now to dig into that paper that @Snow Leopard posted. I'd have to draw some diagrams to work out what is making what go up or down. But @Snow Leopard, or anyone else, if you have the time and interest to translate and summarise, I'd appreciate an easy way into understanding a bit more about this.
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I don't really know that much and don't have the energy to explain much. I'm not sure what needs explaining either.

A key point is that these are "inwardly rectifying" channels, meaning it is easier for K+ ions to travel into, rather than out of the cell. This means they are meant to be closed during depolarisation, and open during repolarisation.

Wikipedia says this: (on https://en.wikipedia.org/wiki/Depolarization)

Endothelium is a thin layer of simple squamous epithelial cells that line the interior of both blood and lymph vessels. The endothelium that lines blood vessels is known as vascular endothelium, which is subject to and must withstand the forces of blood flow and blood pressure from the cardiovascular system. To withstand these cardiovascular forces, endothelial cells must simultaneously have a structure capable of withstanding the forces of circulation while also maintaining a certain level of plasticity in the strength of their structure. This plasticity in the structural strength of the vascular endothelium is essential to overall function of the cardiovascular system. Endothelial cells within blood vessels can alter the strength of their structure to maintain the vascular tone of the blood vessel they line, prevent vascular rigidity, and even help to regulate blood pressure within the cardiovascular system. Endothelial cells accomplish these feats by using depolarization to alter their structural strength. When an endothelial cell undergoes depolarization, the result is a marked decrease in the rigidity and structural strength of the cell by altering the network of fibers that provide these cells with their structural support. Depolarization in vascular endothelium is essential not only to the structural integrity of endothelial cells, but also to the ability of the vascular endothelium to aid in the regulation of vascular tone, prevention of vascular rigidity, and the regulation of blood pressure.[6]
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Not that the function in veins/arteries is to maintain flow while keeping pressure in bounded range (and under central control). Whereas in capillaries, the goal is to maintain flow, even if pressure can be relatively high or relatively low in comparison to the arteries.

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