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Sexual dimorphism in vascular ATP-sensitive K⁺ channel function supporting interstitial PO2 via convective and/or diffusive O₂ transport.

ABSTRACT:

Key points

Inhibition of pancreatic ATP-sensitive K⁺ (K_ATP ) channels is the intended effect of oral sulphonylureas to increase insulin release in diabetes. However, pertinent to off-target effects of sulphonylurea medication, sex differences in cardiac K_ATP channel function exist, whereas potential sex differences in vascular K_ATP channel function remain unknown. In the present study, we assessed vascular K_ATP channel function (topical glibenclamide superfused onto fast-twitch oxidative skeletal muscle) supporting blood flow and interstitial O₂ delivery-utilization matching ( PO2 is) during twitch contractions in male, female during pro-oestrus and ovariectomized female (F+OVX) rats. Glibenclamide decreased blood flow (convective O₂ transport) and interstitial PO2 in male and female, but not F+OVX, rats. Compared to males, females also demonstrated impaired diffusive O₂ transport and a faster fall in interstitial PO2 . Our demonstration, in rats, that sex differences in vascular K_ATP channel function exist support the tentative hypothesis that oral sulphonylureas may exacerbate exercise intolerance and morbidity, especially in premenopausal females.

Abstract

Vascular ATP-sensitive K⁺ (K_ATP ) channels support skeletal muscle blood flow ( Q̇m ), interstitial O₂ delivery ( Q̇O2 )-utilization ( V̇O2 ) matching (i.e. interstitial-myocyte O₂ flux driving pressure; PO2 is) and exercise tolerance. Potential sex differences in skeletal muscle vascular K_ATP channel function remain largely unexplored. We hypothesized that local skeletal muscle K_ATP channel inhibition via glibenclamide superfusion (5 mg kg^-1 GLI; sulphonylurea diabetes medication) in anaesthetized female Sprague-Dawley rats, compared to males, would demonstrate greater reductions in contracting (1 Hz, 7 V, 180 s) fast-twitch oxidative mixed gastrocnemius (97% type IIA+IID/X+IIB) Q̇m (15 μm microspheres) and PO2 is (phosphorescence quenching), resulting from more compromised convective ( Q̇O2 ) and diffusive ( DO2 ) O₂ conductances. Furthermore, these GLI-induced reductions in ovary-intact females measured during pro-oestrus would be diminished following ovariectomy (F+OVX). GLI similarly impaired mixed gastrocnemius V̇O2 in both males (↓28%) and females (↓33%, both P < 0.032) via reduced Q̇m (male: ↓31%, female: ↓35%, both P < 0.020), Q̇O2 (male: 5.6 ± 0.5 vs. 4.0 ± 0.5, female: 6.4 ± 1.1 vs. 4.2 ± 0.6 mL O₂ min^-1 100 g tissue^-1 , P < 0.022) and the resulting PO2 is, with females also demonstrating a reduced DO2 (0.40 ± 0.07 vs. 0.30 ± 0.04 mL O₂ min^-1 100 g tissue^-1 , P < 0.042) and a greater GLI-induced speeding of PO2 is fall (mean response time: Sex × Drug interaction, P = 0.026). Conversely, GLI did not impair the mixed gastrocnemius of F+OVX rats. Therefore, in patients taking sulphonylureas, these results support the potential for impaired vascular K_ATP channel function to compromise muscle Q̇m and therefore exercise tolerance. Such an effect, if present, would likely contribute to adverse cardiovascular events in premenopausal females more than males.

SUBMITTER: Colburn TD

PROVIDER: S-EPMC8451062 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Key pointsOral 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 ( V̇ O2 max) 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 V̇ O2 max 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 V̇ O2 max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O2 delivery, and thus V̇ O2 , especially within fast-twitch oxidative skeletal muscle.AbstractVascular 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 ( V̇ O2 max) 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 (PO2 is; phosphorescence quenching) and convective and diffusive O2 transport ( Q̇ O2 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 V̇ O2 max (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 PO2 isnadir (5.9 ± 0.9 vs. 4.7 ± 1.1 mmHg) during twitch contractions. Furthermore, MG V̇ O2 was reduced via impaired Q̇ O2 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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Sexual dimorphism in vascular ATP-sensitive K⁺ channel function supporting interstitial PO2 via convective and/or diffusive O₂ transport.

Key points

Abstract

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Dataset Information

Sexual dimorphism in vascular ATP-sensitive K+ channel function supporting interstitial PO2 via convective and/or diffusive O2 transport.

Key points

Abstract

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Sexual dimorphism in vascular ATP-sensitive K⁺ channel function supporting interstitial PO2 via convective and/or diffusive O₂ transport.