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

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 O 2 delivery‐utilization matching ( is ) during twitch contractions in male, female during pro‐oestrus and ovariectomized female (F+OVX) rats. Glibenclamide decreased blood flow (convective O 2 transport) and interstitial in male and female, but not F+OVX, rats. Compared to males, females also demonstrated impaired diffusive O 2 transport and a faster fall in interstitial . 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 ( ), interstitial O 2 delivery ( )‐utilization ( ) matching (i.e. interstitial‐myocyte O 2 flux driving pressure; 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) (15 μm microspheres) and is (phosphorescence quenching), resulting from more compromised convective ( ) and diffusive ( ) O 2 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 in both males (↓28%) and females (↓33%, both P < 0.032) via reduced (male: ↓31%, female: ↓35%, both P < 0.020), (male: 5.6 ± 0.5 vs . 4.0 ± 0.5, female: 6.4 ± 1.1 vs . 4.2 ± 0.6 mL O 2 min –1 100 g tissue –1 , P < 0.022) and the resulting is , with females also demonstrating a reduced (0.40 ± 0.07 vs . 0.30 ± 0.04 mL O 2 min –1 100 g tissue –1 , P < 0.042) and a greater GLI‐induced speeding of 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 and therefore exercise tolerance. Such an effect, if present, would likely contribute to adverse cardiovascular events in premenopausal females more than males.