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

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 ( $$ is) during twitch contractions in male, female during pro-oestrus and ovariectomized female (F+OVX) rats. Glibenclamide decreased blood flow (convective O₂ transport) and interstitial $$ 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 $$ . 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.

Vascular ATP-sensitive K⁺ (K_ATP ) channels support skeletal muscle blood flow ( $$ ), interstitial O₂ delivery ( $$ )-utilization ( $$ ) matching (i.e. interstitial-myocyte O₂ flux driving pressure; $$ 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 ( $$ ) and diffusive ( $$  ) 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 $$ in both males (↓28%) and females (↓33%, both P < 0.032) via reduced $$ (male: ↓31%, female: ↓35%, both P < 0.020), $$ (male: 5.6 ± 0.5 vs. 4.0 ± 0.5, female: 6.4 ± 1.1 vs. 4.2 ± 0.6 mL O₂  min^-1 100 g tissue^-1 , P < 0.022) and the resulting $$ is, with females also demonstrating a reduced $$  (0.40 ± 0.07 vs. 0.30 ± 0.04 mL O₂  min^-1 100 g tissue^-1 , P < 0.042) and a greater GLI-induced speeding of $$ 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.