Sexual dimorphism in vascular ATP-sensitive K+ channel function supporting interstitial PO2 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 (PO2is) 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 PO2 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 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. Vascular ATP-sensitive K+ (K-ATP) channels support skeletal muscle blood flow (Q?m), interstitial O-2 delivery (Q?O2)-utilization (V?O2) matching (i.e. interstitial-myocyte O-2 flux driving pressure; PO2is) 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) Q?m (15 mu m microspheres) and PO2is (phosphorescence quenching), resulting from more compromised convective (Q?O2) and diffusive (DO2( )) 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 V?O2 in both males (down arrow 28%) and females (down arrow 33%, both P < 0.032) via reduced Q?m (male: down arrow 31%, female: down arrow 35%, both P < 0.020), Q?O2 (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 PO2is, with females also demonstrating a reduced DO2( ) (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 PO2is fall (mean response time: Sex x 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 Q?m and therefore exercise tolerance. Such an effect, if present, would likely contribute to adverse cardiovascular events in premenopausal females more than males.

Automated summary

The study demonstrated sex differences in vascular K-ATP channel function in rats, suggesting potential exacerbation of exercise intolerance and morbidity with oral sulphonylureas, especially in premenopausal females. There was a greater reduction in muscle blood flow and exercise tolerance observed in female rats compared to males when treated with glibenclamide, highlighting the importance of considering sex-related effects in medication.