Sexual dimorphism in the physiological function of ATP-sensitive potassium channels



Journal Title

Journal ISSN

Volume Title



ATP-sensitive K⁺ (K[subscript ATP]) channels are metabolic sensors present in vascular (endothelial), muscle (smooth, cardiac and skeletal), nervous and pancreatic tissues which open in response to a decreasing ATP:ADP ratio (i.e., during exercise and/or hypoxia) and close following pharmacological blockade (i.e., sulphonylureas such as glibenclamide (GLI)). Comprised of four pore-forming inward rectifying K⁺ subunits surrounded by four sulphonylurea receptors, vascular K[subscript ATP] channels support increased muscle blood flow (Q̇m) and microvascular oxygen delivery (Q̇O[subscript 2mv])-to-utilization (V̇O[subscript 2mv]) matching (PO[subscript 2mv]) in exercising/contracting skeletal muscle by hyperpolarizing smooth muscle cells via K⁺ efflux and subsequently reducing the influx of calcium ions. There is also evidence that K[subscript ATP] channels limit myocardial damage following ischemia in a sex-dependent manner, via greater ventricular K[subscript ATP] channel content in females. GLI is a commonly prescribed diabetes medication that inhibits pancreatic K[subscript ATP] channels and increases insulin release. Unfortunately, one off-target consequence of GLI is inhibition of vascular K[subscript ATP] channel-mediated vasodilation which may impair exercise tolerance. Therefore, the overall aim of this dissertation was to determine whether vascular K[subscript ATP] channel function supports exercise tolerance, and whether sex differences in K[subscript ATP] channel function exist in determining fast-twitch oxidative muscle Q̇O₂ and V̇O₂; since this muscle type is recruited at the threshold between heavy- and severe-intensity exercise in humans leading to V̇O[subscript 2max] and exhaustion.

In order to assess Q̇O₂ and V̇O₂ in subsequent K[subscript ATP] channel studies, our first investigation (Chapter 2) compared the partial pressure of O₂ in the interstitial (PO[subscript 2is]) and microvascular (PO[subscript 2mv]) compartments during twitch contractions in muscles spanning the range of fiber types and oxidative capacity. We demonstrated that a significant resistance to transcapillary O₂ flux resides in all muscles such that PO[subscript 2is] is significantly lower than PO[subscript 2mv] (transcapillary PO₂ = PO[subscript 2mv] – PO[subscript 2is]), and that this resistance was lowest in highly oxidative fast-twitch muscle. This novel finding provided the ability to estimate PO[subscript 2mv] from PO[subscript 2is] measurements in Chapters 3 and 4, and estimate convective (Q̇O₂) and diffusive (DO₂) O₂ transport since the convergence of Q̇O₂ and DO₂ establishes muscle O₂ utilization (V̇O₂). In the second investigation (Chapter 3), we demonstrated that systemic GLI administration in female rats reduced V̇O[subscript 2max] and submaximal exercise tolerance during treadmill running (critical speed (CS), metabolic threshold separating heavy-intensity exercise from severe-intensity exercise which leads to V̇O[subscript 2max]). Topical administration of GLI via superfusion onto fast-twitch oxidative muscle impaired Q̇m and PO[subscript 2is] and subsequently lowered V̇O₂ during twitch contractions via reduced Q̇O₂ and DO₂. The third investigation further utilized male and ovariectomized female (F+OVX) rats (Chapter 4) to assess sex differences in vascular K[subscript ATP] channel function (male vs female) and the effect of ovariectomy (female vs F+OVX; models for pre- and post-menopause). GLI superfusion lowered V̇O₂ via impaired Q̇m and Q̇O₂, and thus PO[subscript 2is], in male and female, but not F+OVX, rats. Furthermore, females demonstrated impaired DO₂ which, in combination with impaired Q̇O₂, would help describe or account for the greater GLI-induced speeding of PO[subscript 2is] fall during the rest-contraction transient compared to males.

Collectively, the results herein demonstrate that vascular K[subscript ATP] channels support submaximal exercise tolerance in health via improved convective and diffusive O₂ transport in fast-twitch oxidative muscle. GLI-induced K[subscript ATP] channel inhibition lowers the threshold separating heavy- and severe-intensity exercise (i.e., CS) and ultimately leads to compromised V̇O[subscript 2max] and earlier onset of exhaustion. Furthermore, exercise intolerance and adverse cardiovascular events in diabetic patients may be further exacerbated by sulphonylurea medication, especially in premenopausal females.



Vascular control, Microcirculation, Skeletal muscle oxygenation, Sex, Sulphonylurea, Exercise tolerance

Graduation Month



Doctor of Philosophy


Department of Kinesiology

Major Professor

Timothy I. Musch