{"doi":"10.1113/jp281120","title":"Sexual dimorphism in vascular ATP‐sensitive K<sup>+</sup> channel function supporting interstitial via convective and/or diffusive O<sub>2</sub> 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 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 &lt; 0.032) via reduced (male: ↓31%, female: ↓35%, both P &lt; 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 &lt; 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 &lt; 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.","journal":"The Journal of Physiology","year":2021,"id":211984,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.961,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":451513,"name":"Ramona E. Weber","orcid":"0000-0001-5110-270X","position":1,"is_corresponding":false},{"id":451515,"name":"Kiana M. Schulze","orcid":"0000-0001-6467-5179","position":2,"is_corresponding":false},{"id":452302,"name":"K. Sue Hageman","orcid":null,"position":3,"is_corresponding":false},{"id":483628,"name":"Andrew G. Horn","orcid":"0000-0003-4435-4022","position":4,"is_corresponding":false},{"id":451517,"name":"Bradley J. Behnke","orcid":"0000-0002-8928-928X","position":5,"is_corresponding":false},{"id":324212,"name":"David C. Poole","orcid":"0000-0003-2441-3793","position":6,"is_corresponding":false},{"id":324214,"name":"Timothy I. Musch","orcid":"0000-0003-1599-1751","position":7,"is_corresponding":false},{"id":444282,"name":"Trenton D. Colburn","orcid":"0000-0002-1346-8695","position":0,"is_corresponding":true}],"reference_count":89,"raw_metadata":null,"created_at":"2026-07-18T23:52:23.670339Z","pmid":"34101850","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}