{"doi":"10.1113/jp280232","title":"Vascular ATP‐sensitive K<sup>+</sup> channels support maximal aerobic capacity and critical speed via convective and diffusive O<sub>2</sub> transport","abstract":"Key points Oral sulphonylureas, widely prescribed for diabetes, inhibit pancreatic ATP‐sensitive K + (K ATP ) channels to increase insulin release. However, K ATP channels are also located within vascular (endothelium and smooth muscle) and muscle (cardiac and skeletal) tissue. We evaluated left ventricular function at rest, maximal aerobic capacity ( O 2 max ) and submaximal exercise tolerance (i.e. speed–duration relationship) during treadmill running in rats, before and after systemic K ATP channel inhibition via glibenclamide. Glibenclamide impaired critical speed proportionally more than O 2 max but did not alter resting cardiac output. Vascular K ATP channel function (topical glibenclamide superfused onto hindlimb skeletal muscle) resolved a decreased blood flow and interstitial PO 2 during twitch contractions reflecting impaired O 2 delivery‐to‐utilization matching. Our findings demonstrate that systemic K ATP channel inhibition reduces O 2 max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O 2 delivery, and thus O 2 , especially within fast‐twitch oxidative skeletal muscle. Abstract Vascular ATP‐sensitive K + (K ATP ) channels support skeletal muscle blood flow and microvascular oxygen delivery‐to‐utilization matching during exercise. However, oral sulphonylurea treatment for diabetes inhibits pancreatic K ATP channels to enhance insulin release. Herein we tested the hypotheses that: i) systemic K ATP channel inhibition via glibenclamide (GLI; 10 mg kg −1 i.p. ) would decrease cardiac output at rest (echocardiography), maximal aerobic capacity ( O 2 max ) and the speed–duration relationship (i.e. lower critical speed (CS)) during treadmill running; and ii) local K ATP channel inhibition (5 mg kg −1 GLI superfusion) would decrease blood flow (15 µm microspheres), interstitial space oxygen pressures (PO 2 is ; phosphorescence quenching) and convective and diffusive O 2 transport ( O 2 and DO 2 , respectively; Fick Principle and Law of Diffusion) in contracting fast‐twitch oxidative mixed gastrocnemius muscle (MG: 9% type I+IIa fibres). At rest, GLI slowed left ventricular relaxation (2.11 ± 0.59 vs . 1.70 ± 0.23 cm s −1 ) and decreased heart rate (321 ± 23 vs . 304 ± 22 bpm, both P &lt; 0.05) while cardiac output remained unaltered (219 ± 64 vs . 197 ± 39 ml min −1 , P &gt; 0.05). During exercise, GLI reduced O 2 max (71.5 ± 3.1 vs . 67.9 ± 4.8 ml kg −1 min −1 ) and CS (35.9 ± 2.4 vs . 31.9 ± 3.1 m min −1 , both P &lt; 0.05). Local K ATP channel inhibition decreased MG blood flow (52 ± 25 vs . 34 ± 13 ml min −1 100 g tissue −1 ) and PO 2 is nadir (5.9 ± 0.9 vs . 4.7 ± 1.1 mmHg) during twitch contractions. Furthermore, MG O 2 was reduced via impaired O 2 and DO 2 ( P &lt; 0.05 for each). Collectively, these data support that vascular K ATP channels help sustain submaximal exercise tolerance in healthy rats. For patients taking sulfonylureas, K ATP channel inhibition may exacerbate exercise intolerance.","journal":"The Journal of Physiology","year":2020,"id":89263,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9614,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","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":452302,"name":"K. Sue Hageman","orcid":null,"position":2,"is_corresponding":false},{"id":451514,"name":"Jacob T. Caldwell","orcid":"0000-0002-2893-4986","position":3,"is_corresponding":false},{"id":451515,"name":"Kiana M. Schulze","orcid":"0000-0001-6467-5179","position":4,"is_corresponding":false},{"id":451516,"name":"Carl J. Ade","orcid":"0000-0002-1837-2342","position":5,"is_corresponding":false},{"id":451517,"name":"Bradley J. Behnke","orcid":"0000-0002-8928-928X","position":6,"is_corresponding":false},{"id":324212,"name":"David C. Poole","orcid":"0000-0003-2441-3793","position":7,"is_corresponding":false},{"id":324214,"name":"Timothy I. Musch","orcid":"0000-0003-1599-1751","position":8,"is_corresponding":false},{"id":444282,"name":"Trenton D. Colburn","orcid":"0000-0002-1346-8695","position":0,"is_corresponding":true}],"reference_count":95,"raw_metadata":null,"created_at":"2026-07-18T22:01:50.225871Z","pmid":"32798233","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":[]}