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Risk factors were induced in 12 female swine by intravenous streptozotocin injections (DM), a high fat diet (HFD) and renal artery embolization (CKD). Female healthy swine (<jats:italic>n<\/jats:italic>\u2009=\u200913) on normal diet served as controls (Normal). After 5\u00a0months, swine were chronically instrumented and studied at rest and during exercise. DM\u2009+\u2009HFD\u2009+\u2009CKD swine demonstrated significant hyperglycaemia, dyslipidaemia and impaired kidney function compared to Normal\u00a0swine. These risk factors were accompanied by coronary microvascular endothelial dysfunction both in vivo and in isolated small arteries, due to a reduced NO bioavailability, associated with perturbations in myocardial oxygen balance at rest and during exercise. NO synthase inhibition caused coronary microvascular constriction in exercising Normal swine, but had no effect in DM\u2009+\u2009HFD\u2009+\u2009CKD animals, while inhibition of phosphodiesterase 5 produced similar vasodilator responses in both groups, indicating that loss of NO bioavailability was principally responsible for the observed coronary microvascular dysfunction. This was associated with an increase in myocardial 8-isoprostane levels and a decrease in antioxidant capacity, while antioxidants restored the vasodilation to bradykinin in isolated coronary small arteries, suggesting that oxidative stress was principally responsible for the reduced NO bioavailability. In conclusion, five months of combined exposure to DM\u2009+\u2009HFD\u2009+\u2009CKD produces coronary endothelial dysfunction due to impaired NO bioavailability, resulting in impaired myocardial perfusion at rest and during exercise.<\/jats:p>","DOI":"10.1007\/s00395-021-00890-8","type":"journal-article","created":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T03:25:06Z","timestamp":1629948306000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Reduced nitric oxide bioavailability impairs myocardial oxygen balance during exercise in swine with multiple risk factors"],"prefix":"10.1007","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7133-3046","authenticated-orcid":false,"given":"Jens","family":"van de Wouw","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3713-4136","authenticated-orcid":false,"given":"Oana","family":"Sorop","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5383-4960","authenticated-orcid":false,"given":"Ruben W. 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