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In the present study, we investigated the adrenergic reserve both in\u00a0vivo and in cardiomyocytes of a murine cardiometabolic HFpEF model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>12\u2010week\u2010old male C57BL\/6J mice were fed regular chow (control) or a high\u2010fat diet and L\u2010NAME (HFpEF) for 15\u2009weeks. At 27\u2009weeks, we performed (stress) echocardiography and exercise testing and measured the adrenergic reserve and its modulation by nitric oxide and reactive oxygen species in left ventricular cardiomyocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HFpEF mice (preserved left ventricular ejection fraction, increased E\/e', pulmonary congestion [wet lung weight\/TL]) exhibited reduced exercise capacity and a reduction of stroke volume and cardiac output with adrenergic stress. In ventricular cardiomyocytes isolated from HFpEF mice, sarcomere shortening had a higher amplitude and faster relaxation compared to control animals. Increased shortening was caused by a shift of myofilament calcium sensitivity. With addition of isoproterenol, there were no differences in sarcomere function between HFpEF and control mice. This resulted in a reduced inotropic and lusitropic reserve in HFpEF cardiomyocytes. Preincubation with inhibitors of nitric oxide synthases or glutathione partially restored the adrenergic reserve in cardiomyocytes in HFpEF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In this murine HFpEF model, the cardiac output reserve on adrenergic stimulation is impaired. In ventricular cardiomyocytes, we found a congruent loss of the adrenergic inotropic and lusitropic reserve. This was caused by increased contractility and faster relaxation at rest, partially mediated by nitro\u2010oxidative signaling.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.14124","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T10:06:30Z","timestamp":1709546790000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Impairment of the adrenergic reserve associated with exercise intolerance in a murine model of heart failure with preserved ejection fraction"],"prefix":"10.1111","volume":"240","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2933-7566","authenticated-orcid":false,"given":"Lukas","family":"Semmler","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Cardiology German Heart Center Charit\u00e9 (DHZC) \u2013 Campus Virchow\u2010Klinikum  Berlin Germany"},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin  Berlin 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