{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T23:09:02Z","timestamp":1783984142709,"version":"3.55.0"},"reference-count":19,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,31]],"date-time":"2021-12-31T00:00:00Z","timestamp":1640908800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["221805\/Z\/20\/Z"],"award-info":[{"award-number":["221805\/Z\/20\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p><jats:bold>Objective:<\/jats:bold> Although intravenous nitrates are commonly used in clinical medicine, they have been shown to increase myocardial oxygen consumption and inhibit complex IV of the electron transport chain. As such we sought to measure whether myocardial energetics were impaired during glyceryl trinitrate (GTN) infusion.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> 10 healthy volunteers underwent cardiac magnetic resonance imaging to assess cardiac function and <jats:sup>31<\/jats:sup>phosphorus magnetic resonance spectroscopy to measure Phosphocreatine\/ATP (PCr\/ATP) ratio and creatine kinase forward rate constant (CK <jats:italic>k<jats:sub>f<\/jats:sub><\/jats:italic>) before and during an intravenous infusion of GTN.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> During GTN infusion, mean arterial pressure (78\u2009\u00b1\u20097 vs. 65\u2009\u00b1\u20096\u2009mmHg, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001), left ventricular (LV) stroke work (7,708\u2009\u00b1\u20092,782 vs. 6,071\u2009\u00b1\u20092,660\u2009ml\u2009mmHg, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001), and rate pressure product (7,214\u2009\u00b1\u20091,051 vs. 6,929\u2009\u00b1\u2009976\u2009mmHg\u2009bpm, <jats:italic>p<\/jats:italic>\u2009=\u20090.06) all fell. LV ejection fraction increased (61\u2009\u00b1\u20093 vs. 66\u2009\u00b1\u20094%, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001), with cardiac output remaining constant (6.2\u2009\u00b1\u20091.5 vs. 6.5\u2009\u00b1\u20091.4\u2009l\/min, <jats:italic>p<\/jats:italic>\u2009=\u20090.37). Myocardial PCr\/ATP fell during GTN infusion (2.17\u2009\u00b1\u20090.2 vs. 1.99\u2009\u00b1\u20090.22, <jats:italic>p<\/jats:italic>\u2009=\u20090.03) with an increase in both CK <jats:italic>k<jats:sub>f<\/jats:sub><\/jats:italic> (0.16\u2009\u00b1\u20090.07 vs. 0.25\u2009\u00b1\u20090.1\u2009s<jats:sup>\u22121<\/jats:sup>, <jats:italic>p<\/jats:italic>\u2009=\u20090.006) and CK flux (1.8\u2009\u00b1\u20090.8 vs. 2.6\u2009\u00b1\u20091.1\u2009\u03bcmol\/g\/s, <jats:italic>p<\/jats:italic>\u2009=\u20090.03).<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> During GTN infusion, despite reduced LV stroke work and maintained cardiac output, there was a 44% increase in myocardial ATP delivery through CK. As PCr\/ATP fell, this increase in ATP demand coincided with GTN-induced impairment of mitochondrial oxidative phosphorylation. Overall, this suggests that while GTN reduces cardiac work, it does so at the expense of increasing ATP demand beyond the capacity to increase ATP production.<\/jats:p>","DOI":"10.3389\/fphys.2021.790525","type":"journal-article","created":{"date-parts":[[2021,12,31]],"date-time":"2021-12-31T04:36:35Z","timestamp":1640925395000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Myocardial Energy Response to Glyceryl Trinitrate: Physiology Revisited"],"prefix":"10.3389","volume":"12","author":[{"given":"William D.","family":"Watson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peregrine G.","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ladislav","family":"Valkovi\u010d","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Herring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Neubauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver J.","family":"Rider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,31]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/0006-2952(71)90140-7","article-title":"Effects of glycerol trinitrate, mannitol hexanitrate and erythritol tetranitrate on electron transport and phosphorylation in liver mitochondria","volume":"20","author":"Boime","year":"1971","journal-title":"Biochem. Pharmacol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1161\/01.CIR.19.5.697","article-title":"Action of nitroglycerin on the coronary circulation in Normal and in mild cardiac subjects","volume":"19","author":"Brachfeld","year":"1959","journal-title":"Circulation"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/0014-5793(94)01290-3","article-title":"Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase","volume":"356","author":"Brown","year":"1994","journal-title":"FEBS Lett."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e4085","DOI":"10.1002\/nbm.4085","article-title":"Localized rest and stress human cardiac creatine kinase reaction kinetics at 3 T","volume":"32","author":"Clarke","year":"2019","journal-title":"NMR Biomed."},{"key":"ref5","first-page":"346","article-title":"Alteration in oxyhemoglobin equilibrium (P-50) and myocardial oxygen consumption (MVO2) by nitroglycerin (GTN)","volume":"193","author":"Gross","year":"1975","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"5604","DOI":"10.1073\/pnas.93.11.5604","article-title":"Nitric oxide inhibits creatine kinase and regulates rat heart contractile reserve","volume":"93","author":"Gross","year":"1996","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e104","DOI":"10.1161\/01.RES.0000100067.62876.50","article-title":"Does nitric oxide mediate the vasodilator activity of nitroglycerin?","volume":"93","author":"Kleschyov","year":"2003","journal-title":"Circ. Res."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1161\/01.CIR.50.6.1179","article-title":"Hemodynamic predictors of myocardial oxygen consumption During static and dynamic exercise","volume":"50","author":"Nelson","year":"1974","journal-title":"Circulation"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1056\/NEJMra063052","article-title":"The failing heart - an engine out of fuel","volume":"356","author":"Neubauer","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1161\/CIRCULATIONAHA.119.043450","article-title":"Cardiac energetics in patients With aortic stenosis and preserved versus reduced ejection fraction","volume":"141","author":"Peterzan","year":"2020","journal-title":"Circulation"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"H597","DOI":"10.1152\/ajpheart.00731.2016","article-title":"Metabolic remodeling in hypertrophied and failing myocardium: a review","volume":"313","author":"Peterzan","year":"2017","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1161\/01.CIR.97.7.666","article-title":"Functional and metabolic evaluation of the athlete's heart by magnetic resonance imaging and dobutamine stress magnetic resonance spectroscopy","volume":"97","author":"Pluim","year":"1998","journal-title":"Circulation"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"e0185356","DOI":"10.1371\/journal.pone.0185356","article-title":"OXSA: An open-source magnetic resonance spectroscopy analysis toolbox in MATLAB","volume":"12","author":"Purvis","year":"2017","journal-title":"PLoS One"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"ehab663","DOI":"10.1093\/eurheartj\/ehab663","article-title":"Obesity modifies the energetic phenotype of dilated cardiomyopathy","author":"Rayner","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1161\/CIRCULATIONAHA.119.042770","article-title":"Myocardial energetics in obesity: enhanced ATP delivery Through creatine kinase With blunted stress response","volume":"141","author":"Rayner","year":"2020","journal-title":"Circulation"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1002\/mrm.22347","article-title":"Triple repetition time saturation transfer (TRiST) (31)P spectroscopy for measuring human creatine kinase reaction kinetics","volume":"63","author":"Sch\u00e4r","year":"2010","journal-title":"Magn. Reson. Med."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0014-2999(69)90122-8","article-title":"Nutritional circulation in the heart. II. A reappraisal of the effect of nitroglycerin on myocardial hemodynamics, oxygen consumption and nutritional blood flow in the isolated supported heart preparation","volume":"8","author":"Somani","year":"1969","journal-title":"Eur. J. Pharmacol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1002\/nbm.1350","article-title":"Reproducibility of 31P cardiac magnetic resonance spectroscopy at 3\u2009T","volume":"22","author":"Tyler","year":"2009","journal-title":"NMR Biomed."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1073\/pnas.0408962102","article-title":"ATP flux through creatine kinase in the normal, stressed, and failing human heart","volume":"102","author":"Weiss","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.790525\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,31]],"date-time":"2021-12-31T04:36:43Z","timestamp":1640925403000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.790525\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,31]]},"references-count":19,"alternative-id":["10.3389\/fphys.2021.790525"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.790525","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,31]]},"article-number":"790525"}}