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However, the mechanisms of the antiarrhythmic effects of PDE5 inhibition are unknown. Diastolic calcium (Ca\n              <jats:sup>2+<\/jats:sup>\n              ) waves lead to arrhythmias by inducing delayed afterdepolarizations (DADs). Ca\n              <jats:sup>2+<\/jats:sup>\n              waves are initiated when sarcoplasmic reticulum (SR) Ca\n              <jats:sup>2+<\/jats:sup>\n              content reaches a threshold level and the SR releases Ca\n              <jats:sup>2+<\/jats:sup>\n              spontaneously and generates a depolarizing inward sodium-calcium exchange current.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>\n              To determine the effects of PDE5 inhibition on the propensity for ventricular arrhythmias in a proarrhythmic large animal model and establish the role of alterations of intracellular Ca\n              <jats:sup>2+<\/jats:sup>\n              cycling\/SR Ca\n              <jats:sup>2+<\/jats:sup>\n              content.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              Arrhythmia burden, monophasic action potentials, and beat-to-beat variability of repolarization were measured in a sheep model using the\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>Kr<\/jats:sub>\n              inhibitor dofetilide to induce QT prolongation and arrhythmia. Ca\n              <jats:sup>2+<\/jats:sup>\n              transients, Ca\n              <jats:sup>2+<\/jats:sup>\n              waves, and SR Ca\n              <jats:sup>2+<\/jats:sup>\n              content were measured in isolated ventricular myocytes. PDE5 inhibition was achieved using acute application of sildenafil, and PKG (protein kinase G) was inhibited with KT5823. PDE5 inhibition reduced beat-to-beat variability of repolarization and suppressed afterdepolarizations, premature ventricular complexes, and torsade de pointes in vivo. In single cells, dofetilide-induced delayed afterdepolarizations and triggered action potentials were suppressed by PDE5 inhibition. PDE5 inhibition decreased Ca\n              <jats:sup>2+<\/jats:sup>\n              wave frequency in all cells and abolished waves in 12 of 22 cells. A decrease in SR Ca\n              <jats:sup>2+<\/jats:sup>\n              uptake, increased trans-sarcolemmal Ca\n              <jats:sup>2+<\/jats:sup>\n              efflux, and reduced trans-sarcolemmal Ca\n              <jats:sup>2+<\/jats:sup>\n              influx led to a reduction of SR Ca\n              <jats:sup>2+<\/jats:sup>\n              content and Ca\n              <jats:sup>2+<\/jats:sup>\n              wave abolition. These effects were dependent on PKG activation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              PDE5 inhibition acutely suppresses triggered ventricular arrhythmias in vivo, and cellular data suggests this occurs via suppression of cellular Ca\n              <jats:sup>2+<\/jats:sup>\n              waves. These novel antiarrhythmic properties of PDE5 inhibition are mediated by a reduction of SR Ca\n              <jats:sup>2+<\/jats:sup>\n              content and are PKG dependent.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.121.318473","type":"journal-article","created":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T09:00:10Z","timestamp":1626080410000},"page":"650-665","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["PDE5 Inhibition Suppresses Ventricular Arrhythmias by Reducing SR Ca\n            <sup>2+<\/sup>\n            Content"],"prefix":"10.1161","volume":"129","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5402-8565","authenticated-orcid":true,"given":"David C.","family":"Hutchings","sequence":"first","affiliation":[{"name":"Unit of Cardiac Physiology, Division of Cardiovascular Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester 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