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Cervantes, Daniel O; Andrade-Vicenty, Alejandro; Sun, Chaoyu; Anand, Saketh; Pope, Jillian; Dorilio, Jessica R; Sun, Dong; Cannata, Antonio; Cianflone, Eleonora; Vinukonda, Govindaiah; Hintze, Thomas H; O’Malley, Heather; Isom, Lori L; Jacobson, Jason T; Rota, Marcello

Abstract 461: Sodium Influx Modulates the Modality of Cardiac Relaxation

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  • Medientyp: E-Artikel
  • Titel: Abstract 461: Sodium Influx Modulates the Modality of Cardiac Relaxation
  • Beteiligte: Cervantes, Daniel O; Andrade-Vicenty, Alejandro; Sun, Chaoyu; Anand, Saketh; Pope, Jillian; Dorilio, Jessica R; Sun, Dong; Cannata, Antonio; Cianflone, Eleonora; Vinukonda, Govindaiah; Hintze, Thomas H; O’Malley, Heather; Isom, Lori L; Jacobson, Jason T; Rota, Marcello
  • Erschienen: Ovid Technologies (Wolters Kluwer Health), 2019
  • Erschienen in: Circulation Research
  • Sprache: Englisch
  • DOI: 10.1161/res.125.suppl_1.461
  • ISSN: 0009-7330; 1524-4571
  • Schlagwörter: Cardiology and Cardiovascular Medicine ; Physiology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p> Aging in experimental animals is coupled with protracted electrical recovery of the heart and increased late Na <jats:sup>+</jats:sup> current (I <jats:sub>NaL</jats:sub> ) in cardiomyocytes. These electrophysiological alterations are coupled with impaired cardiac relaxation, raising the possibility of a causative link between enhanced I <jats:sub>NaL</jats:sub> and diastolic dysfunction. To test this hypothesis, genetic and pharmacological interventions were introduced to assess the consequences of enhanced Na <jats:sup>+</jats:sup> influx in myocytes on diastolic properties of the mouse heart, together with effects on mechanical properties of isolated cells. Using Langendorff preparations, acute enhancement of I <jats:sub>NaL</jats:sub> with anemone toxin II increased diastolic and systolic pressure in the mouse heart. Importantly, a shift of the diastolic pressure-volume relationship toward higher pressure values was observed with activation of I <jats:sub>NaL</jats:sub> . To test the in vivo effects of increased Na <jats:sup>+</jats:sup> influx, mice with inducible, cardiac restricted deletion of the beta1 subunit of the Na <jats:sup>+</jats:sup> channel (Scn1b-KO) were employed. Scn1b-KO male mice presented protracted electrical recovery with respect to control (Ctrl) animals, a condition that was reversed by administration of a specific I <jats:sub>NaL</jats:sub> inhibitor (GS967, 0.5 mg/kg body weight). By invasive hemodynamics, left ventricular (LV) developed pressure was preserved in Scn1b-KO mice, but maximal velocities of pressure development and decay were attenuated by 16% and 25%, respectively. By echocardiography, LV end-diastolic volume and ejection fraction (EF) were preserved in Scn1b-KO. In contrast, using Doppler modality, LV filling pattern was altered and isovolumic relaxation time was prolonged by ~30%. I <jats:sub>NaL</jats:sub> inhibition (GS967) in Scn1b-KO mice ameliorated LV filling and normalized isovolumic relaxation time, without effects on EF. Using isolated cardiomyocyte preparations, Scn1b deletion had no consequences on fractional cell shortening, but led to a ~5% prolongation of kinetics of contraction and relaxation. Inhibition of I <jats:sub>NaL</jats:sub> (300 nM GS697) in Scn1b-KO myocytes accelerated contraction and relaxation kinetics and attenuated fractional shortening. In conclusion the late Na <jats:sup>+</jats:sup> current modulates the modality of myocyte contraction and relaxation with important effects on diastolic function of the heart. </jats:p>
  • Zugangsstatus: Freier Zugang