Abstract 461: Sodium Influx Modulates the Modality of Cardiac Relaxation
| Autor: | Jessica R Dorilio, Heather A. O'Malley, Chaoyu Sun, Daniel O Cervantes, Dong Sun, Lori L. Isom, Alejandro Andrade-Vicenty, Eleonora Cianflone, Govindaiah Vinukonda, Marcello Rota, Jillian Pope, Saketh Anand, Jason T. Jacobson, Antonio Cannatà, Thomas H. Hintze |
|---|---|
| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Circulation Research. 125 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Aging in experimental animals is coupled with protracted electrical recovery of the heart and increased late Na + current (I NaL ) in cardiomyocytes. These electrophysiological alterations are coupled with impaired cardiac relaxation, raising the possibility of a causative link between enhanced I NaL and diastolic dysfunction. To test this hypothesis, genetic and pharmacological interventions were introduced to assess the consequences of enhanced Na + 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 NaL 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 NaL . To test the in vivo effects of increased Na + influx, mice with inducible, cardiac restricted deletion of the beta1 subunit of the Na + 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 NaL 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 NaL 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 NaL (300 nM GS697) in Scn1b-KO myocytes accelerated contraction and relaxation kinetics and attenuated fractional shortening. In conclusion the late Na + current modulates the modality of myocyte contraction and relaxation with important effects on diastolic function of the heart. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|