Abstract 12473: A Novel Selective EP4 Receptor Agonist Improves Intracellular Ca2+ Handling and Cardiomyocyte Function in Intact Failing Cardiomyocytes
Background: Prostaglandin E2 (PGE2) has four receptor subtypes, EP1-EP4. EP4 is reported to be a dominant receptor subtype expressed in cardiac tissue. However, the precise role of EP4 receptor in heart failure has not yet been elucidated. Here, we investigated the effect of a selective EP4 agonist the intracellular Ca2+ handling and the cardiomyocyte function in normal and failing cardiomyocytes in comparison with phosphodiesterase III inhibitor (milrinone).
Methods and results: Cardiomyocytes were isolated from the left ventricles (LV) of normal dog (n=5) and heart failure model by 4-week’s rapid pacing (n=5). First, we investigated the effect of the various concentrations of selective EP4 agonist, Ono-4232 (Ono pharmaceutical Co., Ltd.) or milrinone on intracellular Ca2+ transient and cell shortening in intact normal and failing cardiomyocytes. Although Ono-4232 have no appreciable effect at each dose (1nM, 10nM, 100nM, 1000nM) in normal cardiomyocytes, it significantly increased peak intracellular Ca transient ( % pCaT ) by 15% and peak cell shortening (% CS ) by 15% , compared with baseline, at more than 10 nM in failing cardiomyocytes. On the other hand, milrinone significantly increased % pCaT (20 %) and % CS (20%), compared with baseline, at half maximum effect dose (3 μM ) in both normal and failing cardiomyocytes. Then, we investigated the effect of Ono-4232 or milrinone on diastolic Ca2+ spark frequency (SpF) and sarcoplasmic reticulum Ca2+ content ([Ca2+]SR) by confocal microscopy in normal and failing cardiomyocytes. In failing cardiomyocytes, CaSF(+60%) was significantly increased as compared with normal cardiomyocytes (=100%). Furthermore, addition of 3 μM milrinone to failing cardiomyocytes markedly increased CaSF(+300%) with a slight increase in [Ca2+]SR. However, addition of 10 nM Ono-4232 did not increase SpF with the same level of [Ca2+]SR as 3 μM milrinone.
Conclusion: These results suggest that a selective EP4 receptor agonist improves Ca2+ handling and cardiac function without enhancing diastolic Ca2+ leak from SR only in failing cardiomyocytes, leading to suppression of arrhythmogenesis. Therefore, modulation of abnormal Ca2+ handling by selective EP4 agonist may become a new strategy for heart failure.
- © 2013 by American Heart Association, Inc.