Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor

Abstract

Background— Prostaglandin E2 (PGE 2 ) EP receptors EP3 and EP4 signal via decreased and increased cAMP production, respectively. Previously, we reported that cardiomyocyte-specific EP4 knockout mice develop dilated cardiomyopathy with reduced ejection fraction. Thus, we hypothesized that PGE 2 increases contractility via EP4 but decreases contractility via EP3. Methods and Results— The effects of PGE 2 and the EP1/EP3 agonist sulprostone on contractility were examined in the mouse Langendorff preparation and in adult mouse cardiomyocytes. Isolated hearts of adult male C57Bl/6 mice were perfused with PGE 2 (10 −6 M) or sulprostone (10 −6 M) and compared with vehicle. Both PGE 2 and sulprostone decreased +dp/dt ( P <0.01) and left ventricular developed pressure ( P <0.001) with reversal by an EP3 antagonist. In contrast, the EP4 agonist had the opposite effect. Adult mouse cardiomyocytes contractility was also reduced after treatment with either PGE 2 or sulprostone for 10 minutes. We then examined the acute effects of PGE 2 , sulprostone, and the EP4 agonist on expression of phosphorylated phospholamban and sarcoendoplasmic reticulum Ca 2+ -ATPase 2a in adult mouse cardiomyocytes using Western blot. Treatment with either PGE 2 or sulprostone decreased expression of phosphorylated phospholamban corrected to total phospholamban, whereas treatment with the EP4 agonist had the opposite effect. Sarcoendoplasmic reticulum Ca 2+ -ATPase 2a expression was unaffected. Finally, we examined the effect of these compounds in vivo using pressure–volume loops. Both PGE 2 and sulprostone decreased +dp/dt, whereas the EP4 agonist increased +dp/dt. Conclusions— Contractility is reduced via the EP3 receptor but increased via EP4. These effects may be mediated through changes in phospholamban phosphorylation and has relevance to detrimental effects of inflammation.