Abstract 15345: ONO-4232, an EP4-selective Agonist, Improves Left Ventricular Diastolic Dysfunction and Ameliorates Acute and Chronic Heart Failure in Animal Models

Background: Prostaglandin E2 (PGE2) has four receptor subtypes, EP1-EP4. Among these EP2 and EP4 are known to be expressed in blood vessels and involved in vasodilation. EP4 is also reported to be a dominant receptor subtype expressed in cardiac tissue, and EP4 agonists have been shown to provide protection from cardiac ischemia/reperfusion injury. Therefore, we investigated the efficacy of ONO-4232 (ONO), an EP4-selective agonist, in experimental models of acute (AHF) and chronic heart failure (CHF). Methods and Results: (1) AHF was induced in dogs by combined volume overload, coronary ligation, and methoxamine infusion producing an elevation of LVEDP and systemic vascular resistance (SVR), increase in tau, reduction of LV dP/dt max and cardiac output (CO) in vehicle treated animals. ONO (3, 10 ng/kg/min, i.v. infusion) reduced both LVEDP and SVR and prevented the decrease in CO. Moreover, ONO significantly reduced tau, the time constant of LV relaxation, without apparent influence on LV dP/dt max. On th...