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 the other hand, the inotropic milrinone (1, 3 μ g/kg/min, i.v. infusion) not only reduced LVEDP and SVP but also produced a marked dose-dependent increase in LV dP/dt max. Reduction of tau was only observed at high milrinone doses. (2) A non-ischemic model of CHF was induced by feeding 8% salt-containing diet to Dahl rats from 6 week of age. Beginning at 12 weeks these rats received daily ONO (0.03, 0.1 mg/kg p.o. b.i.d.), candesartan (0.3, 1 mg/kg p.o. q.d.), or a combination of these compounds (N=20) for 80 days. The number of surviving rats in each group at the end of the treatment period was Vehicle: 1, ONO L: 11, ONO H: 15, candesartan L: 12, candesartan H: 17, ONO L + candesartan L: 19, ONO L + candesartan H: 20. ONO also prevented fibrosis of cardiac tissue and this may have contributed to the improved survival.
Conclusion: ONO improves LV diastolic function by promoting LV relaxation and also prevents cardiac fibrosis, and represents a novel drug candidate for AHF and CHF.
- © 2012 by American Heart Association, Inc.