Abstract P297: The Deleterious Role of Prostaglandin E2 EP3 Receptor in Ang II-induced Hypertension

Abstract

High blood pressure (BP) is a major risk factor for heart and renal disease. Prostaglandin E2 (PGE2) is a product of the arachidonic acid cascade and is known to mediate inflammation and have vasodilatory effects. Previous data from our lab have shown that PGE2 reduces cardiac contractility when signaling through its EP3 receptor subtype and that EP3 expression increases in the left ventricle of mice subjected to Angiotensin II (Ang II) hypertension. We therefore hypothesized that EP3 activation would worsen BP in the Ang II hypertension model and would also decrease cardiac function. To test our hypothesis, we treated 10-12 wk. old C57Bl/6 mice with either Ang II (1.4 mg/kg/d) or vehicle via osmotic mini pump and simultaneously treated them with the EP3 agonist, Sulprostone (80 μg/kg/d, S.C.), or vehicle for 2 weeks. As expected, Ang II infusion increased BP significantly (115 mmHg ± 4.8 vs. 172 mmHg ± 12.1; p< 0.005). After 2 weeks, however, there was no difference in BP between the Ang II group and the Ang II + Sulp. group. Echocardiography in conscious animals demonstrated that treatment with Ang II + Sulp. group reduced shortening fraction (SF) from 61.28 ± 1.82 % to 56.71 ± 0.91 %; (p<0.05) whereas Ang II treatment alone did not affect SF. This suggests that EP3 activation combined with Ang II infusion may reduce cardiac function in as little as 2 weeks. We then repeated this protocol using the EP3 inhibitor, L798, 106 (40 μg/kg/d). Remarkably, the increase in BP with Ang II was almost completely abolished when animals received the inhibitor (168.3 mmHg ± 6.5 for Ang II group vs. 117.9 mmHg ± 17.1 for Ang II + L798, 106 group; p< 0.05) without changes in cardiac function. Since the effects on BP are independent of changes in cardiac function, we hypothesize the effects are on total peripheral resistance and future experiments will examine the vasculature to identify possible mechanism(s). In conclusion, EP3 receptor activation did not worsen BP after Ang II infusion but treatment with the EP3 inhibitor completely normalized blood pressure. This suggests that there is commonality between the EP3 and Ang II signaling pathways. We also propose that EP3 receptor activation is deleterious in an Ang II model since treatment with Sulprostone reduces cardiac function after only 2 weeks.