The deleterious role of the prostaglandin E EP receptor in angiotensin II hypertension.

Angiotensin II (ANG II) plays a key role in regulating blood pressure and inflammation. Prostaglandin E (PGE) signals through four different G protein-coupled receptors, eliciting a variety of effects. We reported that activation of the EP receptor reduces cardiac contractility. More recently, we have shown that overexpression of the EP receptor is protective in a mouse myocardial infarction model. We hypothesize in this study that the relative abundance of EP and EP receptors is a major determinant of end-organ damage in the diseased heart. Thus EP is detrimental to cardiac function and promotes inflammation, whereas antagonism of the EP receptor is protective in an ANG II hypertension (HTN) model. To test our hypothesis, male 10- to 12-wk-old C57BL/6 mice were anesthetized with isoflurane and osmotic minipumps containing ANG II were implanted subcutaneously for 2 wk. We found that antagonism of the EP receptor using L798,106 significantly attenuated the increase in blood pressure with ANG II infusion. Moreover, antagonism of the EP receptor prevented a decline in cardiac function after ANG II treatment. We also found that 10- to 12-wk-old EP-transgenic mice, which overexpress EP in the cardiomyocytes, have worsened cardiac function. In conclusion, activation or overexpression of EP exacerbates end-organ damage in ANG II HTN. In contrast, antagonism of the EP receptor is beneficial and reduces cardiac dysfunction, inflammation, and HTN. This study is the first to show that systemic treatment with an EP receptor antagonist (L798,106) attenuates the angiotensin II-induced increase in blood pressure in mice. The results from this project could complement existing hypertension therapies by combining blockade of the EP receptor with antihypertensive drugs.