Angiotensin II (ANG II) plays a key role in regulating blood pressure and inflammation. Prostaglandin E₂ (PGE₂) signals through four different G protein-coupled receptors, eliciting a variety of effects. We reported that activation of the EP₃ receptor reduces cardiac contractility. More recently, we have shown that overexpression of the EP₄ receptor is protective in a mouse myocardial infarction model. We hypothesize in this study that the relative abundance of EP₃ and EP₄ receptors is a major determinant of end-organ damage in the diseased heart. Thus EP₃ is detrimental to cardiac function and promotes inflammation, whereas antagonism of the EP₃ 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 EP₃ receptor using L798,106 significantly attenuated the increase in blood pressure with ANG II infusion. Moreover, antagonism of the EP₃ receptor prevented a decline in cardiac function after ANG II treatment. We also found that 10- to 12-wk-old EP₃-transgenic mice, which overexpress EP₃ in the cardiomyocytes, have worsened cardiac function. In conclusion, activation or overexpression of EP₃ exacerbates end-organ damage in ANG II HTN. In contrast, antagonism of the EP₃ receptor is beneficial and reduces cardiac dysfunction, inflammation, and HTN.NEW & NOTEWORTHY This study is the first to show that systemic treatment with an EP₃ 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 EP₃ receptor with antihypertensive drugs.

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