Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting
Youfei Guan, Yahua Zhang, Jing Wu, Zhonghua Qi, Guangrui Yang, Dou Dou, Yuansheng Gao, Lihong Chen, Xiaoyan Zhang, Linda S. Davis, Mingfeng Wei, Xuefeng Fan, Monica Carmosino, Chuanming Hao, John D. Imig, Richard M. Breyer, Matthew D. Breyer
Youfei Guan, Yahua Zhang, Jing Wu, Zhonghua Qi, Guangrui Yang, Dou Dou, Yuansheng Gao, Lihong Chen, Xiaoyan Zhang, Linda S. Davis, Mingfeng Wei, Xuefeng Fan, Monica Carmosino, Chuanming Hao, John D. Imig, Richard M. Breyer, Matthew D. Breyer
View: Text | PDF
Research Article Cardiology

Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

Abstract

Clinical use of prostaglandin synthase–inhibiting NSAIDs is associated with the development of hypertension; however, the cardiovascular effects of antagonists for individual prostaglandin receptors remain uncharacterized. The present studies were aimed at elucidating the role of prostaglandin E2 (PGE2) E-prostanoid receptor subtype 1 (EP1) in regulating blood pressure. Oral administration of the EP1 receptor antagonist SC51322 reduced blood pressure in spontaneously hypertensive rats. To define whether this antihypertensive effect was caused by EP1 receptor inhibition, an EP1-null mouse was generated using a “hit-and-run” strategy that disrupted the gene encoding EP1 but spared expression of protein kinase N (PKN) encoded at the EP1 locus on the antiparallel DNA strand. Selective genetic disruption of the EP1 receptor blunted the acute pressor response to Ang II and reduced chronic Ang II–driven hypertension. SC51322 blunted the constricting effect of Ang II on in vitro–perfused preglomerular renal arterioles and mesenteric arteriolar rings. Similarly, the pressor response to EP1-selective agonists sulprostone and 17-phenyltrinor PGE2 were blunted by SC51322 and in EP1-null mice. These data support the possibility of targeting the EP1 receptor for antihypertensive therapy.

Authors

Youfei Guan, Yahua Zhang, Jing Wu, Zhonghua Qi, Guangrui Yang, Dou Dou, Yuansheng Gao, Lihong Chen, Xiaoyan Zhang, Linda S. Davis, Mingfeng Wei, Xuefeng Fan, Monica Carmosino, Chuanming Hao, John D. Imig, Richard M. Breyer, Matthew D. Breyer

×

Figure 3

Effect of EP1 gene disruption on in vivo effects of Ang II.

Options: View larger image (or click on image) Download as PowerPoint
Effect of EP1 gene disruption on in vivo effects of Ang II. (A) Reduced ...
(A) Reduced pressor response to Ang II in EP1–/– versus EP1+/+ mice. MAP was recorded by intracarotid arterial monitoring before and during i.v. infusion of Ang II (75 pmol/kg/min). n = 8 per group. ***P < 0.005. (B) The pressor response to Ang II integrated over time was significantly reduced in EP1–/– compared with EP1+/+ mice. AUC, area under the curve. **P < 0.01. (C) Effect of chronic Ang II infusion (1,000 ng/kg/min) on systolic blood pressure determined by tail cuff. Baseline blood pressure was significantly lower in EP1–/– mice than in EP1+/+ mice (n = 5 per group) and the difference between genotypes increased following Ang II infusion. ***P < 0.001; ****P < 0.0001. (D) The change in systolic blood pressure following Ang II minipump was significantly greater in EP1+/+ than in EP1–/– mice (n = 5). ****P < 0.0001. (E) MAP determined by intracarotid catheterization was significantly greater in EP1+/+ (n = 3) than in EP1–/– (n = 4) mice infused with Ang II. *P < 0.05. (F) Expression of EP1 receptor mRNA in microdissected mouse mesenteric arteries and aortic tissue. Lack of RT was utilized as a negative control and β-actin served as RNA loading control. (G) Reduced constriction of Ang II on in vitro mesenteric arteriolar rings following pretreatment with the EP1 receptor antagonist SC51322. n = 7 per group. (H) Reduced Ang II constriction of preglomerular arterioles following treatment with EP1 receptor antagonist SC51322 (1 μM). n = 7 per group. *P < 0.005.