The	Journal	of	Clinical	Investigation	 	 	 http://www.jci.org	 	 	 Volume 117	 	 	 Number 9	 	 	 September 2007
Antihypertensive effects of selective
prostaglandin E2 receptor subtype 1 targeting
Youfei Guan,1,2 Yahua Zhang,1 Jing Wu,2 Zhonghua Qi,1 Guangrui Yang,2 Dou Dou,2
Yuansheng Gao,2 Lihong Chen,2 Xiaoyan Zhang,2 Linda S. Davis,1 Mingfeng Wei,2 Xuefeng Fan,1
Monica Carmosino,1 Chuanming Hao,1 John D. Imig,3 Richard M. Breyer,4 and Matthew D. Breyer1,5
1Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
2Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, People’s Republic of China.
3Department of Physiology, Medical College of Georgia, Augusta, Georgia, USA. 4Department of Pharmacology and
5Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
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	uncharacter-
ized.	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	pr