Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting.
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.
Guan
Youfei
Y
Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. youfeiguan@bjmu.edu.cn
Zhang
Yahua
Y
Wu
Jing
J
Qi
Zhonghua
Z
Yang
Guangrui
G
Dou
Dou
D
Gao
Yuansheng
Y
Chen
Lihong
L
Zhang
Xiaoyan
X
Davis
Linda S
LS
Wei
Mingfeng
M
Fan
Xuefeng
X
Carmosino
Monica
M
Hao
Chuanming
C
Imig
John D
JD
Breyer
Richard M
RM
Breyer
Matthew D
MD
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000187:drug effects; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype
C545636:Ptger1 protein, mouse; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D000804:Angiotensin II; C061570:protein kinase N; D011493:Protein Kinase C; D015232:Dinoprostone
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