Novel dual action AT1 and ETA receptor antagonists reduce blood pressure in experimental hypertension.
Angiotensin II and endothelin-1 activate their respective AT(1) and ET(A) receptors on vascular smooth muscle cells, producing vasoconstriction, and both peptides are implicated in the pathogenesis of essential hypertension. Angiotensin II potentiates the production of endothelin, and conversely endothelin augments the synthesis of angiotensin II. Both AT(1) and ET(A) receptor antagonists lower blood pressure in hypertensive patients; thus, a combination AT(1)/ET(A) receptor antagonist may have greater efficacy and broader utility compared with each drug alone. By rational drug design a biphenyl ET(A) receptor blocker was modified to acquire AT(1) receptor antagonism. These compounds (C and D) decreased Sar-Ile-Angiotensin II binding to AT(1) receptors and endothelin-1 binding to ET(A) receptors, and compound C inhibited angiotensin II- and endothelin-1-mediated Ca(2+) transients. In rats compounds C and D reduced blood pressure elevations caused by intravenous infusion of angiotensin II or big endothelin-1. Compound C decreased blood pressure in Na(+)-depleted spontaneously hypertensive rats and in rats with mineralocorticoid hypertension. Compound D was more efficacious than AT(1) receptor antagonists at reducing blood pressure in spontaneously hypertensive rats, and its superiority was likely due to its partial blockade of ET(A) receptors. Therefore compounds C and D are novel agents for treating a broad spectrum of patients with essential hypertension and other cardiovascular diseases.
Kowala
Mark C
MC
Department of Metabolic and Cardiovascular Drug Discovery 025-289, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. mark.kowala@pfizer.com
Murugesan
Natesan
N
Tellew
John
J
Carlson
Kenneth
K
Monshizadegan
Hossain
H
Ryan
Carol
C
Gu
Zhengxiang
Z
Kane
Bridgette
B
Fadnis
Leena
L
Baska
Rose Ann
RA
Beyer
Sophie
S
Arthur
Susan
S
Dickinson
Kenneth
K
Zhang
Donglu
D
Perrone
Mark
M
Ferrer
Pam
P
Giancarli
Mary
M
Baumann
Jergen
J
Bird
Eileen
E
Panchal
Balkrushna
B
Yang
Yifan
Y
Trippodo
Nick
N
Barrish
Joel
J
Macor
John E
JE
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D000077405:Irbesartan; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D010080:Oxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D065130:Endothelin A Receptor Antagonists; D010080:Oxazoles; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D013777:Tetrazoles; D003900:Desoxycorticosterone; D012964:Sodium; D000077405:Irbesartan; D019808:Losartan; D002118:Calcium