(Hypertension. 1999;33:823-829.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Kinin B1 Receptor Antagonists Containing 
-Methyl-L-Phenylalanine: In Vitro and In Vivo Antagonistic Activities
From the Department of Pharmacology, Medical School, Université de Sherbrooke, Sherbrooke (Québec), Canada.
Correspondence to Dr Fernand Gobeil Jr, Department of Pharmacology, Medical School, Université de Sherbrooke, 3001 12th Ave North, Sherbrooke (Québec) J1H 5N4, Canada. E-mail fgobei01{at}courrier.usherb.ca
Abstract—To protect from
metabolism and to improve potency of the
AcLys-[D-ßNal7,Ile8]desArg9-bradykinin
(BK) (R 715), we prepared and tested 3 analogues containing
-methyl-L-Phe ([Me]Phe) in position 5:
these are the
AcLys-[(Me)Phe5,D-ßNal7,Ile8]desArg9BK
(R 892),
Lys-Lys-[(Me)Phe5,D-ßNal7,Ile8]desArg9BK
(R 913), and
AcLys-Lys-[(Me)Phe5,D-ßNal7,Ile8]desArg9BK
(R 914). The new compounds were tested against the contractile effect
induced by desArg9BK on 2 B1 receptor
bioassays, the human umbilical vein, and the rabbit aorta. Their
antagonistic activities were compared with those of the
early prototypes (Lys-[Leu8]desArg9BK and
[Leu8]desArg9BK) and with other recently
described peptide antagonists. The 3 (Me)Phe
analogues showed high antagonistic potencies
(pA2) at both the human (8.8, 7.7, and 8.7, respectively)
and rabbit (8.6, 7.8, and 8.6, respectively) B1 receptors.
No antagonistic effects (pA2<5) were observed
on the B2 receptors that mediate the contractile effects of
BK on the human umbilical vein, the rabbit jugular vein, and the guinea
pig ileum. Moreover, these new B1 antagonists
were found to be resistant to in vitro degradation by purified
angiotensin-converting enzyme from rabbit lung. The
N-acetylated forms, R 892 and R 914, were
resistant to aminopeptidases from human plasma.
In vivo antagonistic potencies (ID50) of
B1 receptor antagonists were evaluated in
anesthetized lipopolysaccharide-treated (for
B1 receptor) and nontreated (for B2 receptor)
rabbits against the hypotensive effects of exogenous
desArg9BK and BK. R 892 efficiently inhibited
(ID50 2.8 nmol/kg IV) hypotension induced by
desArg9BK without affecting that evoked by BK
(ID50 >600 nmol/kg IV). Conversely, the peptide
antagonists
Lys-Lys-[Hyp3,Igl5,D-Igl7,Oic8]desArg9BK
(B 9858) and
DArg-[Hyp3,Thi5,D-Tic7,Oic8]
desArg9BK (S 0765) showed dual
B1/B2 receptor antagonism in vitro and in vivo.
It is concluded that R 892 and congeners provide selective, highly
potent, and metabolically stable B1 kinin
receptor antagonists that can be useful for the assessment
of the physiological and pathological roles of
kinin B1 receptors.
Key Words: receptors, bradykinin • human • rabbit • bioassay • antagonists
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