Hoe 140 a new potent and long acting bradykinin-antagonist: in vivo studies.
1. The potency, duration of action and tolerability of Hoe 140, a novel and highly potent bradykinin (BK) antagonist in vitro, has been tested in different in vivo models and compared with the well-known BK antagonist D-Arg-[Hyp2, Thi5,8, D-Phe7]BK. 2. Hoe 140 is highly potent and long acting in inhibiting BK-induced hypotensive responses in the rat. Four hours after s.c. administration of 20 nmol kg-1, inhibition still amounted to 60% whereas the effect of 200 nmol kg-1 of D-Arg-[Hyp2, Thi5,8, D-Phe7]BK was not significant. 3. BK-induced bronchoconstriction in guinea-pigs was strongly inhibited by Hoe 140. The magnitude and duration of inhibition confirmed the findings obtained in the blood pressure experiments in the rat. 4. Carrageenin-induced inflammatory oedema of the rat paw was considerably inhibited at i.v. doses between 0.1 and 1 mg kg-1. 5. In conscious dogs, intravenous doses of 0.01 and 0.1 mg kg-1 of Hoe 140 and D-Arg-[Hyp2, Thi5,8, D-Phe7]BK were well tolerated. At doses of 1 mg kg-1 adverse effects occurred that were attributed to the residual BK agonistic activity of both compounds. 6. Hoe 140 has been shown to be a highly potent and long acting BK antagonist in vivo in different animal species and models. This makes it appropriate to investigate further the physiological and pathophysiological role of BK.
Hoechst AG, Pharmaceutical Division, PGU Heart Circulation, Frankfurt, F.R.G.
K
K
Wirth
F J
FJ
Hock
U
U
Albus
W
W
Linz
H G
HG
Alpermann
H
H
Anagnostopoulos
S
S
Henk
G
G
Breipohl
W
W
König
J
J
Knolle
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D004285:Dogs; D004487:Edema / Q000517:prevention & control; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
C065679:icatibant; D001920:Bradykinin