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.
Wirth
K
K
Hoechst AG, Pharmaceutical Division, PGU Heart Circulation, Frankfurt, F.R.G.
Hock
F J
FJ
Albus
U
U
Linz
W
W
Alpermann
H G
HG
Anagnostopoulos
H
H
Henk
S
S
Breipohl
G
G
König
W
W
Knolle
J
J
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