Effects of the bradykinin antagonist B4310 on smooth muscles and blood pressure in the rat, and its enzymatic degradation.
1. Six competitive bradykinin (Bk) antagonists were tested for their agonistic properties on the rat uterus. Five of these peptides showed agonistic effects only at concentrations at least two orders of magnitude higher than those of bradykinin. 2. The antagonistic potency of Lys-Lys-3-Hyp-5,8-Thi-7-DPhe-Bk (B4310) in the rat uterus (pA2 = 7.24) and in the rat duodenum (pA2 = 7.31) was very similar to that determined in an earlier study for the antagonism of the bradykinin-induced stimulation of the trigeminal nerve in the rabbit iris sphincter muscle preparation (pA2 = 7.59). 3. The fall in mean arterial blood pressure induced by i.a. injections of bradykinin was greatly reduced during an i.a. infusion of B4310, but not 10 min thereafter, which indicates a rapid inactivation of B4310 in vivo. Bacitracin possibly interferes with the enzymatic cleavage of B4310 but seems to have no effect on the degradation of bradykinin. 4. An i.a. infusion of captopril greatly enhanced the potency of bradykinin in inducing a fall in arterial blood pressure, confirming the important role of angiotensin converting enzyme in the cleavage of bradykinin. However, the design of this experiment did not allow conclusions about the effect of captopril on the degradation of B4310. 5. B4310 incubated with rat lung tissue disappeared from the incubation medium within a few minutes, i.e. as fast as bradykinin, which explains its short duration of action in vivo. Captopril partially inhibited the cleavage of both bradykinin and B4310. 6. The present results show that the bradykinin antagonists available at present are useful tools for the investigation of the biological role of bradykinin. However, the susceptibility to enzymatic degradation may limit their usefulness in animal experiments or in clinical studies.
Griesbacher
T
T
Department of Experimental & Clinical Pharmacology, University of Graz, Austria.
Lembeck
F
F
Saria
A
A
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000037:antagonists & inhibitors*; D002216:Captopril / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004054:Diethylstilbestrol / Q000494:pharmacology; D004386:Duodenum / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D007609:Kallidin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D014599:Uterus / Q000187:drug effects
C059832:B 4310; D007609:Kallidin; D004054:Diethylstilbestrol; D002216:Captopril; D001920:Bradykinin