Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

The effects of bradykinin and the bradykinin B(2) receptor antagonists D-Arg-[Hyp(3),Thi(5,8),D-Phe(7)]-bradykinin (NPC 349) and D-Arg-[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-bradykinin (Hoe 140) were examined in the electrically-stimulated rat vas deferens. Cumulative additions of bradykinin (1-3000 nM) produced two distinct responses: an enhancement in the magnitude of the basal electrically-induced twitch response (neurogenic response) and an increase in the baseline tension (musculotropic response). NPC 349 (10-100 microM) produced concentration-dependent surmountable rightward shifts of both the bradykinin neurogenic and musculotropic response curves. In contrast, while Hoe 140 (10-100 nM) caused an apparently surmountable antagonism of the bradykinin neurogenic response, it caused an apparent insurmountable antagonism of the bradykinin musculotropic response. Interestingly, co-incubation of Hoe 140 (30 nM) with NPC 349 (30 and 100 microM) resulted in a concentration-related upwards displacement of the Hoe 140-suppressed bradykinin musculotropic response curve. Thus, Hoe 140 can be described as a pseudo-irreversible antagonist against the bradykinin musculotropic response. No time-dependent changes were observed in the maximum bradykinin musculotropic response attainable when NPC 349 (100 microM) additions were made for the final 2 or 18 min of the Hoe 140 incubation (20 min). These findings indicate that slow reversibility of Hoe 140 from the bradykinin B(2) receptor is unlikely to be the mechanism responsible for the pseudo-irreversible antagonism of the bradykinin-induced musculotropic response. Instead, we propose an alternative explanation involving a third, unstable and inactive form of the bradykinin B(2) receptor.

Type

Journal article

Journal

Eur J Pharmacol

Publication Date

09/06/2000

Volume

398

Pages

131 - 138

Keywords

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, Angiotensin II, Animals, Bradykinin, Bradykinin Receptor Antagonists, Dose-Response Relationship, Drug, Electric Stimulation, In Vitro Techniques, Male, Muscle Contraction, Muscle, Smooth, Norepinephrine, Rats, Rats, Wistar, Vas Deferens