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.