New, long‐acting, potent bradykinin antagonists

1 Vasodepressor responses to intravenous (i.v.) injection of bradykinin (BK) and des-Arg9-BK, a selective B, kinin receptor agonist, were characterized following i.v. pretreatment with selective B, ([Leu8]-des-Arg9-BK) and B2 (Hoe 140) kinin receptor antagonists in anaesthetized dogs. 2 Des-Arg9-BK (0.05-3.3 nmol kg-') produced dose-dependent decreases in mean arterial blood pressure with a ED_0 0.4 nmol kg-'. The vasodepressor effects evoked by des-Arg9-BK (0.6 nmol kg-') and BK (0.2 nmol kg-') were greater after i.v. and i.a. injections, respectively. 3 The vasodepressor response to BK (0.6 nmol kg-') but not to des-Arg9-BK (0.6 nmol kg-') was significantly (P<0.001) blocked by pretreatment with the B2 receptor antagonist, Hoe 140. 4 The vasodepressor response to des-Arg9-BK (0.6 nmol kg-') but not to BK (0.6 nmol kg-') was significantly (P<0.001) reduced by pretreatment with the selective B, receptor antagonist, [Leu8]-desArg9-BK. Although both B, and B2 receptor antagonists caused a transient fall in blood pressure, their inhibitory action was unlikely to be related to a desensitization mechanism. 5 Inhibition of prostaglandin synthesis with indomethacin prevented the vasodepressor response induced by arachidonic acid (1 mg kg-', i.v.) but not that to BK or des-Arg9-BK (0.6 nmol kg-').6 These results suggest, firstly, that the vasodepressor responses to i.v. BK and des-Arg9-BK are mediated by the activation of B2 and B, receptors, respectively; secondly, that prostaglandins are not involved in the vasodepressor responses to kinins. These findings provide pharmacological evidence for the existence of functionally active B, receptors in canine cardiovascular homeostasis.

Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Mediation by B₁ and B₂ receptors of vasodepressor responses to intravenously administered kinins in anaesthetized dogs

Nakhostine

Ribuot

Lamontagne

et al. 1993

“…In radiogland binding studies D-Arg-[Hyp3,Thi5,D-Tic7,0ic8]BK (Hoe 140) was reported to displace BK with a K, value of 8 x 101°M . In isolated tissue assays, Hoe 140 antagonized the action of BK at the BK2-receptor with pA2 values ranging from 9.3 in the rat uterus to 8.1 in the guinea-pig ileum (Lembeck et al, 1991;Hock et al, 1991). The compound was reported to be devoid of activity at the BK1 receptor .…”

Section: Introductdonmentioning

confidence: 99%

Differential sensitivity of antinociceptive assays to the bradykinin antagonist Hoe 140

Heapy

Shaw

Farmer

1993

“…Icatibant has been shown to be inactive against a great variety of mediators including angiotensin II, noradrenaline, histamine, acetylcholine, 5-hydroxytryptamine, substance P and neurokinin A (Lembeck et al, 1991;Wirth et al, 1991;Damas & Remacle-Volon, 1992;Rhaleb et al, 1992). Since icatibant does not inhibit the action of des-Arg9-BK at the B1 receptor Rhaleb et al, 1992), the present results point towards an involvement of B2, but not B. receptors in collagenase-induced paw oedema.…”

Section: Discussionmentioning

confidence: 52%

“…For reasons of clarity only the first 30 min after the collagenase injection are given in the graph; thereafter, until the end of the observation period, the difference in the sensitivity scores for rats pretreated with icatibant and for control rats remained unchanged (*P <0.02 mammalian collagenases in their mode of action (Hatheway, 1990). Clostridial collagenases act on all known types of collagen and can cleave native triple helical collagen into small fragments, mostly tripeptides, whereas mammalian collagenases are specific for certain types of collagen and often cleave only one protein bond in a polypeptide chain of triple helical collagen, resulting in two polypeptide fragments (Han et al, 1992 (Lembeck et al, 1991) or Hoe-140 Wirth et al, 1991)], caused a pronounced reduction of the collagenaseinduced paw oedema and of plasma protein extravasation. In addition, icatibant abolished the increase in sensitivity scores in a behaviour test after subplantar injection of collagenase in unanaesthetized rats.…”

Section: Discussionmentioning

confidence: 99%

Mediation by bradykinin of rat paw oedema induced by collagenase from Clostridium histolyticum

Legat

Griesbacher

Lembeck

1994

Self Cite

1 Collagenases are thought to play a major role in the pathology of gas gangrene caused by Clostridium histolyticum, because they can destroy the connective tissue barriers. We investigated possible mediators involved in the oedema formation and plasma protein extravasation which follow the injection of a collagenase (EC 3.4.24.3) from Clostridium histolyticum into one hind paw of anaesthetized rats. 2 The magnitude of the oedema following a subplantar injection was dependent on the dose of collagenase (30, 100 and 300 Lg) injected. It reached its maximum within 30 min and remained unchanged for at least 5 h. Plasma protein extravasation into the paw was most pronounced within 20min of the injection. Heat-inactivated collagenase was ineffective. named Hoe-140) reduced oedema formation in a dose-dependent manner with a maximal reduction of around 65% at a dose of 100 nmol kg-' (s.c.). A significant effect could already be observed at a dose of 10 nmol kg-. The duration of the effect of icatibant (100 nmol kg-1) was found to be at least 3 h. These results demonstrate the high potency and long duration of action of icatibant. Pretreatment of rats with the bradykinin B, antagonist, des-Arg9-[Leu8]-BK did not affect collagenase-induced paw oedema. Thus, the observed collagenase-induced effects are mainly mediated by BK through activation of B2 receptors. 4 Pretreatment of adult rats with capsaicin (125 mg kg-', s.c.) three weeks before the collagenase injection caused a significant attenuation of the paw oedema and of plasma extravasation but was significantly less effective than icatibant (100 nmol kg-', s.c.). The non-peptide substance P antagonist, CP-96,345 (10 ltmol kg', i.v.) significantly reduced collagenase-induced oedema formation to a degree comparable with that seen after capsaicin pretreatment. The inhibition by the substance P antagonist was significantly smaller than that seen after icatibant. The inhibitory effect of icatibant in capsaicinpretreated rats, or of icatibant together with CP-96,345 in untreated rats, was not greater than that of significantly reduced the bradykinin-induced paw oedema. These findings indicate that collagenase leads to the release of bradykinin; bradykinin then stimulates afferent C-fibre terminals and causes the release of substance P and probably also neurokinin A, which augment the oedema-inducing effect of bradykinin. 5 Indomethacin or mepyramine plus cimetidine failed to inhibit collagenase-induced paw oedema. Thus, prostaglandins and histamine do not seem to be involved in collagenase-induced paw oedema. 6 After subplantar injection of collagenase, the sensitivity scores in a modified formalin-test rapidly increased during the first 10 min. This increase was abolished by pretreatment with icatibant (100 nmol kg '-, s.c.) indicating that the stimulation of nociceptive afferent neurones following injection of collagenase is due to the action of released kinins.7 In conclusion, bradykinin appears to be the main mediator of inflammation induced by a collagenase from Clost...