We investigated the effect of bradykinin (BK) on isolated equine basilar arterial rings with and without endothelium. BK induced concentration‐dependent contraction of resting arterial rings and no relaxation when the rings were precontracted by prostaglandin F2α. The maximal response and pD2 value were 161.2 ± 28.1% (to 60 mm KCl‐induced contraction) and 8.24 ± 0.25 respectively. The cumulative concentration–response curve for BK was not shifted to the right by des‐Arg9‐[Leu8]‐BK (a B1‐receptor antagonist), HOE140 (a B2‐receptor antagonist) or NPC567 (another B2‐receptor antagonist). In four of six basilar arteries, NPC567 induced concentration‐dependent contraction. Indomethacin (a cyclooxygenase inhibitor), nordihydroguaiaretic acid (a lipoxygenase inhibitor), quinacrine (a phospholipase A2 inhibitor), tetrodotoxin (a selective blocker of Na+ channels), guanethidine (a nor‐adrenergic neuron blocking drug), phentolamine (an α‐adrenoceptor antagonist), Nω‐nitro‐l‐arginine (l‐NNA, a nitric oxide (NO) synthase inhibitor) and endothelial denudation did not affect the BK‐induced contraction. l‐NNA and indomethacin induced contraction and relaxation under resting vascular tone respectively. These results suggest that endothelial cells are not involved in BK‐induced contraction and that the contraction is not mediated via activation of known B1 and B2 receptors. Arachidonic acid metabolites and neurotransmitters like norepinephrine and NO might not play a role in BK‐induced contraction in equine basilar artery.

01 Jun 2002·Acta Physiologica Scandinavica

Bradykinin is not involved in angiotensin converting enzyme modulation of ovarian steroidogenesis and prostaglandin production in frog Rana esculenta

Article

Author: Luana Quassinti ; Domenico Amici ; Antonino Miano ; Massimo Bramucci ; Anna Gobbetti ; Ennio Maccari ; Oretta Murri ; Massimo Zerani

ABSTRACTAngiotensin converting enzyme (ACE) was demonstrated to modulate the production of 17β‐estradiol, progesterone and prostaglandin E2 (PGE2) in frog ovary of Rana esculenta. However, the activity was not mediated by angiotensin II (Ang II). In an attempt to identify the peptide involved in the pathway modulated by ACE, bradykinin, another physiological substrate of ACE, was chosen and incubated in the presence of the membrane suspension purified from the frog ovary homogenate. The hydrolytic products were analysed by reverse‐phase high‐pressure liquid chromatography (HPLC) analysis and the results showed that bradykinin was metabolized by membrane suspension. The presence of the protease inhibitors in the incubation mixture indicated ACE and neutral endopeptidase as being responsible for the bradykinin hydrolysis. Frog ovary was incubated in vitro in the presence of bradykinin (10 μM), bradykinin receptor antagonist NPC 567 (1 mg mL–1), bradykinin fragment (1–7) (10 μM), ACE (2.5 mU mL–1), captopril (0.1 mM) and lisinopril (0.1 mM). The results showed no modulating activity by bradykinin on ovarian 17β‐estradiol and PGE2 production, thus demonstrating that it was not involved in the ACE‐modulated pathway.

01 Jan 2002·Folia Pharmacologica Japonica

Bradykinin antagonist: Current status and perspective.

Review

Author: Hirayama, Yoshitaka ; Kayakiri, Hiroshi

The kallikrein-kinin system plays an important role in many physiological and pathophysiological conditions such as homeostasis of circulation, inflammation/allergy, pain, shock, etc. Two types of kinin receptor are known, bradykinin (BK) B1 receptor and BK B2 receptor. B2 receptors are constitutively expressed and mediate most physiological actions of kinins, whereas B1 receptors are highly inducible upon inflammatory stimulation or tissue injury, suggesting that they are involved in inflammation and/or nociception. Only three peptide type B2 antagonists, NPC 567, CP-0127 and HOE-140, have been evaluated in clinical studies so far, and some beneficial effects of B2 antagonists have been shown for rhinitis, asthma, systemic inflammatory response syndrome/sepsis and brain injury. However, the results were less convincing than expected. Now several potent and orally active nonpeptide B2-receptor antagonists have been found, which are expected to overcome the weak point of the peptide type antagonists and clarify the therapeutic potential of the B2-receptor antagonist for novel indications as well as those mentioned above. As for B1 receptors, no antagonist has been tested in a clinical trial. The important role of B1 receptors is just being elucidated by use of peptide type antagonists or B1 receptor gene knockout mice. The further development of newer B1 antagonists and clinical evaluation is desired.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	US	Scios, Inc.	-
Asthma	Phase 2	-	Scios Pharma	-
Asthma	Phase 2	GB	GSK Plc	-

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