Effects of the non‐peptide B₂ antagonist FR173657 on kinin‐induced smooth muscle contraction and relaxation, vasoconstriction and prostaglandin release

Abstract

1 The non-peptide bradykinin (BK) antagonist (E)-3-(6-acetamido-3-pyridyl)-N-[N- [2,4-dichloro-3-[(2-methyl-8-quinolinyl)oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide (FR173657) was tested in intestinal, uterine, tracheal and vascular in vitro preparations. The investigation aimed at determining the antagonistic potency, duration of action, speci®city for BK receptors and apparent mode of antagonistic action of FR173657. 2 Contractions of the isolated ileum of the guinea-pig in response to BK were inhibited by FR173657 (10 ± 300 nM) in a concentration-dependent manner. The inhibition lasted for up to 90 min after washout of FR173657. Cumulative concentration-response curves to BK were shifted to the right with a concomitant decrease in the maximum eect. A pK B value of 8.7 was determined. FR173657 had no eect on contractions induced by acetylcholine, histamine, 5-hydroxytryptamine, substance P, angiotensin II or caerulein. 3 The concentration-response curves for B 2 receptor-mediated relaxations of the rat isolated duodenum induced by BK were shifted to the right together with a concomitant reduction of the maximum BK eect in the presence of FR173657 (10 ± 300 nM). A pK B of 9.0+0.2 was calculated. FR173657 had no eect on B 1 receptor-mediated relaxations in response to des-Arg 9 -BK. 4 The concentration-response curves for BK-induced contractions of the rat isolated uterus were shifted to the right by FR173657 (3 ± 300 nM) in a concentration-dependent and parallel manner. The Schild plot for the inhibition caused by FR173657 had a slope of 70.98 indicating a competitive mode of antagonism. A pA 2 value of 9.1 was determined. 5 Contractions of the circular smooth muscles of the guinea-pig isolated trachea in response to BK were concentration-dependently inhibited by FR173657 (10 ± 100 nM). An anity estimate of 9.3 was calculated for FR173657. Contractions induced by acetylcholine and relaxations in response to isoprenaline remained completely unaected by FR173657. 6 In the rabbit isolated perfused ear, BK (0.01 ± 10 nmol) produced a dose-dependent vasoconstriction. In the presence of 30 nM FR173657, the eects of BK were reduced by at least 60%, while FR173657 completely abolished the eects of all BK doses at 300 nM. FR173657 did not aect vasoconstriction induced by noradrenaline or angiotensin II. 7 The arterial injection of BK (10 nmol) into the rabbit isolated perfused ear caused an approximately three fold increase in the release of the prostaglandins E 2 and I 2 into the venous euent. The BKstimulated prostaglandin release was completely abolished in the presence of FR173657 (300 nM) while the basal prostaglandin release was unchanged. 8 In summary, FR173657 was shown to be a highly potent and selective BK antagonist which was active on B 2 , but not B 1 , receptors. FR173657 was a competitive antagonist in the rat uterus but showed a deviation from competitive inhibition in the other preparations studied similar to other second generation peptide antagonists. The inhibitory action in vitro was lo...

Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment

“…These kinins induce smooth muscle cell relaxation and increase vasopermeability resulting in the characteristic and submucosal swellings as seen in hereditary and acquired C1-INH dependent angioedema (12). The importance of BK in the pathogenesis of the subcutaneous and submucosal swellings is illustrated by the following findings: First, increased levels of BK can be measured in patients suffering from a C1INH-HAE/AAE attack as compared to steady state (13,14); second, C1-INH-HAE patients with unilateral edema of extremities had significantly increased BK concentration in the affected extremity as compared to the non-affected extremity, respectively (14); third, blockage of BKreceptor 2 abrogates the vasoeffective effects of BK and prevented angioedema (15,16) and fourth, mice lacking BK-receptor 2 (BKR2) as well as C1-Inh do not have evidence for increased vascular permeability, whereas C1-Inh deficient mice with normal BKR2 suffer from increased vascular permeability (17). Although LysBK can increase vasopermeability and can be measured in circulation, the contribution of LysBK and its desArg forms in the pathogenesis of C1-INH-dependent angioedema is not clear (18).…”

Pharmacological characterisation of the first non-peptide bradykinin B2 receptor agonist FR 190997: an in vitro study on human, rabbit and pig vascular B2 receptors

“…It is an analogue of FR 173657, the first non-peptide B 2 receptor antagonist that has shown high potency and specificity to the human B 2 receptor Gessi et al 1997;Inamura et al 1997;Rizzi et al 1997a), and to B 2 receptors of other species (Griesbacher et al 1997;Inamura et al 1997;Rizzi et al 1997b).…”

Pharmacological Characterization Of Bradykinin B1 and B2 Receptors In IMR-90 and INT-407 Human Cell Lines Using A Microphysiometer

“…With particular relevance to the present study, there is a report demonstrating that, when IMR-90 cells are cultured in the presence of 10% serum, bradykinin B1 and B2 receptors are present in the ratio 1 : 14. 12,21,22 The conflicting reports do not appear to be species related because this antagonist has been shown to be both competitive and non-competitive in various rat tissues 12,21 and in guinea-pig ileum. 14 It is possible that, in the present study, the expression of bradykinin B1 receptors was so low that any bradykinin B1 receptor-mediated acidification response was undetectable using a microphysiometer, even after stimulation with LPS, which is known to induce the expression of bradykinin B1 receptors.…”