Disease relevance of Icatibant

• Bradykinin was released, and the bradykinin receptor antagonist HOE-140 blocked the effects of iberiotoxin on coronary hemodynamic and metabolic parameters during myocardial ischemia [1].
• However, when HOE 140 was administered during the initial reflow period following 5 minutes of ischemia, protection was no longer abolished (15.6 +/- 3.9% infarction versus 13.3 +/- 3.8% without HOE 140, P = NS) [2].
• Because neither enalaprilat nor HOE 140 affected these changes, the enhanced overflow of cGMP and 6-ketoprostaglandin F1 alpha is likely to reflect the actions of other hypersensitivity mediators (eg, histamine and leukotrienes) [3].
• In the ascitic form of S-180, i.p. administration of HOE 140 at 13 microg/kg/12 h initiated immediately after tumor inoculation significantly suppressed formation of S-180 tumor ascites; the life span of ascitic S-180 tumor-bearing mice was prolonged at the same dose of HOE 140 [4].
• In HOE/ENAL, pretreatment with HOE 140 prevented the decrease in albuminuria observed in ENAL [5].

High impact information on Icatibant

• DABK-induced leukocyte trafficking was antagonized by the B(1) receptor antagonist des-arg(10)HOE 140 but not by the B(2) receptor antagonist HOE 140 [6].
• The presence of captopril, an inhibitor of bradykinin degradation by kininase II, drastically potentiated parasitic invasion of HUVECs and CHO-B(2)R, but not of mock-transfected CHO cells, whereas the B(2)R antagonist HOE 140 or monoclonal antibody MBK3 to bradykinin blocked these effects [7].
• HOE 140 led to an increase in coronary vascular resistance (P < .001) and a decrease in coronary blood flow (P < .001) [8].
• Mean arterial pressure was reduced by ramipril compared with the control group (-8 +/- 2 versus +7 +/- 2 mm Hg, P = .03), and this effect was not blunted by the addition of HOE 140 (-7 +/- 3 mm Hg) [9].
• After bradykinin B2 receptor blockade, there was a reduction in flow-dependent dilation (23.4 +/- 6.9% to 3.9 +/- 6.0%, P < .001), the extent of which correlated with the degree of basal vasoconstriction after HOE 140 in the same vessel segment (P < .05) [8].

Chemical compound and disease context of Icatibant

• To evaluate the role of bradykinin in the antihypertrophic effect of the angiotensin-converting enzyme (ACE) inhibitor, ramipril, we investigated the influence of HOE 140, a specific B2-receptor antagonist, on the effects of ramipril on left ventricular hypertrophy (LVH) in rats with aortic banding [10].
• On the other hand, B2 receptor antagonist (HOE 140) and ACE-I (captopril) were only able to control the urinary diabetic proteinuria [11].
• LPS induced thermal and mechanical hyperalgesia which was reversed by i.c.v. HOE 140 and indomethacin i.c.v. and i.v., but not by B1 receptor antagonists [12].
• The potentiation was mimicked by [Hyp3]-bradykinin and inhibited by HOE-140, pertussis toxin, neomycin and U-73122, but not U-73433 [13].
• Using this model, we carried out a study on the preventive effect of Icatibant, a bradykinin B2 receptor antagonist previously called HOE 140, on the development of colitis [14].

Biological context of Icatibant

• The B2 bradykinin receptor antagonist HOE 140 and the B1 bradykinin receptor antagonist des-Arg9[Leu8]bradykinin displaced the binding of [3H]bradykinin from dog membranes with IC50 values of 0.38 and 217.3 nmol/l, respectively, suggesting that bradykinin binds to a B2-type receptor [15].
• Pretreatment with HOE 140 reversed the protective anti-inflammatory and antilethality effects provided by the B(1)R(-/-) phenotype [16].
• However, neither the endothelin A antagonist BQ123 nor the kinin B2 antagonist HOE 140 had an effect on basal blood pressure or altered the pressor or heart rate effects of the neprilysin inhibitors [17].
• However, after HOE 140, cold-air inhalation did not affect baseline airway tone [18].
• In all 3 cases, pretreatment with HOE-140 (2.5 microg IV) fully prevented the inhibition of ANP excretory action, ruling out osmotic effects as the cause of reduced diuresis [19].

Anatomical context of Icatibant

• Interestingly, the peptidic HOE 140 compound and an original nonpeptidic compound LF 16 0335, which both behaved as inverse agonists of the wild-type receptor expressed in COS-7 cells, became potent and efficient agonists of the two constitutively activated mutant N113A and W256F receptors [20].
• Following administration of HOE 140, functional hyperaemia in the soleus muscle was unaffected (blood flow, 17.8 +/- 2.2 ml min-1 (100 g tissue)-1, n = 6; n.s.) white blood flow in the gastrocnemius muscle was reduced to 21.8 +/- 6.0 ml min-1 (100 g tissue)-1 (n = 6; P < 0.05) [21].
• D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]bradykinin (HOE-140) is a potent (Ki = 0.11 nM) inhibitor of [3H]bradykinin binding to bradykinin B2 receptors found on human IMR-90 fetal lung fibroblasts [22].
• The B2 antagonist, HOE-140, was a very weak inhibitor of the B1 response in human ileum and inactive in rabbit aorta [23].
• 3. HOE-140 (1 microg kg(-1)) administered in the same manner, decreased mononuclear cell and eosinophil infiltration in the bronchoalveolar lavage fluid (BALF) of OA-sensitized mice [24].

Associations of Icatibant with other chemical compounds

• Moreover, enalaprilat (1 mumol/L) completely and immediately restored the response of the B2 receptor, desensitized by the agonist (1 mumol/L [Hyp3-Tyr(Me)8]BK); this effect was blocked by the antagonist, HOE 140 [25].
• The extravasation of the Evans blue dye evoked by OVA (5%, 2 min) in sensitized guinea pigs was reduced by HOE 140 (45%) when the animals were perfused after 5 min and by 39% when perfusion was performed at 10 min [26].
• The increase in RL induced by cold air after L-NAME was abolished by the tachykinin NK2-receptor antagonist SR 48968 or the kinin B2-receptor antagonist, HOE 140 [18].
• In contrast, N(G)-nitro-l-arginine methyl ester (10 mg/kg and 0.1 mg. kg(-1). min(-1) iv) and the bradykinin B(2)-receptor antagonist HOE-140 (20 microg/kg and 10 microg x kg(-1) x min(-1) iv) markedly lowered the medullary vasodilation at the highest doses of ANG II only [27].
• Topically applied BK (3 micromol/l) induced vasodilation (62 +/- 12%) after the administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) and indomethacin, which was inhibited by endothelial impairment or by the BK(2) receptor antagonist HOE-140 (0.3 micromol/l) [28].

Gene context of Icatibant

• The increases in IL-6 protein and total mRNA were inhibited by the selective B(2) receptor antagonist HOE-140 but not by the selective B(1) receptor antagonist desArg(9)(Leu(8))-BK [29].
• HOE-140 markedly inhibited the rise in IL-1beta and TNF-alpha levels in pouch fluid triggered by both stimuli [30].
• Ligand efficacy of synthetic ligand HOE 140 decreased in the order B(o)R > CKR-2 > CKR-1 > B(2)R, whereas the efficacy of the endogenous kinin ligand was unchanged [31].
• The stimulatory effect of BK on the IL-1beta- or TNFalpha-stimulated IL-8 production was reduced in the presence of BK B2 receptor antagonist HOE 140, whereas the B1 receptor antagonist Lys-(des-arg9, Leu8)-BK had no effect [32].
• The BK response was decreased (5.09 +/- 0.30, N = 6 to 1.57 +/- 0.12, N = 7, P < 0.001) by the B2 receptor antagonist HOE 140 (0.1 microM, 15 min), while the B1 receptor antagonist des-Arg9-[Leu8]-BK (1 microM, 15 min) had no effect on BK or des-Arg10-Kal actions [33].

Analytical, diagnostic and therapeutic context of Icatibant

• HOE 140 could not block the protection of ischemic preconditioning in isolated hearts [2].
• When the preconditioning stimulus in the in situ model was amplified with four cycles of 5-minute ischemia/10-minute reperfusion, HOE 140 pretreatment could no longer block protection (infarct size was 10.7 +/- 3.5% versus 6.4 +/- 2.0% without HOE 140, P = NS) [2].
• When HOE 140 was administered s.c. at a dose of 13 microg/kg/12 h for 2 weeks after tumor inoculation, growth of the solid tumor was also suppressed by 32%, by tumor weight [4].
• Spectrofluorometry using fura-2-AM revealed that 100 nM BK elicited a significant increase in Ca(i), which was abolished by the receptor antagonist HOE-140 [34].
• Subsequent intraperitoneal infusion of bradykinin antagonist (HOE 140; 1 mg/kg per 24 h) for 2 wk did not affect BP (72 +/- 2 mmHg) or proteinuria (92 +/- 15 mg/24 h) [35].

References