Disease relevance of Icatibant

• In renovascular models of hypertension associated with a stimulated renin-angiotensin system (two-kidney, one-clip), blood pressure reduction by ACE inhibitors was attenuated by icatibant, whereas in rats with genetic hypertension with normal to low plasma renin, blood pressure reduction through ACE inhibitors was not affected [1].
• In rats pretreated with saralasin, Ang-(1-7) induced hypotension at 80 and 380 nmol (deltaMAP: -7.7+/-2.3 and -9.5+/-2.7, respectively; P<.05), whereas icatibant abolished this response [2].
• RESULTS: Antigen challenge caused a significant increase in nasal obstruction and albumin extravasation, which was not affected by icatibant [3].
• Role of kinins in seasonal allergic rhinitis: icatibant, a bradykinin B2 receptor antagonist, abolishes the hyperresponsiveness and nasal eosinophilia induced by antigen [3].
• Glomerular and perivascular fibrosis were unaffected by either ramipril or MDL alone; however, combined treatment with icatibant enhanced glomerular fibrosis (P = 0.0001 versus placebo) [4].

High impact information on Icatibant

• The antiischemic effect of ACE inhibitors and BK were abolished by the addition of L-NNA (1 x 10(-6) mol/l) or icatibant (1 x 10(-9) mol/l) [1].
• Removal of endothelium or treatment with icatibant and L-NAME abolished these AT2-mediated effects [5].
• Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant [6].
• Chronic blockade of B2-receptors by Icatibant (50 nmol/100 g body wt twice a day S.C.) or inhibition of nitric oxide synthase by nitro-L-arginine-methyl ester (0.14 mmol/100 g body wt orally) increased the blood pressure of Bk2r+/+ to the levels of Bk2r-/- mice [7].
• METHODS AND RESULTS: Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant [8].

Chemical compound and disease context of Icatibant

• RESULTS: The development of hypertension and tubulo-interstitial fibrosis was prevented by both ramipril and MDL (P = 0.0001 versus placebo); icatibant annulled the latter effect [4].
• In separate sets of experiments RPC was performed with or without pretreatment with HOE140, a selective B(2)-antagonist or hexamethonium was used to explore the influence of ganglion blockade on RPC [9].
• 4. The bradykinin B2 receptor antagonist icatibant (5 pmol) blocked the development of both SP and capsaicin-induced hyperalgesia [10].
• RESULTS: FR173657 inhibited oedema formation and tissue enzyme retention during pancreatitis at 500 nmol/kg and above after peroral administration, and from 30 nmol/kg after s.c. injection; icatibant was effective at 3 nmol/kg s. c. Protein extravasation in both cystitis models was abolished by s.c. FR173657 at 300 nmol/kg [11].
• Effects of a bradykinin receptor antagonist (HOE140) on taurocholate-induced acute pancreatitis in rats [12].

Biological context of Icatibant

• The recombinantly expressed chicken receptor had IC50 values of 4.7 nM for the authentic ligand, ornithokinin ([Thr6,Leu8]bradykinin), 3.8 nM for HOE140, and >/=10 microM for bradykinin, [des-Arg9]bradykinin, and [des-Arg9,Leu8]bradykinin [13].
• Our results provide direct biochemical evidence that the binding site for the agonist BK in the bovine B2 receptor is adjacent to a cysteine and is differentiated from the binding site(s) for the antagonists NPC17731 and HOE140 [14].
• The protective effect of kallikrein on apoptosis and its signaling mediators was blocked by icatibant and dominant-negative Akt, indicating a kinin B2 receptor-Akt-mediated event [15].
• The B2 receptor antagonist HOE140 and the B1 receptor agonist des-Arg9-bradykinin failed to induce significant phosphorylation of the B2 receptor [16].
• The binding of the agonist bradykinin to the B(2) receptor endogenously expressed on PC-12 cells led to the formation of receptor dimers, whereas the B(2) antagonist HOE140 did not induce dimerization, suggesting that B(2) receptor dimerization was linked to receptor activation [17].

Anatomical context of Icatibant

• Icatibant also reduced the antigen-induced increase in eosinophils, eosinophil cationic protein, kinin, and IL-8 in nasal lavage fluid [3].
• Other variables indicating a systemic inflammatory response (C-reactive protein, leukocyte neutral proteinase inhibitor) remained unaffected by Icatibant [18].
• The respective K(i) values of 0.32, 1.37 and 156 nM were obtained for bradykinin, HOE140 and D-Arg[Hyp3,D-Phe7,Leu8]bradykinin competing for radioligand binding to lamina II of sheep spinal cord sections [19].
• Intranasal (i.n.) administration of MEN16132 (0.01-0.3 nmol/nostril) reduced, in a dose-dependent and long-lasting manner, the nasal mucosa plasma protein extravasation induced by BK (100 nmol/nostril), and it exerted a complete inhibition at about 30-fold lower dose than icatibant [20].
• BK homologous curves performed with lung membranes after treatment with the antagonist MEN16132 or Icatibant (10 nM) displayed only the low affinity site [21].

Associations of Icatibant with other chemical compounds

• Kinins contribute to the cardioprotective effects associated with ischemic preconditioning because preconditioning or BK-induced antiarrhythmic and infarct size-limiting effects are attenuated by icatibant [22].
• Coadministration of icatibant attenuated the mean arterial blood pressure response to perindoprilat (P<0.0005) but had no effect on neurohormonal responses to perindoprilat [23].
• A second aim was to determine whether Icatibant, a selective bradykinin B2-receptor antagonist, prevented the blood pressure changes induced by acute captopril administration in Swiss, c57/B16, J129 Sv and Bk2r-/- mice [24].
• 5. Blood pressure reflexes following i.p. instillation of bradykinin in anaesthetized rats were inhibited by FR173657 s.c. with an ID50 of 1.1 micromol kg(-1), while the peptidic B2 antagonist icatibant (Hoe-140; D-Arg0-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) caused inhibition at significantly lower doses (ID50 8.5 nmol kg(-1) P < 0.001) [25].
• FR190997 and relaxin 3 responses at the hB(2)R and hGPR100, respectively, were not inhibited by Icatibant (1 microM) [26].

Gene context of Icatibant

• After gene delivery, human kallikrein mRNA was identified at the injured vessel and a 3-fold increase occurred in kininogenase activity. cAMP and cGMP levels in balloon-injured aorta increased significantly at 4, 7, and 14 days after kallikrein gene delivery, but icatibant abolished the increase [27].
• Treatment of SaM-1 cells with BK increased the synthesis of both IL-6 and PGE(2) and the increase in both was blocked by HOE140 (B2R antagonist), but not by Des-Arg(9)-[Leu(8)]-BK (B1R antagonist) [28].
• The expression of COX-2 induced by BK in DRG cells was inhibited by a BK B2 receptor antagonist, HOE140, but not a B1 receptor antagonist, Lys-des-Arg9, (Leu8)-BK [29].
• Preincubation of hepatoma cells for 1 h with interleukin-1 alpha (IL-1 alpha) alone reduced T-kininogen concentrations by 37%, and this effect was blocked by co-addition of HOE140 [30].
• The effect was blocked by a B2 receptor antagonist (HOE140) and specific inhibitors of VEGF receptor tyrosine kinases (Tki) and NOS [31].

Analytical, diagnostic and therapeutic context of Icatibant

• Prevention with icatibant of anaphylactoid reactions to ACE inhibitor during LDL apheresis [32].
• Covalent coupling of the receptor to bradykinin or HOE140, followed by Western blotting and immunoprinting with specific anti-ligand antibodies confirmed that the major ligand-binding form of the receptor is of 69 kDa [33].
• Anaphylactoid reactions during hemodialysis were completely prevented by icatibant even after pre-treatment with ENA and in the presence of high BK concentrations [34].
• These protective effects of Z13752A during ischaemia and reperfusion were abolished by the administration of icatibant (0.3 mg kg(-1), i.v.) a selective antagonist of bradykinin at B(2) receptors; the ischaemic changes in dogs given both icatibant and Z13752A were similar to those in the controls [35].
• A KAL antibody or HOE140 (kinin B(2)-receptor antagonist) completely abolished this beneficial effect of IPC (36.6 and 53.0 U l(-1)) when added to the perfusion medium during the reperfusion cycles of IPC prior to the 30 min ischaemia [36].

References