Disease relevance of Efaroxan

• The alpha2-adrenoceptor antagonist 2-methoxyidazoxan partially reversed the hypotension and renal sympathetic nerve activity inhibition due to alpha-methylnoradrenaline when it was administered into the rostral ventrolateral medulla, whereas the mixed alpha2-adrenoceptor/imidazoline receptor antagonists, idazoxan and efaroxan, did not [1].
• Interleukin (IL)-1beta toxicity to islet beta cells: Efaroxan exerts a complete protection [2].
• Efaroxan and 2-Ml reversed the hypotension and bradycardia induced by a single dose of all three agents dose-dependently [3].
• Efaroxan, an alpha-2 antagonist, in the treatment of progressive supranuclear palsy [4].
• Intracisternal BU 224 and 2-BFI, selective I2 ligands, also inhibited the epinephrine-induced arrhythmias dose-dependently; however, these effects were abolished by efaroxan [5].

High impact information on Efaroxan

• Administration of 100 micromol/l phentolamine was somewhat more effective than 100 micromol/l efaroxan to inhibit KATP channel activity in intact cultured beta-cells (reduction by 96 vs. 83%) [6].
• In support of this, we now show that efaroxan can induce functional changes in the secretory pathway of pancreatic beta-cells that are independent of KATP channel blockade [7].
• This response has been attributed to efaroxan-mediated blockade of KATP channels, with the subsequent gating of voltage-sensitive calcium channels [7].
• Desensitization of the imidazoline receptor following exposure to high concentrations of efaroxan, however, was found to result in an increase in SUR1 protein expression and, as a consequence, an upregulation of K(ATP) channel density [8].
• KATP channels were blocked by efaroxan (IC50 8.8 micromol/l, Hill slope -1.1) and by KU14R (IC50 31.9 micromol/l, Hill slope -1.5) [9].

Chemical compound and disease context of Efaroxan

• By contrast, 2-MI was more effective at reversing the clonidine-induced hypotension than was efaroxan (P < .001), suggesting that clonidine acts mainly via alpha 2 adrenoceptors in conscious normotensive rabbits [10].
• The alpha 2 adrenoceptor antagonist effect of efaroxan was compared with 2-MI by performing cumulative dose-response curves in the presence of alpha-methyldopa (400 micrograms/kg i.c.). 2-MI was 5.6 times more potent than efaroxan at reversing 75% of the hypotension elicited by alpha-methyldopa (P < .025) [10].
• Efaroxan, idazoxan, or SKF 86466 alone reduced the threshold dose of ouabain necessary to induce cardiac arrhythmia as a sign for arrhythmogenic effects [11].
• 4) The putative imidazoline (I1) antagonist, efaroxan, injected icvt into the anterior lateral ventricle, inhibited significantly the ocular hypotension produced by icvt MOX, icvt OXY, and unilateral topical OXY [12].

Biological context of Efaroxan

• Central administration of efaroxan on day 9 and day 23 of treatment produced a greater increase in blood pressure than did 2-MI with all three antihypertensive agents [13].
• 4. Comparison of the effects of S-21663 to that of efaroxan, another imidazoline compound shown to act on insulin release in a glucose-dependent way via binding sites distinct from the imidazoline I1 and I2 sites, suggested that S-21663 acts through a novel site which displays a remarkably stable expression along the cell culture [14].
• Culture with 100 microM BTS 67 582 or 100 microM tolbutamide did not affect basal insulin secretion, cellular insulin content, or cell viability and exerted no influence on the secretory responsiveness to 200 microM of the imidazoline, efaroxan [15].
• Topically and intracisternally administered naphazoline was examined for its ability to alter intraocular pressure (IOP) of rabbits in the absence and presence of receptor antagonists (rauwolscine, efaroxan) and a G(i/o)ribosylating agent PTX [16].
• Furthermore, the efaroxan-induced insulin release or vasoconstriction was not affected by the blockade of alpha 2- and alpha 1-adrenoceptors [17].

Anatomical context of Efaroxan

• Interleukin (IL)-1beta-treated rat islets of Langerhans were exposed in vitro either to the imidazoline compound, Efaroxan, or to the selective inducible nitric oxide synthase (iNOS) inhibitor, 1400W, in a medium containing a high concentration of glucose (16.7 mmol/L) [2].
• We found high affinities for unlabeled p-iodoclonidine (subnanomolar), clonidine (0.2 nM), and efaroxan (11 nM), but idazoxan did not compete significantly for the p-[125I]iodoclonidine binding in these membranes [18].
• Metabolic inhibition of intact B-cells by 250muM NaCN, most likely by a decrease of the ATP/ADP ratio, significantly diminished the K(ATP) channel-blocking effect of a low concentration of alinidine (10muM), whereas efaroxan proved to be susceptible even at a highly effective concentration (100muM) [19].
• Sensitive and specific methods for the determination of efaroxan and idazoxan in blood plasma have been developed based on solvent extraction, chromatographic separation and quantification by selected-ion monitoring using a quadruple mass-selective detector [20].
• These effects were dose-dependent, and were significantly reversed by efaroxan (an I1-imidazoline and alpha2-adrenergic blocker) administered via the vertebral artery [21].

Associations of Efaroxan with other chemical compounds

• Essential role of the imidazoline moiety in the insulinotropic effect but not the KATP channel-blocking effect of imidazolines; a comparison of the effects of efaroxan and its imidazole analogue, KU14R [9].
• The action of moxonidine on ERK activation was blocked by the I1-receptor antagonist efaroxan and by D609, an inhibitor of phosphatidylcholine-selective phospholipase C (PC-PLC), previously implicated as the initial event in I1-receptor signaling [22].
• Antagonism of the stimulatory effects of efaroxan and glibenclamide in rat pancreatic islets by the imidazoline, RX801080 [23].
• The antagonism between K(ATP) channel-blocking insulinotropic imidazolines - phentolamine, alinidine, idazoxan and efaroxan - and K(ATP) channel openers, diazoxide and nucleoside diphosphates, was studied in mouse pancreatic islets and B-cells [19].
• SK&F 86466 and efaroxan both antagonized moxonidine-induced inhibition of SP-elicited behavior in all mouse lines [24].

Gene context of Efaroxan

• Moxonidine-induced induction of MKP-2 was time- and dose-dependent and could be blocked by the I(1)-antagonist efaroxan or by D609, an inhibitor of phosphatidylcholine-selective phospholipase C known to block downstream signaling events coupled to I(1)-receptors [25].
• Identification of the monomeric G-protein, Rhes, as an efaroxan-regulated protein in the pancreatic beta-cell [26].
• Cells treated with rilmenidine or moxonidine showed an increased level of extracellular signal-regulated kinase (ERK) phosphorylation in a concentration-dependent manner, which could be reversed by efaroxan or D609, a selective PC-PLC inhibitor [27].
• Neither efaroxan nor rauwolscine alone has any significant effects on ANP secretion and pulse pressure [28].
• The alpha2-adrenergic ligand efaroxan was found to block [3H]rauwolscine binding to the alpha2-adrenergic receptor without significantly affecting binding to the 5-HT2B receptor and was therefore included in all subsequent studies [29].

Analytical, diagnostic and therapeutic context of Efaroxan

• We have employed an amino derivative of the imidazoline ligand, efaroxan, to isolate imidazoline binding proteins from solubilised extracts of rat brain, by affinity chromatography [30].
• Systemic administration of efaroxan, a mixed alpha(2)-adrenoceptor/I(1)-imidazoline antagonist or vagotomy failed to modify the harmane effect [31].
• Determination of underivatised efaroxan and idazoxan in blood plasma by capillary gas chromatography with mass-selective detection [20].
• Prior bilateral microinjections of efaroxan (10 nmol in 80 nl/site) into the RVLM prevented the hypotensive action of moxonidine given i.v. (40 micrograms/kg) [32].
• The separation of the two enantiomers of a basic drug (efaroxan) was achieved by high performance liquid chromatography using an amylose-derivated column with both UV and CD detections [33].

References