Disease relevance of brimonidine

• After overnight incubation with pertussis toxin, inhibition by UK-14,304 and Oxo-M was much reduced [1].
• PURPOSE: To examine the neuroprotective effect of the alpha(2)-adrenergic agonist brimonidine in a chronic ocular hypertension model [2].
• METHODS: According to a 4 x 4 Latin squares design for repeated measures, 27 untreated patients and patients with newly diagnosed primary open-angle glaucoma (POAG) were treated with timolol 0.5% at 8 AM and 8 PM; brimonidine 0.2% at 8 AM and 8 PM; dorzolamide 2% at 8 AM, 2 PM, and 8 PM; and latanoprost 0.005% at 8 PM [3].
• When administered shortly after ischemia (up to 2 hours) AGN 190342 rescued substantial proportions of RGCs destined to die and diminished slow RGC death [4].
• Brimonidine reduced the progressive loss of ganglion cells to 26% +/- 1% and 15% +/- 2% at doses of 0.5 and 1 mg/kg. d, respectively [2].

Psychiatry related information on brimonidine

• The full agonist [3H]bromoxidine (UK 14304) was used to quantitate alpha 2-adrenoceptors in postmortem brains of patients with Alzheimer's disease [5].
• Vomiting was stimulated by apomorphine or UK-14304, and motor activities of striated and smooth muscles were recorded by electromyography and strain-gauge transducers, respectively [6].

High impact information on brimonidine

• Second, the large contraction-induced attenuation in sympathetic vasoconstriction elicited by nerve stimulation or UK 14,304 was partially reversed when the physiologic activation of KATP channels produced by muscle contraction was prevented with glibenclamide [7].
• The pharmacological properties of action potential-evoked NE release paralleled those of N-type Ca2+ channels: Release was completely blocked by Cd2+ or omega-conotoxin GVIA, reduced 50% by 10 microM NE or 62% by 2 microM UK-14,304, an alpha2-adrenergic agonist, and reduced 63% by 10 microM oxotremorine M (Oxo-M), a muscarinic agonist [1].
• However, when extracellular Ca2+ was removed in the presence of UK 14304, [Ca2+]i and MLC phosphorylation fell to resting levels, but force remained significantly elevated above basal levels [8].
• In the previously denuded arteries with regenerated endothelium, the endothelium-dependent relaxations to UK 14304 (a selective alpha 2-adrenergic agonist), serotonin, and aggregating platelets were impaired 4 weeks after endothelium removal and remained so throughout the study [9].
• Systemic intravenous UK-14304, a highly selective alpha 2-adrenoceptor agonist, produced a precipitous, neurogenic vasodilation that lowered vascular resistance below the subsequently denervated resistance, thus indicating that an active vasodilation was involved [10].

Chemical compound and disease context of brimonidine

• Activation of p70s6k by UK 14304 and by LPA, but not by platelet-derived growth factor (PDGF), was blocked by preincubation of cells with pertussis toxin [11].
• Basal lipolysis, maximal lipolytic responses to isoprenaline (beta-AR agonist), dobutamine and procaterol (beta1- and beta2-AR agonists, respectively) as well as maximal antilipolytic effects of epinephrine or UK-14304 (alpha2-AR agonist) were similar before and after weight reduction [12].
• In whole-cell patch-clamp recordings, bradykinin reduced voltage-activated Ca2+ currents in a pertussis toxin-insensitive manner, and this action was additive to the inhibition by UK 14304 [13].
• Three-month comparison of brimonidine and latanoprost as adjunctive therapy in glaucoma and ocular hypertension patients uncontrolled on beta-blockers: tolerance and peak intraocular pressure lowering [14].
• Rilmenidine (30-1000 micrograms kg-1 i.v.) and UK 14304 (1-30 micrograms kg-1 i.v.) elicited the same pattern of changes: transient hypertension followed by prolonged hypotension, bradycardia, a depression of sympathetic nerve firing and a fall in the plasma norepinephrine concentration [15].

Biological context of brimonidine

• With the influence of the central nervous system isolated from the systemic circulation, the direct peripheral vascular effects of two specific, chemically distinct alpha 2-adrenergic receptor agonists, UK 14,304 and B-HT 920, were investigated in 19 dogs on total cardiopulmonary bypass with constant arterial perfusion and central venous pressure [16].
• CONCLUSIONS: Reduction of the formation of aqueous humor in the ciliary body's epithelium (and thus an intraocular pressure decrease) after alpha(2)-adrenergic receptor stimulation by brimonidine is known to be associated with a G(i)-protein-mediated inhibition of adenylylcyclase activity [17].
• PURPOSE: To compare the short-term effects of timolol 0.5%, brimonidine 0.2%, dorzolamide 2%, and latanoprost 0.005% on intraocular pressure (IOP), blood pressure (BP), and diastolic ocular perfusion pressure (DOPP), calculated as the difference between the diastolic blood pressure (DBP) and IOP [3].
• However, epinephrine only partially competed for the 3H-labeled UK 14304 and [3H]idazoxan, suggesting that these imidazolinic radioligands labeled not only alpha 2-adrenoceptors but also nonadrenergic binding sites [18].
• However, the alpha(2)-adrenergic sensitivity, defined as the dose of UK-14304 that produced half-maximal inhibition of lipolysis (IC(50)), was significantly different between groups (P < 0.0001) [19].

Anatomical context of brimonidine

• In the present study, we measured intracellular Ca2+ ([Ca2+]i), myosin light chain (MLC) phosphorylation, and myofilament Ca2+ sensitivity during stimulation with the relatively selective alpha 2-agonist UK 14304 [8].
• The alpha 2-adrenergic agonist UK 14304 stimulated high affinity GTPase activity in membranes from these cells [20].
• The incubation of intact HT29 cells for 30 min in the presence of 10(-5) M benextramine irreversibly blocked more than 95% of the alpha 2-adrenoceptors and totally suppressed the inhibitory effect of UK-14,304 on cyclic AMP production [21].
• In spontaneously hypertensive rats, the inhibitory effect of UK 14,304 and neuropeptide Y on norepinephrine release from the medulla oblongata was significantly less than in age-matched Wistar-Kyoto rats [22].
• In the present study, the neuroprotective activity of the alpha2-adrenoreceptor agonists brimonidine, AGN 191103, and clonidine were examined in an animal model that simulates secondary neuronal degeneration of the optic nerve in a way thought to be independent of elevation of intraocular pressure [23].

Associations of brimonidine with other chemical compounds

• Activation of p70s6k by both UK 14304 and LPA was accompanied by increased phosphorylation of the protein [11].
• Deprivation for glucose or glutamine also impeded the recovery process; by contrast, addition of UK-14,304 or clonidine did not interfere, indicating that the expression of the alpha 2-adrenoceptor is not subject to homologous regulation in the HT29 cell [21].
• Preincubation of human platelet membranes with the full alpha 2-agonist UK 14,304 in the absence of GTP increases the potency of the agonist to inhibit adenylate cyclase in a pre-steady state (15-sec) assay [24].
• The antinociceptive effects of both UK-14,304 and guanfacine were blocked by intraperitoneal injections of yohimbine, a result indicating that both drugs induced their actions by activating alpha 2-adrenoceptors [25].
• The specific alpha 2-agonist UK-14,304 reduced cAMP accumulation (maximum 43% reduction) and inhibited melatonin release (EC50 = 19 nM) in the presence of 3 X 10(-8) M VIP [26].

Gene context of brimonidine

• CONCLUSIONS: Brimonidine appears to maintain BCL-2 levels by supporting the activity of an intrinsic anti-apoptosis signalling system that involves phosphorylation of protein kinase B. Phosphorylated protein kinase B appears to counteract the apoptosis signalling mechanisms which operate in glaucomatous retina [27].
• The preferential R alpha-2A/H alpha-2A AR antagonist, [2-(2H-(1-methyl-1, 3-dihydroisoindole)methyl)-4, 5-dihydro-imidazole (BRL 44408), enhanced hippocampal synthesis of NA and blocked the antinociceptive and motor effects of UK 14,304, xylazine, guanfacine and guanabenz [28].
• The effects on alpha(i2)-mRNA were accompanied by a parallel, albeit weaker effect on the protein level (only GIP and UK 14,304 were investigated) [29].
• The changes in alpha(i2)-mRNA levels by either compound were paralleled by inverse changes in insulin secretion: preincubation with UK 14,304 for 8 h led to an increased insulin secretion when challenged by either GLP-1, GIP or glucose (8.3 mM) [29].
• DESIGN: Prospective longitudinal follow-up of serial visual fields in patients enrolled onto an open-label, nonrandomized pilot study of topical brimonidine purite as prophylactic treatment after first eye involvement in LHON [30].

Analytical, diagnostic and therapeutic context of brimonidine

• However, constrictor responses to UK 14,304, a selective alpha2-AR agonist, were increased in SSc compared with control arterioles (maximal constriction responses of 25+/-5% and 67+/-4% [mean +/- SEM] in control and SSc arterioles, respectively; P = 0.000014) [31].
• Five-minute intra-arterial infusions of UK 14,304 (200 micrograms/min) resulted in increased arterial resistance (mean arterial pressure increased 18 +/- 4 [SEM] mm Hg; p less than 0.01) and a decrease in systemic vascular capacity (81 +/- 20 ml; p less than 0.01) [16].
• Moreover, after treatment with 100 microg/kg brimonidine administered intraperitoneally, the loss of retinal ganglion cells 2 weeks after injury was three times lower than in saline-treated animals [23].
• The antinociceptive actions of intrathecal injections of two alpha 2-adrenergic agonists, UK-14,304 and guanfacine, were investigated in rats after pretreatment of the animals with the noradrenaline neurotoxin N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4) 14 days in advance [25].
• The intradermal injections of norepinephrine, phenylephrine and brimonidine produced little evoked pain [32].

References