Disease relevance of 4-aminopyridine

• These effects of high [Ca2+]o were mimicked by exposure of the preparations to low [Na+]o. Electrical homogeneity was restored and arrhythmias were abolished after addition of the Ito blocker 4-aminopyridine 1 mmol/L [1].
• A highly significant correlation was demonstrated between the amplitude of the epicardial action potential notch and the amplitude of the J wave recorded during interventions that alter the appearance of the electrocardiographic J wave, including hypothermia, premature stimulation, and block of the transient outward current by 4-aminopyridine [2].
• 4-Aminopyridine in multiple sclerosis [3].
• However, subjective side effects such as paresthesias, dizziness, and light-headedness were frequently reported during 4-aminopyridine treatment [4].
• That the conduction block was due to demyelination was indicated by slowing of conduction in large diameter fibres, normal conduction in unmyelinated fibres and the specific effects of temperature and of the potassium channel blocking agent, 4-aminopyridine [5].

Psychiatry related information on 4-aminopyridine

• Effects of 4-aminopyridine in elderly patients with Alzheimer's disease [6].
• AR-R 15896AR prevented tonic seizures in rodents for up to 6 to 8 h in response to maximal electroshock (MES), 4-aminopyridine, bicuculline, or strychnine, as well as characteristic seizures following injections of N-methyl-DL-aspartic or kainic acids [7].
• Two distinct outward potassium currents could be identified: a transient 4-aminopyridine-sensitive current (Ia) and a persistent outward current sensitive to tetraethylammonium (Id) [8].
• Classical conditioning the rabbit nictitating membrane involves changes in synaptic and intrinsic membrane properties of cerebellar Purkinje cell dendrites, and a 4-aminopyridine (4-AP)-sensitive potassium channel underlies these membrane properties [9].
• Atropine- and tetrodotoxin-resistant motor activity, responsive to 4-aminopyridine, present in isolated rabbit jejunum [10].

High impact information on 4-aminopyridine

• This excitatory response was recorded in morphologically identified interneurons in the presence of 4-aminopyridine or after elevation of extracellular potassium concentrations [11].
• Manipulations that blocked Kv4.2 A-type K(+) channels, including a dominant-negative Kv4.2 construct and 4-aminopyridine, increased the amplitude of plateau potentials by allowing them to recruit neighboring dendrites [12].
• Oxygen-induced constriction of rabbit ductus arteriosus occurs via inhibition of a 4-aminopyridine-, voltage-sensitive potassium channel [13].
• Here we characterize the effects of the pharmacological blocker 4-aminopyridine on both the K+ and gating currents of wild-type and mutant Shaker K+ channels [14].
• The six animals that received 4-aminopyridine survived the verapamil intoxication, whereas four of the six animals in the control group died [15].

Chemical compound and disease context of 4-aminopyridine

• Intracoronary flecainide induces ST alternans and reentrant arrhythmia on intact canine heart: A role of 4-aminopyridine-sensitive current [16].
• Electrical homogeneity was restored and arrhythmias abolished after washout of pinacidil or addition of either a transient outward current blocker, 4-aminopyridine, or a blocker of the ATP-regulated potassium channels, glybenclamide [17].
• 4. Tetraethylammonium (20 mM), and 4-aminopyridine (1 mM) reduced the outward current to 54 +/- 7 and 66 +/- 3% of control, respectively, but basal nerve activity was unchanged and the nerve response to hypoxia remained intact [18].
• 3. The changes induced by hyperglycaemic hypoxia in low bicarbonate could be mimicked by exposure of the roots either to 100% CO2 or to a combination of 3 mM tetraethylammonium chloride and 3 mM 4-aminopyridine, to block both fast and slow potassium channels [19].
• INTERVENTIONS: Nonresponders to treatment with 4-aminopyridine (14 patients) were treated with 3,4-diaminopyridine in a 4-week, open-label trial with doses up to 1.0 mg/kg of body weight (before-after design) [20].

Biological context of 4-aminopyridine

• We use 4-aminopyridine (4-AP) to increase the number of transmitter quanta discharged with each nerve impulse, and show that the number of exocytotic vesicles caught by quick-freezing increases commensurately, indicating that one vesicle undergoes exocytosis for each quantum that is discharged [21].
• As expected from their inhibition of the A-current, acetylcholine and 4-aminopyridine both increased the amplitude of the action potential and prolonged its duration [22].
• This current was highly sensitive to 4-aminopyridine (IC50, 74 microM) [23].
• The 4-aminopyridine sensitive transient outward current exhibited slow recovery kinetics compared to those of the other or calcium current, and its inhibition caused elimination of the augmented plateau during electrical restitution [24].
• Administration of 4-aminopyridine (4-AP, 100 microM) at concentrations that selectively depress IAs, reduced outward rectification of spiny neurons at subthreshold membrane potentials [25].

Anatomical context of 4-aminopyridine

• Frog cutaneous pectoris nerve-muscle preparations were soaked in modified Ringer's solution with 1 mM 4-aminopyridine, 10 mM Ca2+, and 10(-4) M d-Tubocurarine and quick-frozen 1-10 ms after a single supramaximal shock [26].
• The sequence of structural changes that occur during synaptic vesicle exocytosis was studied by quick-freezing muscles at different intervals after stimulating their nerves, in the presence of 4-aminopyridine to increase the number of transmitter quanta released by each stimulus [27].
• Only when intoxicated nerves were stimulated in 4-aminopyridine (which grossly exaggerates calcium currents in normal nerves) or when they were soaked in black widow spider venom (which is a nerve-specific calcium ionophore) could nerve mitochondria be induced to swell and accumulate calcium [28].
• METHODS AND RESULTS: We used whole-cell voltage-clamp techniques to study 4-aminopyridine (4-AP)-sensitive voltage-dependent transient outward currents (Ito1) in Purkinje myocytes isolated from LV subendocardial (n = 14) and free-running (n = 15) bundles of the normal canine heart [29].
• In isolated pulmonary arteries, 4-aminopyridine significantly inhibited NO-induced relaxation [30].

Associations of 4-aminopyridine with other chemical compounds

• Blockage of the Ca2+-dependent K+ channel in Na+-free (replaced by Tris) solutions containing 6.8 mM Ca2+ and tetraethylammonium ion or 4-aminopyridine (to block the voltage-dependent K+ current) is seen as a further prolongation of the Ca2+ action potential and diminution of the after-hyperpolarization [31].
• Binding was inhibited by the neuromuscular blockers gallamine and tubocurarine and by the K+ channel blockers quinidine and tetraethylammonium chloride but not by 4-aminopyridine, in agreement with known pharmacological profile for inhibition of apamin-sensitive K+ permeability [32].
• By contrast, adenosine did not reduce the duration of the action potential in the presence of 500 microM 4-aminopyridine (4-AP) [33].
• Two potassium channel blockers, 4-aminopyridine (AP) and 3,4 diaminopyridine (DAP) have been tested in patients with MS [34].
• 4) The K+ ionophore valinomycin, which increases K+ efflux, slightly enhanced IgE-mediated histamine release when used alone, whereas it potentiated the release of histamine from leukocytes previously treated with 4-aminopyridine by 57.0 +/- 18.6% (n = 7) [35].

Gene context of 4-aminopyridine

• In mature adults, selective elimination of IA either with Shaker (Sh) mutations or with 4-aminopyridine (4-AP), had no effect on spike duration or on the delay in excitation [36].
• 4-Aminopyridine-induced epileptogenesis depends on activation of mitogen-activated protein kinase ERK [37].
• Here, we studied the activation state of ERK1/2 in rat hippocampal slices during application of the K(+) channel blocker 4-aminopyridine (4AP, 50 micro m), a procedure that enhances synaptic transmission and leads to the appearance of epileptiform activity [37].
• Furthermore, ST-induced apoptotic cell shrinkage was significantly accelerated in COS-7 cells and rat PASMC transfected with KCNA5, and blockade of KCNA5 channels with 4-aminopyridine (4-AP) reduced K+ currents through KCNA5 channels and inhibited ST-induced apoptosis in KCNA5-transfected COS-7 cells [38].
• Since connexin36 expression levels change after seizures, we examined the expression of both pannexin1 and connexin36 in cerebral cortex, hippocampus, cerebellum and brain stem at different time intervals (2, 4 and 8 h) after i.p. injection of 4-aminopyridine, which resulted in systemic seizures [39].

Analytical, diagnostic and therapeutic context of 4-aminopyridine

• Verapamil caused profound cardiovascular depression and also partial neuromuscular block, both of which were completely reversed by 4-aminopyridine within 50 min, in spite of extremely high serum verapamil concentrations (ranging between 3,700 and 13,500 ng/ml) [15].
• Using whole-cell voltage clamp techniques, we determined that the voltage-dependent, Ca(2+)-independent, 4-aminopyridine-sensitive transient outward current (ito1) occurred in all NZs (n = 16) but existed in only 37% of IZs (n = 16) [40].
• When 4-aminopyridine (5 mM) was added to the perfusion medium, it consistently increased CRF-IR release (4.83 +/- 0.92 fmol/50 microliters, p < 0.05) [41].
• Twelve temperature-sensitive male patients with multiple sclerosis and 5 normal men were monitored before, during, and after the intravenous injection of 7 to 35 mg of 4-aminopyridine (4-AP) in 1- to 5-mg doses, every 10 to 60 minutes [42].
• The effect of 4-aminopyridine on clinical signs in multiple sclerosis: a randomized, placebo-controlled, double-blind, cross-over study [4].

References