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PubMed2026

Early infantile developmental and epileptic encephalopathy: clinical spectrum, diagnosis, outcomes, and evolving treatment strategies.

Early infantile developmental and epileptic encephalopathy (EIDEE) is among the most severe epilepsy syndromes, with onset before three months of age and an estimated incidence of approximately 10 per 100,000 live births. The 2022 International League Against Epilepsy classification unified the historically distinct Ohtahara syndrome and early myoclonic encephalopathy under a single diagnostic framework defined by frequent drug-resistant tonic and/or myoclonic seizures, an abnormal neurological examination, and an abnormal interictal electroencephalogram-most characteristically a burst-suppression pattern. This narrative review synthesizes the clinical, electrophysiological, neuroimaging, genetic, and therapeutic literature within the EIDEE framework. The clinical phenotype is characterized by central hypotonia, postnatal microcephaly, cortical visual impairment, and age-dependent syndromic evolution toward infantile epileptic spasms syndrome or Lennox-Gastaut syndrome in the majority of patients. Electroencephalography remains essential for syndromic classification, while systematic metabolic screening and early trio whole-exome or whole-genome sequencing are central to the etiologic workup, achieving diagnostic yields of 60-65%. The most commonly identified genetic causes include STXBP1, KCNQ2, and SCN2A variants. Outcomes are poor overall and strongly etiology-dependent: vitamin-responsive disorders carry a substantially more favorable prognosis, whereas mortality reaches 25% in genetic cohorts. Genotype-guided pharmacotherapy is now applicable to a clinically meaningful subset of patients, with sodium channel blockers, potassium channel openers, and emerging antisense oligonucleotide therapies representing important therapeutic advances. Gene therapy trials are underway but have encountered early safety signals, underscoring the vulnerability of this population. Critical unmet needs include earlier molecular diagnosis, precision therapies targeting developmental outcomes beyond seizure control, and prospective international registries to characterize the long-term natural history of EIDEE.

Humans↗
PubMed1996

[New features of pharmacologic treatment of erectile dysfunction].

OBJECTIVES: The present article summarizes the latest advancements in the physiology of erection, with special reference to the role of the adenylate and guanylate cyclase-nitric oxide system. METHODS/RESULTS: New aspects in the pharmacological intracavernous treatment of erectile dysfunction are discussed and new drugs in this field are analyzed, such as nitrovasodilators, calcium channel blocker, potassium channel openers, phosphodiesterase inhibitors and the combination of adenylate cyclase stimulators. CONCLUSIONS: A high percentage of patients with erectile dysfunction depends on intracavernous injection of vasoactive drugs for erection. However, this route of administration is painful and causes anxiety in many cases. Other routes of administration (oral, topical or intraurethral) have yet to be developed, as well as drugs that can diminish penile venous blood outflow in cases with venous leakage, and can enhance arterial blood supply at the same time. The combination of phosphodiesterase inhibitors with adenylate and/or guanylate cyclase stimulators or potassium channel openers may further enhance the results achieved to date.

Erectile Dysfunction↗
PubMed2006

A cation-pi interaction between extracellular TEA and an aromatic residue in potassium channels.

Open-channel blockers such as tetraethylammonium (TEA) have a long history as probes of the permeation pathway of ion channels. High affinity blockade by extracellular TEA requires the presence of an aromatic amino acid at a position that sits at the external entrance of the permeation pathway (residue 449 in the eukaryotic voltage-gated potassium channel Shaker). We investigated whether a cation-pi interaction between TEA and such an aromatic residue contributes to TEA block using the in vivo nonsense suppression method to incorporate a series of increasingly fluorinated Phe side chains at position 449. Fluorination, which is known to decrease the cation-pi binding ability of an aromatic ring, progressively increased the inhibitory constant K(i) for the TEA block of Shaker. A larger increase in K(i) was observed when the benzene ring of Phe449 was substituted by nonaromatic cyclohexane. These results support a strong cation-pi component to the TEA block. The data provide an empirical basis for choosing between Shaker models that are based on two classes of reported crystal structures for the bacterial channel KcsA, showing residue Tyr82 in orientations either compatible or incompatible with a cation-pi mechanism. We propose that the aromatic residue at this position in Shaker is favorably oriented for a cation-pi interaction with the permeation pathway. This choice is supported by high level ab initio calculations of the predicted effects of Phe modifications on TEA binding energy.

Amino Acid Sequence↗
PubMed1995

Protection against hypoxic injury of rat proximal tubules by felodipine via a calcium-independent mechanism.

Most evidence for a key role of calcium entry in hypoxia-induced renal damage stems from studies with calcium channel blockers. In proximal tubules, a primary site of renal ischaemic injury, only phenyl-alkylamines, especially verapamil, have been studied. In the present study the effect of the dihydropyridine felodipine on hypoxic injury in isolated rat proximal tubules was investigated. To discriminate between the block of calcium entry and other effects, the enantiomers and a non-calcium blocking derivative of felodipine (H186/86) were included. Cell membrane injury was assessed by measuring the release of lactate dehydrogenase (LDH). At high concentrations (100 microM) felodipine, H186/86 and the two enantiomers all protected rat proximal tubules against hypoxia-induced injury to the same extent. Absence of extracellular calcium did not offer protection, but rather enhanced hypoxic injury. All dihydropyridines used increased the intracellular potassium concentration during normoxia. Felodipine attenuated the hypoxia-induced loss of cellular potassium. We have tried to mimic the effects of felodipine by using potassium channel blockers. The potassium channel blockers quinidine and glibenclamide afforded some protection against hypoxic injury, although their effects on cellular potassium were equivocal. We conclude that the dihydropyridine calcium channel blocker felodipine protects rat proximal tubules against hypoxic injury via a calcium-independent mechanism. We propose that high levels of intracellular potassium and attenuation of potassium loss during hypoxia are important in this protection.

Animals↗
PubMed2005

Taicatoxin inhibits the calcium-dependent slow motility of mammalian outer hair cells.

The effects of taicatoxin on the slow motility of isolated outer hair cells of guinea pig were studied in the experiments. Pretreatment with taicatoxin (0.19 microM) was able to prevent both the cell shortening induced by high K(+) (50mM), and the cell elongation induced by ionomycin (10 microM). These effects of taicatoxin can be mimicked by pretreatment of cells with Ca(2+)-free medium on the slow motility in response to ionomycin or high K(+). Pretreatment with neither calcium channel blockers such as nifedipine (L-type blocker), omega-conotoxin GVIA (N-type blocker), and omega-agatoxin IVA (P-type blocker); nor potassium channel blockers, such as tetraethylammonium chloride (TEA) and 3,4-diaminopyridine (3,4-DAP) can antagonize the cell shortening effect induced by high K(+) and cell elongation induced by ionomycin. The calcium-imaging experiment indicated that taicatoxin, but not nifedipine, did prevent an increase of intracellular Ca(2+) level significantly induced by high K(+). These results demonstrate that the effect of taicatoxin was to block the calcium entry through calcium channels of cell membrane, without relative to its properties of potassium channel blockers. We conclude that taicatoxin-sensitive-calcium channels at least impart, play a significant role in the slow motility of outer hair cell.

Animals↗
PubMed2005

Effects of calcium channel blocker, mibefradil, and potassium channel opener, pinacidil, on the contractile response of mid-pregnant goat myometrium.

The present study was undertaken to investigate the in vitro influence of mibefradil, a calcium channel blocker, and pinacidil, a potassium channel opener, on pregnant goat myometrial spontaneous rhythmic contractility and contractions induced with the agonist, oxytocin. Longitudinal strips from the distal region of uterus, collected from goats at midgestation, were mounted in an organ bath for recording isometric contractions. Mibefradil (10(-8)-10(-4) M) or pinacidil (10(-10)-10(-4) M), added cumulatively to the bath at an increment of 1 log unit, caused concentration-dependent inhibition of the spontaneous rhythmic contractions of isolated uterine strips. The rhythmic contraction was, respectively, abolished at 100 and 10 microM concentrations of mibefradil and pinacidil. In a concentration-dependent manner, mibefradil (1 and 10 microM) antagonized the contractions elicited with oxytocin (10(-5)-10(-2) IU). Pretreatment of uterine strips with glibenclamide (10 microM), a selective KATP channel blocker, caused a rightward shift of the concentration-response curve of pinacidil with a concomitant decrease in its pD2 value. Pinacidil (0.3, 1 and 3 microM), in a concentration-related manner, antagonized the oxytocin (10(-5)-10(-2) IU)-induced contractile response. The inhibition of spontaneous rhythmic contractions and antagonism of oxytocin-induced contraction by mibefradil in the pregnant goat myometrium may be related to the antagonism of voltage-dependent Ca2+ channels, while by pinacidil suggests that KATP channel could be a therapeutic target for tocolysis.

Adenosine Triphosphate↗
PubMed1994

Perturbation of ion channel conductance alters the hypnotic response to the alpha 2-adrenergic agonist dexmedetomidine in the locus coeruleus of the rat.

BACKGROUND: The alpha 2-adrenergic agonists are members of a novel class of hypnotic-anesthetic agents that selectively bind to alpha 2 adrenoceptors in the locus coeruleus (LC) to initiate their pharmacologic action. The postreceptor molecular mechanism of the hypnotic action of alpha 2-adrenergic agonists remains unknown. In this study we addressed the role of conductance through a variety of calcium and potassium ion channels in the hypnotic action of dexmedetomidine in the LC of the rat. METHODS: Cannulas were inserted stereotactically into the LC of halothane-anesthetized rats (n = 318). After at least 48 h, rats were tested for loss of righting reflex in response to administration of the alpha 2-adrenergic agonist dexmedetomidine at a hypnotic (7.0 micrograms LC) or subhypnotic (3.5 micrograms LC) dose. To establish the mediating role of various species of calcium and potassium ion channels in the hypnotic response, rats were pretreated with the following drugs before the administration of dexmedetomidine LC:S(+)202791 (L-type calcium-channel activator), nifedipine and R(-)202791 (L-type calcium-channel blocker), SNX 111 (N-type calcium-channel blocker), SNX 230 (P-type calcium-channel blocker), quinine (calcium-activated and voltage-gated potassium-channel blocker), charybdotoxin (calcium-activated potassium-channel blocker), dendrotoxin (voltage-gated potassium-channel blocker), or glybenclamide (adenosine triphosphate-sensitive potassium-channel blocker). The drugs were used in doses not causing behavioral effects that could have confounded the interpretation of loss of righting reflex. RESULTS: SNX 230 and the dihydropyridines nifedipine and R(-)202791 produced loss of righting reflex in the presence of a subhypnotic dose of dexmedetomidine. The hypnotic-enhancing effects of the dihydropyridines could be blocked with S(+)202791, which also diminished loss of righting reflex in response to dexmedetomidine 7.0 micrograms LC. Quinine, dendrotoxin, and charybdotoxin each attenuated the hypnotic response to dexmedetomidine 7.0 micrograms LC. The hypnotic response to dexmedetomidine was not significantly altered by SNX 111 or glybenclamide. CONCLUSIONS: Inhibition of ion conductance through L- or P-type calcium channels and facilitation of conductance through voltage-gated or calcium-activated potassium channels may be involved in the mechanism of hypnotic action of alpha 2-adrenergic agonists. These changes in ion conductance were capable of producing membrane hyperpolarization and decreasing neuronal excitability. There was no evidence for the involvement of adenosine triphosphate-sensitive potassium channels or N-type calcium channels in the hypnotic response to dexmedetomidine.

Adrenergic alpha-Agonists↗
PubMed2002

FMRFamide modulates potassium currents in circadian pacemaker neurons of Bulla gouldiana.

The peptide FMRFamide (Phe-Met-Arg-Phe-NH(2)) is known to modulate the circadian pacemaker found in the eye of the marine snail Bulla gouldiana. In the present study, we investigated the cellular mechanisms underlying this modulation by examining the effects of FMRFamide on the membrane properties of the circadian pacemaker cells, known as basal retinal neurons in this preparation. Bath application of FMRFamide (0.1-1 microM) increased the membrane conductance, and hyperpolarized the membrane potential of these neurons. Next, perforated-patch recordings were used to demonstrate that FMRFamide reversibly increased the outward current amplitude due to an augmentation of a non-inactivating calcium-independent current. Reversal potential of the tail currents and its dependence on extracellular potassium concentration suggested potassium ions as the charge carrier for this current. The peptide-modulated outward current was blocked by 54% after bath application of the potassium channel blocker tetraethylammonium chloride and completely blocked by substituting cesium for intracellular potassium. Voltage dependence, activation kinetics and tail current kinetics of the FMRFamide-modulated current were consistent with values found for the delayed rectifier current.Overall, our data suggest that FMRFamide modulates a delayed rectifier potassium current and at least one other, less voltage-dependent conductance. This provides a mechanistic explanation for FMRFamide's ability to both shift the phase and attenuate light-induced phase shifts of the circadian pacemaker in B. gouldiana.

Action Potentials↗
PubMed2004

Increased release of serotonin from rat ileum due to dexfenfluramine.

Plasma levels of serotonin are elevated in primary pulmonary hypertension even after bilateral lung transplantation, suggesting a possible etiologic role. Serotonin is released primarily from the small intestine. Anorectic agents, such as dexfenfluramine, which can cause pulmonary hypertension, are known to inhibit potassium channels in vascular smooth muscle cells. We examined the hypothesis that dexfenfluramine may stimulate release of serotonin from the ileum by inhibition of K+ channels. In an isolated loop of rat ileum perfused with a physiological salt solution, the administration of dexfenfluramine, its major metabolite D-norfenfluramine, the potassium channel blocker 4-aminopyridine (5 mM), and caffeine (30 mM) increased serotonin levels in the venous effluent. Potassium chloride (60 mM) tended to increase serotonin levels. In genetically susceptible individuals, dexfenfluramine may induce pulmonary hypertension by increasing cytosolic calcium in enterochromaffin cells of the small intestine, thus releasing serotonin and causing vasoconstriction. This work indicates that dexfenfluramine and its major metabolite d-norfenfluramine can increase serotonin release from the small intestine.

4-Aminopyridine↗
PubMed2004

Atrial-selective antiarrhythmic actions of novel Ikur vs. Ikr, Iks, and IKAch class Ic drugs and beta blockers in pigs.

BACKGROUND: The Kv1.5 channel, underlying IKur, is supposed to be atrial selective in pigs and humans. We investigated the effects of different potassium channel blockers, i.e. the IKur blockers AVE 0118, S9947 and S20951, with amiodarone (AM), dofetilide (DO), azimilide (AZ), ibutilide (IB), the IKs blocker HMR 1556, atropine (ATR), flecainide (FL), propafenone (PR), d,l-sotalol (SO), atenolol (ATE), and esmolol (ES), on the left and right atrial and ventricular refractoriness and left atrial vulnerability (LAV) in vivo in pigs. MATERIAL/METHODS: In pentobarbital-anesthetized pigs (n=81), atrial and ventricular effective refractory periods (ERPs) were measured with the S1-S2-extrastimulus-method and QTc time from electrocardiograms. LAV was assessed after S2-extrastimulus to the left atrium. RESULTS: All IKur blockers prolonged left stronger than right atrial ERP and did not change QTc. All IKr blockers predominantly prolonged the right vs. left atria. AM prolonged both atria equally, and ATR the left only. Pure beta blockers acted predominantly on the left atrium, as did FL and PR, while d,l-sotalol acted predominantly on the right. AVE 0118, S9947, S20951, ibutilide, and d,l-sotalol significantly decreased LAV (-100%, -100%, -82%, -53%, -42%; p<0.05), in contrast to all other drugs. CONCLUSIONS: The IKur blockers exhibited stronger effects on the left atrium, which itself has shorter refractoriness, but strikingly with no effect on ventricular repolarization, while IKr blockers, IKs blockers, and d,l-sotalol exerted predominantly right atrial effects and known ventricular effects. IKur blockers inhibited atrial tachyarrhythmias stronger than all available drugs. Therefore, IKur blockers seem to be promising new atrial-selective antiarrhythmic drugs.

Adrenergic beta-Antagonists↗
PubMed2004

Protection of erythrocytes from sub-hemolytic mechanical damage by nitric oxide mediated inhibition of potassium leakage.

The effects of mechanical stress on red blood cell (RBC) deformability were evaluated by subjecting cells to a uniform fluid shear stress of 120 Pa for 15-120 seconds at 37 degrees C. This level of stress induced significant impairment of RBC deformability as assessed by ektacytometry, with the degree of impairment independent of extracellular calcium concentration. Inhibition of RBC nitric oxide (NO) synthesis by a competitive inhibitor of NO synthases (N-omega-nitro-L-arginine methyl ester, L-NAME) had no effect on deformability after exposure to mechanical stress. The NO donor sodium nitroprusside (SNP) prevented the deterioration of RBC deformability in a dose-dependent manner with 10(-4) M being the most effective concentration. A similar protective effect by the non-selective potassium channel blocker, tetraethylammonium chloride (TEA) suggests that the effect of NO might be mediated by the inhibition of potassium leakage from RBC. These results suggest that NO may prevent mechanical deterioration of RBC exposed to high shear stresses. While RBC are not exposed to such high levels of shear stresses for prolonged periods under normal circulatory conditions, comparable levels of mechanical stress can be encountered under certain situations (i.e., artificial organs, extracorporeal circulation) and may result in subhemolytic damage and hemorheological alterations.

Adult↗
PubMed2000

Pharmacological characterization of ionic currents that regulate the pacemaker rhythm in a weakly electric fish.

Electric organ discharge (EOD) frequency in the brown ghost knifefish (Apteronotus leptorhynchus) is sexually dimorphic, steroid-regulated, and determined by the discharge rates of neurons in the medullary pacemaker nucleus (Pn). We pharmacologically characterized ionic currents that regulate the firing frequency of Pn neurons to determine which currents contribute to spontaneous oscillations of these neurons and to identify putative targets of steroid action in regulating sexually dimorphic EOD frequency. Tetrodotoxin (TTX) initially reduced spike frequency, and then reduced spike amplitude and stopped pacemaker activity. The sodium channel blocker muO-conotoxin MrVIA also reduced spike frequency, but did not affect spike amplitude or production. Two potassium channel blockers, 4-aminopyridine (4AP) and kappaA-conotoxin SIVA, increased pacemaker firing rates by approximately 20% and then stopped pacemaker firing. Other potassium channel blockers (tetraethylammonium, cesium, alpha-dendrotoxin, and agitoxin-2) did not affect the pacemaker rhythm. The nonspecific calcium channel blockers nickel and cadmium reduced pacemaker firing rates by approximately 15-20%. Specific blockers of L-, N-, P-, and Q-type calcium currents, however, were ineffective. These results indicate that at least three ionic currents-a TTX- and muO-conotoxin MrVIA-sensitive sodium current; a 4AP- and kappaA-conotoxin SIVA-sensitive potassium current; and a T- or R-type calcium current-contribute to the pacemaker rhythm. The pharmacological profiles of these currents are similar to those of currents that are known to regulate firing rates in other spontaneously oscillating neural circuits.

4-Aminopyridine↗
PubMed1995

Basic concepts in cellular cardiac electrophysiology: Part II: Block of ion channels by antiarrhythmic drugs.

Antiarrhythmic drugs have relative specificity for blocking each of the major classes of ion channels that control the action potential. The kinetics of block is determined by the state of the channel. Those channel states occupied at depolarized potentials generally have greater affinity for the blocking drugs. The kinetics of the drug-channel interaction is important in determining the blocking profile observed clinically. The increased mortality resulting from drug treatment in CAST and several atrial fibrillation trials has resulted in a shift in antiarrhythmic drug development from the Na+ channel blocking (Class I) drugs to the K+ channel blocking (Class III) drugs. While both Classes of drugs have a proarrhythmic potential, this may be less for the Class III agents. Their lack of negative inotropy also make them more attractive. It is important that the potential advantages of these agents be evaluated in controlled clinical trials. In several laboratories, the techniques of molecular biology and biophysics are being combined to determine the block site of available drugs. This information will aid in the future development of agents with greater specificity, and hopefully greater efficacy and safety than those currently in clinical use.

Action Potentials↗
PubMed2004

Isosteviol acts on potassium channels to relax isolated aortic strips of Wistar rat.

Isosteviol is a derivative of stevioside, a constituent of Stevia rebaudiana, which is commonly used as a noncaloric sugar substitute in Japan and Brazil. In the present study, the role of potassium channels in the vasodilator effect of isosteviol was investigated using potassium channel blockers on isosteviol-induced relaxation of isolated aortic rings prepared from Wistar rats. Isosteviol dose-dependently relaxed the vasopressin (10(-8) M)-induced vasoconstriction in isolated aortic rings with or without endothelium. However, in the presence of potassium chloride (3x10(-2) M), the vasodilator effect of isosteviol on arterial strips disappeared. Only the inhibitors specific for the ATP-sensitive potassium (K(ATP)) channel or small conductance calcium-activated potassium (SK(Ca)) channel inhibited the vasodilator effect of isosteviol in isolated aortic rings contracted with 10(-8) M vasopressin. Also; since the isosteviol-induced relaxation was unchanged by methylene blue, a role of nitric oxide and/or endothelium in the vasodilatation produced by isosteviol could be ruled out. The obtained results indicated that vasodilatation induced by isosteviol is related to the opening of SK(Ca) and K(ATP) channels.

Animals↗
PubMed2005

17beta-estradiol inhibits outward potassium currents recorded in rat parabrachial nucleus cells in vitro.

Evidence is increasingly accumulating in support of a role for the steroid hormone 17beta-estradiol to modify neuronal functions in the mammalian CNS, especially in autonomic centers. In addition to its well known slowly developing and long lasting actions (genomic), estrogen can also rapidly modulate cell signaling events by affecting membrane excitability (non-genomic). Little, however, is known regarding the mechanism(s) by which 17beta-estradiol produces its rapid effects on neuronal membrane excitability. As potassium channels play a crucial role in cell excitability, we hypothesized that 17beta-estradiol caused excitability by modulating potassium flux through the neuronal cell membrane. We tested this hypothesis by examining the effects of 17beta-estradiol on outward potassium currents recorded in cells from the parabrachial nucleus of rats, in vitro. Bath application of 17beta-estradiol (10-100 microM) reversibly reduced voltage-activated outward potassium currents in a concentration-dependent manner. This effect was mimicked by BSA-17beta-estradiol but not mimicked by 17alpha-estradiol and was significantly reduced by ICI 182,780, a selective estrogen receptor antagonist. The inhibitory effect of 17beta-estradiol was dependent on extracellular potassium concentration, with more profound effects observed at lower concentrations. The 17beta-estradiol-induced inhibition of the outward current was blocked by pretreatment with the potassium channel blockers tetraethylammonium and 4-aminopyridine. The time constants of deactivation of tail currents were decreased by 17beta-estradiol over a range of test potentials (-140 to -80 mV). Finally, the inhibitory effect of 17beta-estradiol on the outward potassium currents was blocked following pre-incubation of slices in lavendustin A, a tyrosine kinase inhibitor. Taken together, these results suggest that 17beta-estradiol acts rapidly at an extracellular membrane receptor to reduce tetraethylammonium- and 4-aminopyridine-sensitive outward potassium currents by accelerating the closure of potassium channels. This may be the ionic basis of 17beta-estradiol-induced enhancement of neuronal excitability.

Animals↗
PubMed1996

In the absence of streptomycin, minoxidil potentiates the mitogenic effects of fetal calf serum, insulin-like growth factor 1, and platelet-derived growth factor on NIH 3T3 fibroblasts in a K+ channel-dependent fashion.

There is considerable evidence to suggest that the opening of K+ channels plays an important role in stimulating mitogenesis. K+ channel blockers have been shown to inhibit mitogenesis in vitro, mitogens increase cytosolic membrane K+ channel permeability, K+ channel openers stimulate hair growth in vivo, and the Ras/Raf signal transduction pathway induces K+ channel activity. Paradoxically, however, K+ channel openers such as minoxidil have been reported in vitro not to modulate, or even to inhibit, mitogenesis in a range of cell types. Only untherapeutic concentrations have stimulated mitogenesis. These experiments, however, appear to have been carried out in the presence of aminoglycoside antibiotics, which inhibit potassium channel activity. We now report that in the absence of aminoglycoside antibiotics, minoxidil at 10 microg/ml (0.05 mM) causes a significant stimulation of proliferation of NIH 3T3 fibroblasts maintained over a 10-d period in 5% fetal calf serum-supplemented medium. Further, we show that in the presence of 100 microg streptomycin per ml, minoxidil at 10 microg/ml produces an initial inhibition of proliferation, which apparently confirms, in NIH 3T3 fibroblasts, that the inhibition of mitogenesis by minoxidil in the presence of streptomycin is an artifact. The potentiation of NIH 3T3 cell growth by minoxidil can be attributed to the opening of potassium channels, because the potassium channel blocker tolbutamide (5 mM) or combinations of the blockers tolbutamide (1 mM)/tetraethylammonium (2 mM) or glibenclamide (1 microM)/apamin (10 nM) block the minoxidil-induced stimulation of growth. We also demonstrate that minoxidil is able to significantly potentiate the mitogenic effects of both platelet-derived growth factor and insulin-like growth factor 1 on NIH 3T3 fibroblasts in the presence of CPSR-2 (a cytokine free serum substitute). Thus we have shown that minoxidil potentiates the mitogenic effects of fetal calf serum in vitro on NIH 3T3 fibroblasts by opening potassium channels and is also able to potentiate the mitogenic effects of the growth factors platelet-derived growth factor and insulin-like growth factor 1.

3T3 Cells↗
PubMed1992

A group of potassium-channel blockers-acetylcholine releasers: new potentials for Alzheimer disease? A review.

This review of the literature examines systematically the data currently available for potassium-channel blockers to reassess their clinical potential in Alzheimer disease. The conclusion is that potassium-channel blockers may have been dismissed prematurely for the treatment of Alzheimer disease, an impression supported by data indicating intimate relationships between potassium-channel blockade and cholinergic transmission.

Acetylcholine↗
PubMed2002

Voltage-gated ionic currents in an identified modulatory cell type controlling molluscan feeding.

An important modulatory cell type, found in all molluscan feeding networks, was investigated using two-electrode voltage- and current-clamp methods. In the cerebral giant cells of Lymnaea, a transient inward Na+ current was identified with activation at -58 +/- 2 mV. It was sensitive to tetrodotoxin only in high concentrations (approximately 50% block at 100 microm), a characteristic of Na+ channels in many molluscan neurons. A much smaller low-threshold persistent Na+ current (activation at < -90 mV) was also identified. Two purely voltage-sensitive outward K+ currents were also found: (i) a transient A-current type which was activated at -59 +/- 4 mV and blocked by 4-aminopyridine; (ii) a sustained tetraethylammonium-sensitive delayed rectifier current which was activated at -47 +/- 2 mV. There was also evidence that a third, Ca2+-activated, K+ channel made a contribution to the total outward current. No inwardly rectifying currents were found. Two Ca2+ currents were characterized: (i) a transient low-voltage (-65 +/- 2 mV) activated T-type current, which was blocked in NiCl2 (2 mm) and was completely inactivated at approximately -50 mV; (ii) A sustained high voltage (-40 +/- 1 mV) activated current, which was blocked in CdCl2 (100 microm) but not in omega-conotoxin GVIA (10 microm), omega-agatoxin IVA (500 nm) or nifedipine (10 microm). This current was enhanced in Ba2+ saline. Current-clamp experiments revealed how these different current types could define the membrane potential and firing properties of the cerebral giant cells, which are important in shaping the wide-acting modulatory influence of this neuron on the rest of the feeding network.

Action Potentials↗