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PubMed2001

Relative importance of calcium-activated potassium channels in nipradilol-induced aortic relaxation in rats.

Nipradilol (CAS 81486-22-8), a vasodilatory beta-blocker, has been shown to dilate smaller vessels than nitroglycerin does, and the vasodilative effects of nipradilol have been reported to be less mediated by cyclic GMP (guanosine monophosphate) than those of nitroglycerin. To test the hypothesis that cyclic GMP-independent potassium channels have a larger role in nipradilol-induced aortic relaxation than cyclic GMP-dependent mechanisms, the effects of a potassium channel blocker, tetraethylammonium (TEA, CAS 56-34-8), and of a guanylate cyclase inhibitor, methylene blue (MB, CAS 61-73-4), on nipradilol-induced aortic relaxation were investigated and compared with those on nitroglycerin-induced aortic relaxation in isolated rat aortic rings. Relaxation response was expressed as percent relaxation, which is a percentage of the tension developed by 10(-7) mol/l norepinephrine. Nitroglycerin and nipradilol similarly relaxed the aortic ring in a concentration-dependent manner (10(-9)-10(-4) mol/l). In contrast, desnitronipradilol, a nipradilol analogue which has no nitroxy group, induced almost no aortic relaxation. TEA at 10(-3) mol/l, which is selective for calcium-activated potassium channels, inhibited the aortic relaxation induced by nipradilol (10(-5) mol/l) to a significantly greater extent than that induced by nitroglycerin (10(-5) mol/l) (% relaxation: 30.0 +/- 6.8 vs. 51.1 +/- 6.1%, p < 0.05). MB (10(-5) mol/l) suppressed the relaxation by nitroglycerin slightly but not significantly more than that by nipradilol. (% relaxation: 54.7 +/- 9.9 vs. 64.6 +/- 5.7%). The combination of TEA and MB almost completely eliminated the relaxation induced by nipradilol as well as by nitroglycerin. Thus, cyclic GMP-independent calcium activated potassium channels may be more involved in the aortic relaxation by nipradilol than that by nitroglycerin in rats.

Adrenergic beta-Antagonists↗
PubMed2006

Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB1 in rat dorsal root ganglion neurons.

Potassium channels contribute to basic neuronal excitability and modulation. Here, we examined expression patterns of the voltage-gated potassium channel Kv1.4, the nociceptive transduction channels TRPV1 and TRPV2 as well as the putative anti-nociceptive cannabinoid receptor CB1 by immunofluorescence double-labelings in sections of rat dorsal root ganglia (DRGs). Kv1.4, TRPV1 and CB1 were each detected in about one third of neurons (35.7+/-0.5%, 29.4+/-1.1% and 36.4+/-0.5%, respectively, mean diameter 19.1+/-0.3 microm). TRPV2 was present in 4.4+/-0.4% of all neurons that were significantly larger in diameter (27.4+/-0.7 microm; P < 0.001). Antibody double-labeling revealed that the majority of Kv1.4-positive neurons co-expressed TRPV1 (73.9+/-1.5%) whereas none expressed TRPV2. The largest overlap was found with CB1 (93.1+/-0.1%). CB1 expression resembled that seen for Kv1.4 since the majority of neurons expressing CB1-protein also expressed TRPV1 (69.4+/-6.5%) but not TRPV2 (0.6+/-0.3%). When CB1-mRNA was detected using in situ hybridizations an additional subset of larger neurons was labeled including 82.4+/-17.7% of the TRPV2 expressing neurons. However, co-localization of Kv1.4 with CB1-mRNA (92%, mean diameter: 18.5 microm) was essentially the same as with CB1-protein. The almost complete overlap of CB1 and Kv1.4 in nociceptive DRG neurons suggests a functional synergistic action between Kv1.4 and CB1. The potassium channel may have two important roles in nociception. As the molecular basis of A-type current it could be involved in the control of repetitive discharges at peripheral terminals and as a downstream signal transduction site of CB1 in the control of presynaptic transmitter release at central terminals.

Animals↗
PubMed1993

The effects of potassium channel openers on isolated pregnant human myometrium before and after the onset of labor: potential for tocolysis.

OBJECTIVE: Our purpose was to investigate the effects and pharmacologic properties of potassium channel openers in isolated pregnant human myometrium. STUDY DESIGN: Biopsy specimens of myometrium obtained from 67 women during pregnancy and labor were used for isometric recording under physiologic conditions. RESULTS: Levcromakalim and pinacidil, two prototype potassium channel openers, are potent inhibitors of spontaneous and induced (0.5 nmol/L oxytocin and 10 mumol/L phenylephrine) contractions in isolated human pregnant myometrium, obtained before and after the onset of labor. The sulfonylurea glibenclamide is an apparent competitive antagonist of this inhibition. No antagonism was observed with the sulfonylurea tolbutamide. Both potassium channel openers significantly inhibited contractility evoked by low (10 and 20 mmol/L) but not high (40 and 80 mmol/L) concentrations of extracellular potassium chloride. CONCLUSION: These findings suggest that the relaxant ability of levcromakalim and pinacidil in human pregnant myometrium is because of potassium channel activation. This introduces a potential new approach for tocolysis.

Benzopyrans↗
PubMed1987

Potassium channels in Necturus proximal tubule.

Potassium channels from the apical and basolateral membranes of Necturus proximal tubule were studied using the patch-clamp technique. The conductance of the basolateral channel was dependent on the pipette K+ concentration (apparent Km, 65.5 mM K+; maximum channel conductance, 49.8 pS). The permeability ratio (PK+/PNa+) was approximately 10:1. The fractional open time increased with hyperpolarization, whereas mean open times did not change. Ba2+ (0.1 mM pipette concentration) blocked the channel and reduced the mean open time. The apical K+ channel was activated with depolarization and had a slope conductance of 60 pS in the inside-out configuration (100 mM KCl in the pipette and 2.5 mM KCl in the bath). The K+-Na+ selectivity ratio was 32:1. These different channel types will allow independent control of the apical and basolateral membrane K+ conductances.

Animals↗
PubMed1994

Antigen-induced airway responses are inhibited by a potassium channel opener.

We have investigated the effect of a potassium channel opener, BRL 38227, on antigen-induced bronchoconstriction and airway microvascular leakage in sensitized guinea pigs by simultaneously measuring pulmonary resistance (Rl) and extravasation of Evans blue dye. Guinea pigs were sensitized 3 wk before experimentation with ovalbumin (OA) and aluminum hydroxide. The trachea was cannulated, and lungs were mechanically ventilated. All animals were pretreated 30 min before experimentation with atropine (1 mg/kg intravenously) and propranolol 1 mg/kg to block muscarinic and beta-adrenergic responses, respectively. BRL 38227 (200 micrograms/kg) was administered intravenously 1 min before intravenous dye injection (30 mg/kg); OA (3 mg/ml) was inhaled using an ultrasonic nebulizer (for 30 s) 1 min after dye injection. BRL 38227 significantly inhibited OA-induced bronchoconstrictor response (p < 0.01) and plasma leakage in trachea (p < 0.05) and main bronchi (p < 0.05). BRL 38227 also had an inhibitory effect on exogenous histamine- and leukotriene-induced bronchoconstriction and microvascular leakage. However, BRL 38227 did not affect OA-induced histamine release from minced lung tissues in sensitized guinea pigs. We conclude that the allergic bronchoconstrictor response and airway plasma leakage are inhibited by a potassium channel opener, possibly as a result of its effect on the airway smooth muscle and the postcapillary venule level.

Administration, Inhalation↗
PubMed1996

Molecular and functional heterogeneity of inward rectifier potassium channels in brain and heart.

We have cloned cDNAs encoding three background inward rectifier potassium channels from a mouse brain cDNA library. We designated them mouse brain (MB)- IRK1, MB-IRK2, and MB-IRK3, based on their amino acid sequences and the electrophysiological properties of currents expressed in Xenopus oocytes. Xenopus oocytes injected with cRNAs derived from these clones expressed K+ currents that showed classical inward rectifier potassium channel characteristics at whole cell current level and that were blocked by Ba2+ and Ca+ in a concentration- and voltage- dependent manner. The single channel recordings revealed, however, that the unitary conductance of MB-IRKI was approximately 22pS; MB-IRK2, approximately 34pS; and MB-IRK3, approximately 12pS. By Northern blot analysis, MB-IRKI was more predominantly expressed in forebrain than in cerebellum, and vice versa in the case MB-IRK2. MB-IRK3 was expressed specifically in forebrain. On the other hand, MB-IRK1 and MB-IRK2, but not MB-IRK3, were expressed in heart. These results indicate the heterogeneity of the molecular structure and functional role of the two transmembrane region type of background inward rectifier potassium channels in brain and heart.

Amino Acid Sequence↗
PubMed2002

Isoflurane inhibits neutrophil-endothelium interactions in the coronary circulation: lack of a role for adenosine triphosphate-sensitive potassium channels.

UNLABELLED: Isoflurane protects myocardium during ischemia-reperfusion via a mechanism involving the adenosine triphosphate-sensitive potassium channels. We tested the hypothesis that an inhibition of the neutrophil-endothelium interactions by isoflurane contributes to this effect. Polymorphonuclear neutrophils and coronary artery segments were obtained from 35 healthy dogs. Superoxide production by neutrophils, stimulated with platelet-activating factor (PAF; 1.0 microM), was measured spectrophotometrically. Adherence of PAF-activated neutrophils to the endothelium of coronary segments was assessed by direct counting of neutrophils labeled with fluorescent dye. Coronary artery rings were exposed to PAF-activated neutrophils, and, after washing and preconstriction with U46619, they were evaluated for vasorelaxation responses to acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent). Measurements were performed in the absence and presence of isoflurane (1 and 2 minimum alveolar anesthetic concentration) both with and without glibenclamide (10 microM). Isoflurane inhibited superoxide production and adherence by neutrophils and abolished neutrophil-induced reductions in coronary vascular relaxation responses to acetylcholine. Glibenclamide did not alter the effects of isoflurane on neutrophils or coronary artery endothelium. In conclusion, isoflurane had an inhibitory action on neutrophil-endothelium interactions and neutrophil-mediated coronary endothelial dysfunction--effects that may be involved in its cardioprotective action in vivo. These inhibitory actions of isoflurane were not mediated by adenosine triphosphate-sensitive potassium channels. IMPLICATIONS: Isoflurane inhibited neutrophil-endothelium interactions and the inflammatory response in vitro via a pathway independent of the adenosine triphosphate-sensitive potassium channels. This action could be involved in the cardioprotection by isoflurane observed in vivo.

Acetylcholine↗
PubMed1997

Hyperpolarized cardioplegic arrest with nicorandil: advantages over other potassium channel openers.

BACKGROUND: Our laboratory has demonstrated that the potassium channel openers (PCOs) aprikalim and pinacidil are effective cardioplegic agents but exhibit toxicity at high doses. In this study, the effectiveness of another PCO, nicorandil, was investigated for several reasons. The chemical structure of nicorandil is distinct from other PCOs, in part because of a nitrate moiety, which may confer additional cardioprotection. Moreover, nicorandil has been approved for human use and has not been shown to exhibit significant toxicity in clinical trials. METHODS AND RESULTS: Using a blood-perfused, parabiotic, isolated rabbit heart model, 45 hearts underwent 30 minutes of global normothermic ischemia after infusion of 50 mL of cardioplegia, followed by 30 minutes of reperfusion. Cardioplegia consisted of Krebs-Henseleit solution either alone (control) or with nicorandil (100 micromol/L, 300 micromol/L, or 1 mmol/L), 20 mmol/L KCl, or nicorandil (100 micromol/L) plus glibenclamide (10 micromol/L), a potassium channel blocker. Over a wide range of volumes, left ventricular systolic function and diastolic compliance were measured at baseline and after reperfusion. The percentage of recovery of developed pressure (mean+/-SEM) for control, glibenclamide plus nicorandil, 100 micromol/L nicorandil, 1 mmol/L nicorandil, and 20 mmol/L KCl was 44.1+/-3.4%, 44.9+/-2.9%, 61.1+/-4.7%, 58.4+/-3.0%, and 63.2+/-1.5%, respectively. Postreperfusion end-diastolic pressures were significantly increased in control, 300 micromol/L nicorandil, and nicorandil plus glibenclamide groups. CONCLUSIONS: Nicorandil (100 micromol/L and 1 mmol/L) significantly improved functional recovery compared with control and was as effective as KCl cardioplegia. The protective effect of nicorandil was eliminated by glibenclamide, indicating that nicorandil is cardioprotective primarily through its capability as a PCO. In contrast to other PCOs, nicorandil produced mechanical arrest as quickly as KCl and did not show toxicity.

Animals↗
PubMed2000

Cloning, localisation and functional expression of a novel human, cerebellum specific, two pore domain potassium channel.

We have isolated, by degenerate PCR, a complementary DNA encoding a novel two pore domain potassium channel. This is the 7th functional member of the human tandem pore domain potassium channel family to be reported. It has an open reading frame of 1.125 kb and encodes a 374 amino acid protein which shows 62% identity to the human TASK-1 gene: identity to other human members of the family is 31-35% at the amino acid level. We believe this gene to be human TASK-3, the ortholog of the recently reported rat TASK-3 gene: amino acid identity between the two is 74%. 'Taqman' mRNA analysis demonstrated a very specific tissue distribution pattern, showing human TASK-3 mRNA to be localised largely in the cerebellum, in contrast rat TASK-3 was reported to be widely distributed. We have shown by radiation hybrid mapping that human TASK-3 can be assigned to chromosome 8q24.3. Human TASK-3 was demonstrated to endow Xenopus oocytes with a negative resting membrane potential through the presence of a large K(+) selective conductance. TASK-3 is inhibited by extracellular acidosis with a mid-point of inhibition around pH 6. 5, supporting the predictions from the sequence data that this is a third human TASK (TWIK-related acid sensitive K(+) channel) gene.

Amino Acid Sequence↗
PubMed1999

Anti-ulcer activity of SKP-450, a novel potassium channel activator, in rats.

The anti-ulcer effects of SKP-450, a new potassium channel activator, were evaluated on basal and histamine-induced gastric acid secretion, and against experimentally-induced ulcers such as ethanol-induced and NaOH-induced gastric ulcers. In the pylorus-ligated rat, SKP-450 (0.1-0.5 mg kg(-1)) significantly decreased volume and concentration of gastric juice, and total acid output (ED(50): 0.12 mg kg(-1)). SKP-450 (0.3-3.0 mg kg(-1)) also inhibited histamine-induced gastric acid secretion, maximal effects being achieved at 1.0 mg kg(-1)(37.9% inhibition). In the 95% ethanol-treated rats, SKP-450 significantly reduced the mucosal lesions (46.9 and 31.4% inhibition at 0.1 and 0.2 mg kg(-1), respectively). A significant reduction in the ulcer index by SKP-450 was also observed in 0.3 n NaOH-treated rats (31.5 and 64.3% inhibition at 0.5 and 1.0 mg kg(-1), respectively). The effects of SKP-450 on histamine-induced acid secretion and on NaOH-induced ulcers were inhibited by glibenclamide (20 mg kg(-1), i.v.), a selective blocker of ATP-sensitive potassium channel. These results indicate that SKP-450 possesses anti-ulcer effects and its effects may be mediated by activation of ATP-sensitive potassium channels.

Animals↗
PubMed2000

Role of ATP sensitive potassium channel on 7-hydroxy flavone induced antinociception and possible association with changes in glycaemic status.

Opioid type of analgesics open ATP sensitive potassium channel at the cellular level to produce antinociceptive response. These channels have also been shown to modulate insulin secretion by the pancreas. 7-hydroxy flavone, an antinociceptive agent shown to act through opioid pathways was investigated for its effect on glycaemic state and associated algesic state. The involvement of ATP sensitive potassium channel in the action was examined by using glybenclamide. The result reveal that 7-HF per se did not elicit any significant change in the glycaemic state simultaneously eliciting antinociceptive response as tested by acetic acid induced abdominal constriction assay procedure. Glibenclamide treatment attenuated the antinociceptive effect of 7-HF and while maintained its hypoglycaemic response. The present finding suggest that 7-HF induces antinociception like morphine, utilise ATP sensitive potassium channel at the cellular level and do not suggest a cause-effect relationship between the changes in the glycaemic and algesic state. Possibly, insulin which is controlled by ATP sensitive potassium channel at the cellular level might also modulate antinociception exhibiting a cause-effect relationship between them.

Adenosine Triphosphate↗
PubMed2006

K+ conduction in the selectivity filter of potassium channels is monitored by the charge distribution along their sequence.

Potassium channels display a high conservation of sequence of the selectivity filter (SF), yet nature has designed a variety of channels that present a wide range of absolute rates of K(+) permeation. In KcsA, the structural archetype for K channels, under physiological concentrations, two K(+) ions reside in the SF in configurations 1,3 (up state) and 2,4 (down state) and ion conduction is believed to follow a throughput cycle involving a transition between these states. Using free-energy calculations of KcsA, Kv1.2, and mutant channels, we show that this transition is characterized by a channel-dependent energy barrier. This barrier is strongly influenced by the charges partitioned along the sequence of each channel. These results unveil therefore how, for similar structures of the SF, the rate of K(+) turnover may be fine-tuned within the family of potassium channels.

Amino Acid Sequence↗
PubMed2004

Potassium channel gating in adhesion: from an oocyte-silicon to a neuron-astrocyte adhesion contact.

In a neuron-astrocyte adhesion contact the ionic current due to the opening of voltage-dependent potassium channels has to flow along a narrow intercellular cleft, generating there an extracellular voltage. This voltage might be large enough to affect significantly the dependence of channel gating from the intracellular voltage. In order to test this hypothesis, we considered a Xenopus oocyte expressing voltage-dependent potassium channels adhering to a layer of silicon oxide as a simplified model of cell-cell adhesion; here the cell membrane and silicon oxide are separated by a narrow cleft and form a junction of circular shape. We measured directly the extracellular voltage along the diameter of the cleft and investigated its effect on channel gating using a linear array of field effect transistors integrated in the silicon substrate. On this experimental basis we demonstrated that the voltage dependence of potassium channels is strongly affected by adhesion, as can be predicted using a model of a two-dimensional cable and electrodiffusion theory. Computations based on the model showed that along a neuron-astrocyte adhesion contact the opening of voltage-dependent Kv2.1 potassium channels is significantly reduced with respect to identical channels facing an open extracellular space.

Animals↗
PubMed1997

Synthetic putative transmembrane region of minimal potassium channel protein (minK) adopts an alpha-helical conformation in phospholipid membranes.

Minimal potassium channel protein (minK) is a potassium channel protein consisting of 130 amino acids, possessing just one putative transmembrane domain. In this study we have synthesized a peptide with the amino acid sequence RDDSKLEALYILMVLGFFGFFTLGIMLSYI, containing the putative transmembrane region of minK, and analysed its secondary structure by using Fourier-transform IR and CD spectroscopy. The peptide was virtually insoluble in aqueous buffer, forming intermolecular beta-sheet aggregates. On attempted incorporation of the peptide into phospholipid membranes with a method involving dialysis, the peptide adopted a predominantly intermolecular beta-sheet conformation identical with that of the peptide in aqueous buffer, in agreement with a previous report [Horvàth, Heimburg, Kovachev, Findlay, Hideg and Marsh, (1995) Biochemistry 34, 3893-3898]. However, by using an alternative method of incorporating the peptide into phospholipid membranes we found that the peptide adopted a predominantly alpha-helical conformation, a finding consistent with various proposed structural models. These observed differences in secondary structure are due to artifacts of aggregation of the peptide before incorporation into lipid.

Amino Acid Sequence↗
PubMed1997

Potassium channels of the lamprey erythrocyte membrane exhibit a high selectivity to K+ over Rb+: a comparative study of 86Rb and 41K transport.

In order to assess the specificity of potassium channels, we examined the K+ transport pathways in the lamprey red blood cells using 86Rb and stable isotope 41K as tracers measured by the mass spectrometric method. Upon replacing 4 mmol/l K+ with 4 mmol/l Rb+ in the incubation medium, the rate coefficient for unidirectional 86Rb influx (Kin) was significantly reduced from 1.48 +/- 0.10 h-1 to 0.82 +/- 0.05 h-1 (P < 0.001). Addition of 1 mmol/l Ba2+ to the incubation medium significantly decreased 86Rb influx in K(+)- (by 53%) and Rb(+)-media (by 26%). Thus, the reduction in the rate coefficient for 86Rb influx in Rb(+)-medium as compared to K(+)-medium was mainly due to the Ba(2+)-sensitive component (0.23 +/- 0.04 vs. 0.78 +/- 0.10 h-1, P < 0.001). The ouabain-sensitive component of 86Rb influx was also higher in K(+)-(Kin = 0.62 +/- 0.05 h-1) than in Rb(+)-medium (Kin = 0.54 +/- 0.05 h-1, P < 0.05). In the presence of 4 mmol/l 41KCl, the average value of the rate coefficient for the total 41K influx was 8.1 +/- 0.5 h-1. The rate coefficient for 41K influx was reduced to 0.82 +/- 0.13 h-1 in the presence of 1 mmol/l Ba2+. Under the conditions of our assays, the rate of 86Rb uptake via potassium channels of the lamprey red cells was only about 11% in K(+)-medium and only about 3% in Rb(+)-medium compared to 41K influx. These data clearly demonstrate a high selectivity of potassium channels for K+ over Rb+, as already reported for some potassium channels in a variety of cells and tissues.

Animals↗
PubMedDate not supplied

EMD 52692 (bimakalim), a new potassium channel opener, attenuates luminol-enhanced chemiluminescence and superoxide anion radical formation by zymosan-activated polymorphonuclear leukocytes.

We investigated the relationship of potassium channel activation on modulation of oxidative respiratory bursts in canine neutrophils. Generation of superoxide anion radicals in opsonized zymosan-activated cells was determined using the technique of ferricytochrome c reduction. Preincubation of cells with the selective potassium channel opener, EMD 52692 (1-100 microM), attenuated superoxide anion radical production. Furthermore, EMD 52692 also produced a concentration-dependent inhibition of luminol-enhanced chemiluminescence by activated neutrophils. Glyburide, a selective antagonist of ATP-sensitive potassium channels, prevented the modulatory effect of EMD 52692 on both superoxide anion generation and luminol-enhanced chemiluminescence. The results suggest that ATP-sensitive potassium channels may play a significant role in regulating oxygen-derived free radical production in neutrophil-induced tissue injury.

Animals↗
PubMed2001

A mechanism for ATP-sensitive potassium channel diversity: Functional coassembly of two pore-forming subunits.

ATP-sensitive potassium channels are an octomeric complex of four pore-forming subunits of the Kir 6.0 family and four sulfonylurea receptors. The Kir 6.0 family consists of two known members, Kir 6.1 and Kir 6.2, with distinct functional properties. The tetrameric structure of the pore-forming domain leads to the possibility that mixed heteromultimers may form. In this study, we examine this by using biochemical and electrophysiological techniques after heterologous expression of these subunits in HEK293 cells. After the coexpression of Kir 6.1 and Kir 6.2, Kir 6.1 can be coimmunoprecipitated with isoform-specific Kir 6.2 antisera and vice versa. Coexpression of SUR2B and Kir 6.2 with Kir 6.1 dominant negatives at a 1:1 expression ratio and vice versa led to a potent suppression of current. Kir 6.1, and Kir 6.2 dominant negative mutants were without effect on an inwardly rectifying potassium channel from a different family, Kir 2.1. Single-channel analysis, after coexpression of SUR2B, Kir 6.1, and Kir 6.2, revealed the existence of five distinct populations with differing single-channel current amplitudes. All channel populations were inhibited by glibenclamide. A dimeric Kir 6.1-Kir 6.2 construct expressed with SUR2B had a single-channel conductance intermediate between that of either Kir 6.2 or Kir 6.1 expressed with SUR2B. In conclusion, Kir 6.1 and Kir 6.2 readily coassemble to produce functional channels, and such phenomena may contribute to the diversity of nucleotide-regulated potassium currents seen in native tissues.

ATP-Binding Cassette Transporters↗
PubMed2000

Stereoselective interactions of the enantiomers of chromanol 293B with human voltage-gated potassium channels.

Selective inhibitors of the slow component of the cardiac delayed rectifier K(+) current, I(Ks), are of interest as novel class III antiarrhythmic agents and as tools for studying the physiologic roles of the I(Ks) current. Racemic chromanol 293B is an inhibitor of both native I(Ks) and its putative molecular counterpart, the KvLQT1+minK ion channel complex. We synthesized the (+)-[3S,4R] and (-)-[3R,4S] enantiomers of chromanol 293B using chiral intermediates of known absolute configuration and determined their relative potency to block recombinant human K(+) channels that form the basis for the major repolarizing K(+) currents in human heart, including KvLQT1+minK, human ether-a-go-go-related gene product (hERG), Kv1.5, and Kv4.3, corresponding to the slow (I(Ks)), rapid (I(Kr)), and ultrarapid (I(Kur)) delayed rectifier currents and the transient outward current (I(To)), respectively. K(+) channels were expressed in mammalian cells and currents were recorded using the whole-cell patch-clamp technique. We found that the physicochemical properties and relative potency of the enantiomers differed from those reported previously, with (-)-[3R,4S]293B nearly 7-fold more potent in block of KvLQT1+minK than (+)-[3S,4R]293B, indicating that the original stereochemical assignments were reversed. K(+) current inhibition by (-)-293B was selective for KvLQT1+minK over hERG, whereas the stereospecificity of block for KvLQT1+minK and Kv1.5 was preserved, with (-)-293B more potent than (+)-293B for both channel complexes. We conclude that the (-)-[3R,4S] enantiomer of chromanol 293B is a selective inhibitor of KvLQT1+minK and therefore a useful tool for studying I(Ks).

Animals↗