Effects Of Potassium Channel Blockers Research Articles

Effect of potassium channel blockers on electrophysiological parameters of the atrium and pulmonary veins in hypoxia and acidification

Effect of potassium channel blockers on electrophysiological parameters of the atrium and pulmonary veins in hypoxia and acidification

Electrophysiological modeling of the effect of potassium channel blockers on the distribution of stimulation wave in the human gastric wall cells

The purpose of this study is to model the electrophysiological behavior of excitable membrane and wavefront propagation in the Stomach Wall in physiological and pharmacological states. The propagation of this wave is based on cellular electrophysiological activity and ionic channel properties. In this study, we arranged the stomach wall cells together using the Gap Junctions approach. Slow wave is generated by gastric pacemaker cells. This wave propagates via the interaction of cells with each other throughout the stomach wall. Potassium currents are one of the main factors in regulating the pattern of wavefront propagation. To investigate the effect of limiting the exchange of potassium currents from cell membranes, 10%, 50%, 90%, and complete blockade were applied on both non-inactivating potassium current (IKni) and fast-inactivating potassium current (IKfi). The results show that IKniion channel blockage has a considerable effect on the plateau phase in the propagation of the excitation wave. The maximum value of the action potential in the plateau phase in the excitation wave with complete obstruction from −40.92 mV in the physiological state reached −18.97 mV, which is about 54% higher than the physiological state. Also, compared to the physiological state, complete blockage of the I_Kfi causes a 15% increase in the slow-wave spike phase (from −36.72 mV to −31.36 mV). Using this model, the effect of ions in different phases of slow-wave can be investigated. In addition, by blocking ion channels, functional disorders and smooth muscle contraction can be improved.

Synergistic effects of potassium channel blockers and pyrethroids: mosquitocidal activity and neuronal mode of action†.

The purpose of this research was to explore the possibility of co-applying pyrethroids (agonists of voltage-sensitive sodium channels) with potassium channel blockers in order to potentiate the neurological effects of pyrethroids on Anopheles gambiae. We hypothesized that the toxicity of pyrethroids caused by persistent sodium currents would be augmented by blockage of outward potassium current flow, which normally repolarizes the membrane potential during a nerve membrane action potential. Topical treatments with LD10 s (10% mortality doses) of synergists were given with pyrethroids. 2S-65465 (2S) showed the best synergism of permethrin (8.6-fold) and deltamethrin (7.2-fold), whereas piperonyl butoxide and 4-aminopyridine only showed 2.2- to 3.4-fold synergism with these pyrethroids. In electrophysiological recordings of Periplaneta americana giant axons, 2S (10μm) and 4-AP (30 μm) caused multiple spikes after a single stimulation. Permethrin at 10μm showed significant summating depolarization (4.5 ± 1.1mV) after a train of ten stimuli were applied at 5Hz, and deltamethrin at 0.03 μm showed significant membrane depolarization of 2.9± 0.4mV without stimuli. 2S at 0.3μm and 4-AP at 1-3μm significantly synergized the effects of 3μm permethrin and 0.01 μm deltamethrin. Co-application of potassium channel blockers 2S and 4-AP with pyrethroids can synergize the mosquitocidal activities on An.gambiae, and these activities are correlated with synergistic effects at the level of the nerve membrane. If deployed in the field, this approach can potentially reduce the amount of chemicals needed for effective control of mosquitoes. © 2020 Society of Chemical Industry.

The role of total flavone of Camellia on cerebrovascular vasopasm after subarachnoid hemorrhage in rats

Background: This study was undertaken to explore the role of total flavones of Camellia (TFC) on the cerebrovascular dysfunction in rats after experimental subarachnoid hemorrhage (SAH). Materials and Methods: The contraction and dilation of cerebral basilar artery (BA), nitric oxide (NO) level, and nitric oxide synthase (NOS) activity in rat serum and the expression of endothelial NOS (eNOS) in cerebral vessels were measured. Furthermore, the effect of potassium channel blockers, endothelium removal, L-NG-nitroarginine methyl ester (L-NAME), or prostacyclin I2 (PG I2) production inhibitor on the response of isolated BA derived from normal rats was also evaluated to explore the underlying mechanism of vasodilation induced by total flavones. Results: The contraction of rat BA to U46619 markedly increased and the vasodilation to acetylcholine remarkably reduced after SAH. Interestingly, these vascular dysfunctions were profoundly ameliorated by pretreatment of TFC. Moreover, total flavones could induce a concentration-dependent relaxation in isolated BA from normal rats, which was obviously eliminated by co-application of potassium channel blockers, ChTx and Apamin, application of L-NAME, or endothelial removal. In addition, total flavones pretreatment obviously improved the expression of eNOS in BA, serum NO level, and NOS activity at 48 h after SAH. Conclusion: These findings revealed that TFC has protective effect on cerebrovascular dysfunction after SAH and demonstrated that the protection could be due to its upregulation of eNOS expression and activation of potassium channel.

Nonlinear effects of potassium channel blockers on endothelium-dependent hyperpolarization

In a number of published studies on endothelium-dependent hyperpolarization and relaxation, the results of the effects of K+ blockers have been difficult to interpret. When the effects of two blockers have been studied, often either blocker by itself had little effect, whereas the two blockers combined tended to abolish the responses. Explanations suggested in the literature include an unusual pharmacology of the K+ channels, and possible blocker binding interactions. In contrast, when we applied the same blockers to segments of small blood vessels under voltage clamp, the blockers reduced the endothelium-dependent K+ current in a linearly additive manner. Resolution of these contrasting results is important as endothelium-derived hyperpolarization (EDH) makes its greatest contribution to vasorelaxation in arterioles and small resistance arteries, where it can exert a significant role in tissue perfusion and blood pressure regulation. Furthermore, EDH is impaired in various diseases. Here, we consider why the voltage-clamp results differ from earlier free-running membrane potential and contractility studies. We fitted voltage-clamp-derived current-voltage relationships with mathematical functions and considered theoretically the effects of partial and total block of endothelium-derived K+ -currents on the membrane potential of small blood vessels. When the K+ -conductance was partially reduced, equivalent to applying a single blocker, the effect on EDH was small. Total block of the endothelium-dependent K+ conductance abolished the hyperpolarization, in agreement with various published studies. We conclude that nonlinear summation of the hyperpolarizing response evoked by endothelial stimulation can explain the variable effectiveness of individual K+ channel blockers on endothelium-dependent hyperpolarization and resulting relaxation.

4-aminopyridine decreases MPTP-induced behavioral disturbances in animal model of Parkinson’s disease

Background and purpose: Progressive degeneration of dopaminergic neurons in the midbrain is the main mechanism of Parkinson’s disease (PD). Although potassium channels affect neural activity and death in this area, little research has investigated the effect of potassium channel blockers, such as 4-aminopyridine in the pretreatment of PD. Methods: Fifty-six healthy male Wistar rats were selected for this study. They were divided into seven groups according to receiving saline or 4-aminopyridine, receiving a low or high dose of 4-aminopyridine and receiving 4-aminopyridine for short or long periods. Apomorphine-induced rotational test, elevated body swing test and rotarod test were done to examine behavioral performances. Results: 4-aminopyridine could not completely block behavioral disturbances induced by MPTP, however, it decreased them in all behavioral tests. Long administration of 4-aminopyridine was more effective than short administration in lowering behavioral disturbances. Although high dose of 4-aminopyridine was more effective than low dose in initial trials of each behavioral test, there was no difference between them in the last trial. Conclusion: Long administration of low dose of 4-aminopyridine is the best way to lessen behavioral disturbances induce by MPTP and also avoiding side effects of high dose of 4-aminopyridine.

Mechanism of Proarrhythmic Effects of Potassium Channel Blockers.

Any disturbance of electrical impulse formation in the heart and of impulse conduction or action potential (AP) repolarization can lead to rhythm disorders. Potassium (K(+)) channels play a prominent role in the AP repolarization process. In this review we describe the causes and mechanisms of proarrhythmic effects that arise as a response to blockers of cardiac K(+) channels. The largest and chemically most diverse groups of compound targets are Kv11.1 (hERG) and Kv7.1 (KvLQT1) channels. Finally, the proarrhythmic propensity of atrial-selective K(+) blockers inhibiting Kv1.5, Kir3.1/3.4, SK, and K2P channels is discussed.

Proarrhythmic and Torsadogenic Effects of Potassium Channel Blockers in Patients.

The most common arrhythmia requiring drug treatment is atrial fibrillation (AF), which affects 2 to 5 million Americans and continues to be a major cause of morbidity and increased mortality. Despite recent advances in catheter-based and surgical therapies, antiarrhythmic drugs continue to be the mainstay of therapy for most patients with symptomatic AF. However, many antiarrhythmics block the rapid component of the cardiac delayed rectifier potassium current (IKr) as a major mechanism of action, and marked QT prolongation and pause-dependent polymorphic ventricular tachycardia (torsades de pointes) are major class toxicities.

The Clubroot Pathogen (Plasmodiophora brassicae) Influences Auxin Signaling to Regulate Auxin Homeostasis in Arabidopsis.

The clubroot disease, caused by the obligate biotrophic protist Plasmodiophora brassicae, affects cruciferous crops worldwide. It is characterized by root swellings as symptoms, which are dependent on the alteration of auxin and cytokinin metabolism. Here, we describe that two different classes of auxin receptors, the TIR family and the auxin binding protein 1 (ABP1) in Arabidopsis thaliana are transcriptionally upregulated upon gall formation. Mutations in the TIR family resulted in more susceptible reactions to the root pathogen. As target genes for the different pathways we have investigated the transcriptional regulation of selected transcriptional repressors (Aux/IAA) and transcription factors (ARF). As the TIR pathway controls auxin homeostasis via the upregulation of some auxin conjugate synthetases (GH3), the expression of selected GH3 genes was also investigated, showing in most cases upregulation. A double gh3 mutant showed also slightly higher susceptibility to P. brassicae infection, while all tested single mutants did not show any alteration in the clubroot phenotype. As targets for the ABP1-induced cell elongation the effect of potassium channel blockers on clubroot formation was investigated. Treatment with tetraethylammonium (TEA) resulted in less severe clubroot symptoms. This research provides evidence for the involvement of two auxin signaling pathways in Arabidopsis needed for the establishment of the root galls by P. brassicae.

Effect and mechanism of Danhong injection on isolated mesenteric arterial rings in rats

To study the effect and mechanism of Danhong injection on isolated mesenteric arterial rings in rats. An isolated vascular ring experiment was conducted to determine the changes in tension of vascular rings with a biological signal collection and analytical system. Danhong injection had no impact on the tension of vascular rings. Danhong injection showed a significant vasodilatation effect on treated arteria rings of norepinephrine, and no remarkable impact was made on the effect without endothium. It showed notable effect on blood vessels treated with Ca(2+) and no significant impact on those treated with caffeine. It could inhibit NE-induced intracellular calcium from releasing and external calcium from inflowing. No effects of potassium channel blockers on aorta ring tensile force were found. Danhong injection shows significant vasodilation effect, which mainly works through vascular smooth muscle. Its vasodilation effect may be related to inhibitory receptor, voltage-dependent Ca(2+)-release and IP3 receptor-mediated Ca(2 +)-influx.

Differential Effects of Potassium Channel Blockers on Dopamine Release from Rat Striatal Slices

The effects of different potassium channel blockers on tritiated dopamine [( 3H]DA) release were investigated in rat striatal slices in the presence of pargyline and nomifensine (10 microM each). 4-Aminopyridine (4-AP; 10 and 30 microM) and 3,4-diaminopyridine (3,4-DAP; 30 microM) markedly increased the basal tritium outflow, whereas tetraethylammonium (TEA; 100-1000 microM) was without effect. The facilitating effect of 4-AP (10 microM) on spontaneous release was Ca(2+)- and K(+)-dependent. Moreover, the 4-AP-induced increase in spontaneous release was abolished in the presence of tetrodotoxin, indicating that voltage-dependent Na+ channels were involved in the release mechanism. 4-AP (10 and 30 microM) induced a dose-dependent decrease in K(+)-evoked [3H]DA release. This effect was confirmed with 3,4-DAP (30 microM). When striatal slices were depolarized with veratridine (5 microM), these two aminopyridines increased the evoked release of [3H]DA. TEA increased both K(+)- and veratridine-evoked [3H]DA release. These biochemical results are consistent with electrophysiological differences between the mechanism of action of aminopyridines and that of TEA.

The effects of potassium channel blockers on progesterone-induced suppression of rat portal vein contractility.

The suppression of contractility of rat portal vein caused by progesterone appears to be due to the potassium (K+) channel opening effect of this hormone. The identity of the specific K+ channels involved has been investigated using a variety of K+ channel blockers. Incubation with 100 nM iberiotoxin antagonised the progesterone-induced inhibition of spontaneous and 20 mM K+-induced phasic activity of the portal vein such that the contractions resembled those of the non-progesterone, non-iberiotoxin control tissues treated with the corresponding solvent vehicles. Incubation with barium chloride (20 and 100 microM), 4-aminopyridine (1 mM), tetraethylammonium chloride (1 mM), glibenclamide (1 microM) or apamin (1 microM) did not, however, have the same antagonistic effect. These results suggest that progesterone's selective suppression of rat portal vein contractility is mediated by the opening of BKCa channels.

Effects of Potassium Channel Blockers on Changes in Refractoriness of Atrial Cardiomyocytes Induced by Stretch

Shortening of the effective refractory period (ERP) is regarded as one of the key mechanisms of atrial fibrillation (AF). Stretch is an important predisposing factor in the pathogenesis of AF. However, effective methods to counteract alteration of ERP induced by stretch still need to be explored. Although potassium channels play important roles in cardiac repolarization and refractoriness, the effects of potassium channel blockers on the alteration of repolarization and refractoriness induced by stretch are still unknown. Action potential duration (APD) and ERP were recorded using the standard intracellular microelectrode technique in the left atrial appendage cardiomyocytes of guinea pigs. Stretch accelerated repolarization of atrial cardiomyocytes and also shortened the ERP (P < 0.05). Dofetilide, a rapid delayed rectifying potassium ion channel (I(Kr)) blocker; 4-AP, a transient outward potassium ion channel (I(to)) blocker; and BaCl(2), an inward rectifying potassium ion channel (I(K1)) blocker could counteract the shortening of APD and ERP (P < 0.01). Glibenclamide, an ATP-sensitive potassium ion channel (I(KATP)) blocker; 293-B, a slow delayed rectifying potassium channel (I(Ks)) blocker; and DPO-1, an ultra-rapid delayed rectifying potassium ion channel (I(Kur)) blocker all had no effect on APD and ERP (P > 0.05). Stretch could accelerate repolarization of atrial cardiomyocytes and shorten their ERP, and the I(to), I(Kr), and I(K1) blockers could counteract the effects of stretch.

Targeting natural killer cell potassium channels for selective immunomodulation (134.14)

Abstract Natural killer (NK) lymphocytes play roles in the innate immune defense against tumors and viruses but also participate in graft-versus-host disease and organ transplant rejection. Selective immunomodulation of NK cell subsets would therefore prove beneficial. We have found that human NK cells express two types of potassium channels: Kv1.3 and KCa3.1. Interestingly, NK cells adherent to plastic in the presence of cytokines up-regulate KCa3.1 channels while non-adherent NK cells up-regulate Kv1.3 channels. In going with these results, we found that selective blockers of Kv1.3 channels preferentially inhibited natural cytotoxicity, antibody-mediated cytotoxicity and Fas-mediated cytotoxicity by non-adherent NK cells while selective blockers of KCa3.1 channels preferentially targeted adherent NK cells. We observed the same dichotomy when studying the effects of potassium channel blockers on the ability of adherent and non-adherent NK cells to proliferate and produce cytokines. We have successfully used selective Kv1.3 channel blockers to inhibit autoreactive T lymphocytes for the treatment of autoimmune diseases without inducing generalized immunosuppression. Targeting NK cell potassium channels may prove beneficial for the selective immunomodulation of NK cell subsets. Funded by the American Heart Association and Baylor College of Medicine.

Contribution of potassium channels in human umbilical artery contractions

Bradykinin (BK) and serotonin (5-HT) are vasoactive agents that significantly contribute to the normal functioning of fetoplacental blood flow, including modulation of smooth muscle tone in umbilical vein and arteries. Accordingly, umbilical artery is a crucial component of fetoplacental circulation with the vital function of providing suitable perfusion and nutrition for placenta. The aim of this study was to investigate the effect of potassium channel blockers, namely glibenclamide (an ATP-sensitive K+ channel blocker), tetraethylammonium (a non-selective K+ channel blocker), Ba2+ (an inwardly rectifying K+ channel blocker) and apamin (a small conductance Ca2+-activated K+ channel blocker) in BK- and 5-HT-induced actions on isolated human umbilical artery (HUA) in normal pregnancy. The experiments were performed on vascular rings of HUA isolated from umbilical cords that were obtained immediately after vaginal delivery in women with uncomplicated pregnancy. Only the remnant tissue, which would have been otherwise disposed of, has been utilized. Isometric tension of suspended artery rings was continuously recorded. BK (1 nM – 1 μM) and 5-HT (1 nM – 30 μM) produced concentration-dependent contractions of HUA. Control contractions produced by BK were notably (p < 0.05) enhanced only in the presence of apamin (20 μM), while unaltered by other inhibitors. 5-HT-induced effect was not influenced by any of applied blockers. Our results suggest that small conductance Ca2+-activated potassium channels contribute to the fine regulation of maximal BK-induced contraction of HUA in normal pregnancy. On the other hand, potassium channels do not seem to be involved in 5-HT-evoked contractile response of umbilical artery.

Inhibitory effects of potassium channel blockers on carbachol-induced contraction in rat detrusor muscle.

We present accidental findings that potassium channel blockers, such as tetraethyl-ammonium (TEA) or 4-aminopyridine (4-AP), inhibit the sustained tonic contraction induced by carbachol in rat detrusor muscle strips. The relatively lower concentrations (<2 mM) of TEA and 4-AP inhibited phasic and tonic contractions induced by 5 micro M carbachol, whilst the relatively higher concentrations of TEA and 4-AP (>5 mM) potentiated phasic contractions. The potentiation of phasic contraction was not observed in nicardipine pretreated condition. In nicardipine pretreated condition, the concentration-response curves for the negative inotropic effect of potassium channel blockers were shifted to the right by the increasing concentration of carbachol from 0.5 microM to 5 microM. IC50 was changed significantly from 0.19 to 0.64 mM (TEA) and from 0.21 to 0.96 (4-AP). Such inhibitory effects were also observed in Ca2+ depleted condition, where 0.1 mM EGTA and 1 microM thapsigargin were added into Ca2+ free solution. In conclusion, inhibitory effects of potassium channel blockers on carbachol-induced contraction may be ascribed to the direct inhibition of receptor-agonist binding.

Inhibitory effects of potassium channel blockers on tetramethylpyrazine-induced relaxation of rat aortic strip in vitro

Tetramethylpyrazine (TMP) is one of the active principles contained in Ligusticum chuanxiong Hort. (Umbelliferae), a herb that has been widely used to treat vascular disorders in China. In the present study, role of potassium channel in the vasodilatation of TMP was investigated using the effect of potassium channel blocker on TMP induced relaxation in isolated aortic rings from Wistar rats. TMP produced a concentration-dependent relaxation in the aortic rings precontracted with vasopressin or phenylephrine. Similar effect of TMP on vasoconstrictions by phenylephrine and vasopressin, induced through two different receptors, indicating the direct vasodilatation of TMP. Specific inhibitors for potassium channel were used to characterize the role of potassium channel in this action of TMP. Only the inhibitors specific to small conductance calcium-activated potassium (SK Ca) channel or ATP-sensitive potassium (K ATP) channel inhibited the action of TMP. Also, the TMP-induced relaxation was reversed by the inhibitor of soluble guanylyl cyclase in a way similar to that of K ATP channel blockade. The obtained results indicated that vasodilatation induced by TMP is related to the opening of SK Ca and K ATP channels.

Effects of potassium channel blockers on hyperinflation-induced rapidly adapting pulmonary stretch receptor stimulation in the rabbit

The effects of K + channel blockers, such as 4-aminoprydine (4-AP) and tetraethylammonium (TEA), on the excitatory responses of rapidly adapting pulmonary stretch receptor (RAR) activity to hyperinflation (inflation volume=3 tidal volumes) were investigated in anesthetized, artificially ventilated rabbits after vagus nerve section. The changes in the RAR adaptation index (AI) produced by constant-pressure (approximately 30 cmH 2O, 29.7±0.2 cmH 2O) inflation of the lungs were also examined before and after pretreatment with 4-AP and TEA. The administration of 4-AP (0.7 and 2.0 mg/kg) potentiated hyperinflation-induced RAR stimulation in a dose-dependent manner. During hyperinflation after 2.0 mg/kg 4-AP administration the discharge of RARs showed a relatively regular firing pattern in both inflation and deflation phases. The RAR AI values during constant-pressure inflation of the lungs were significantly reduced by 4-AP treatment (2.0 mg/kg). TEA treatment (2.0 and 7.0 mg/kg) did not significantly alter either the excitatory response of RAR activity to hyperinflation or the RAR AI values seen during constant-pressure inflation of the lungs. These results suggest that during hyperinflation in in vivo experiments on rabbits, RARs may be maintained at a lower activity by opening the 4-AP-sensitive K + channels on the receptor endings, which can determine accommodation of the receptor discharge.

Oxygen dilation in fetal pulmonary arterioles: role of K(+) channels.

Oxygen is a potent stimulus for pulmonary vasodilation. Potassium channels have been implicated as both sensors and effectors for oxygen-induced changes in pulmonary vascular tone. We have examined the effect of potassium channel blockers on oxygen-induced vasodilation in isolated pulmonary arterioles from fetal rats at term. Third generation pulmonary arterioles were isolated from fetal rats on Day 22 of gestation, cannulated, pressurized at constant distending pressures, and preconstricted by suffusion with a salt solution bubbled with a "hypoxic gas" mixture (pO(2) <or=50 mm Hg). Oxygen-induced vasodilation was measured as percentage reversal of the "hypoxic" vasoconstriction after 30 min of suffusion with "normoxic" solution (pO(2) 90-145 mm Hg). Responses were recorded in the absence of blockers (controls) or in the presence of a voltage-gated K(+) channel (K(v)) blocker, 4-aminopyridine; an ATP-sensitive K(+) channel (K(ATP)) blocker, glibenclamide; a Ca(2+)-activated K(+) channel (K(Ca)) blocker, charybdotoxin; or a nonspecific K(+) channel blocker, tetraethylammonium. In control arterioles, normoxic suffusion for 30 min reversed hypoxic preconstriction by 83 +/- 19%. 4-aminopyridine significantly attenuated (44 +/- 9%), and glibenclamide and charybdotoxin had no effect (80 +/- 16 and 79 +/- 20%) on the magnitude of normoxic vasodilation. Our results are consistent with a contribution of K(v) channels, but not K(ATP) or K(Ca) channels, to oxygen-induced vasodilation in third generation pulmonary arterioles from term fetal rats.

Sensitivity of the Slow Component of the Delayed Rectifier Potassium Current (IKs) to Potassium Channel Blockers: Implications for Clinical Reverse Use-Dependent Effects

The slow delayed rectifier potassium current (I_Ks) is unique in its slow activation and deactivation kinetics. It is important during cardiac repolarization, especially when the heart rate is fast. We compared the effects of quinidine, procainamide, sotalol, and amiodarone on I_Ks and correlated the findings with the clinical reverse use-dependent effects of potassium channel blockers. Human minK RNA was obtained by reverse transcription-polymerase chain reaction using explanted human heart. The RNA was injected into Xenopus oocytes for heterologous expression of I_Ks. A two-electrode voltage clamp technique was performed to investigate the I_Ks. We demonstrated that quinidine, sotalol and procainamide had no effects on I_Ks up to a concentration of 300 μM while amiodarone inhibited I_Ks in a concentration-dependent manner starting from 10 μM. The inhibition by amiodarone was state-dependent with gradual unblocking after depolarization. The degree of inhibition was 53% immediately after depolarization and 19% at the end of a 5-second depolarization. I_Ks is 30 times more sensitive to amiodarone than to quinidine, sotalol, and procainamide. Quinidine, sotalol and procainamide have reverse use-dependent effects while amiodarone does not. This is compatible with the hypothesis that no inhibition of I_Ks at clinical concentrations contributes to the clinical reverse use-dependent effects.