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Results for “Potassium Channel Blockers”

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At least 649 records · Page 36Linked to original sources

PubMed1998

Involvement of K+ATP channels in nitric oxide-induced inhibition of spontaneous contractile activity of the nonpregnant human myometrium.

Nitric oxide (NO), an important endogenous substance, is known to be a strong relaxant of smooth muscle, including myometrium. It has been postulated that the relaxing effect of NO on smooth muscle is achieved by the stimulation of soluble guanylyl cyclase, which leads to an increase in the cyclic guanosine 3',5'-monophosphate (cGMP) levels and hyperpolarization of the cellular membrane. The aim of our study was to investigate the involvement of K+ATP channels in the mechanism of cGMP-independent nitric oxide-induced inhibition of contractile activity of the nonpregnant human myometrium, obtained at hysterectomy. Nitric oxide's influence on contractile activity was recorded in the presence of methylene blue and glybenclamide, blockers of soluble guanylyl cyclase and K+ATP channels, respectively. Nitric oxide, generated by the NO donor DEA/NO, caused a dose-dependent inhibition of the spontaneous contractile activity of human nonpregnant myometrium. Preincubation with methylene blue (5 microM) did not prevent NO-induced relaxation of uterine strips, while 1.5 microM glybenclamide blocked this effect. Our results indicate that nitric oxide relaxes human non-pregnant uterus through K+ATP channels, independent of the cGMP pathway.

Adult↗

PubMed2000

Tethered blockers as molecular 'tape measures' for a voltage-gated K+ channel.

The propagation of electrical signals in excitable cells is orchestrated by a molecular family of voltage-dependent ion channel proteins. These K+, Na+, and Ca++ channels are all composed of four identical or similar units, each containing six transmembrane segments (S1-S6) in a roughly four-fold symmetric structure. The S5-S6 sequences fold into a central pore unit, which is surrounded by a voltage-gating module composed of S1-S4. The recent structure of KcsA, a two-transmembrane bacterial K+ channel, illuminates the physical character of the pore unit, but little is known about the arrangement of the surrounding S1-S4 sequences. To locate regions of this gating module in space, we synthesized a series of compounds of varying length that function as molecular 'tape measures': quaternary ammonium (QA) pore blockers that can be tethered to specific test residues. We show that in a Shaker K+ channel, the extracellular ends of S1 and S3 are approximately 30 ¿ from the tetraethylammonium (TEA) blocking site at the external opening of the pore. A portion of the S3-S4 loop is, at 17-18 ¿, considerably closer.

Amino Acid Substitution↗

PubMed2006

The nitric oxide-cyclic GMP-protein kinase G-K+ channel pathway participates in the antiallodynic effect of spinal gabapentin.

The possible participation of the nitric oxide (NO)-cyclic GMP-protein kinase G (PKG) pathway on gabapentin-induced spinal antiallodynic activity was assessed in spinal nerve injured rats. Intrathecal gabapentin, diazoxide or pinacidil reduced tactile allodynia in a dose-dependent manner. Pretreatment with NG-L-nitro-arginine methyl ester (L-NAME, non-specific inhibitor of NO synthase NOS), 7-nitroindazole (neuronal NO synthase inhibitor), 1H-[1,2,4] -oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor) or (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo-[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor), but not NG-D-nitro-arginine methyl ester (D-NAME) or okadaic acid (protein phosphatase 1 and 2 inhibitor) prevented gabapentin-induced antiallodynia. Pinacidil activity was not blocked by L-NAME, D-NAME, 7-nitroindazole, ODQ, KT-5823 or okadaic acid. Moreover, KT-5823, glibenclamide (ATP-sensitive K+ channel blocker), apamin and charybdotoxin (small- and large-conductance Ca2+-activated K+ channel blockers, respectively), but not margatoxin (voltage-gated K+ channel blocker), L-NAME, 7-nitroindazole, ODQ or okadaic acid, reduced diazoxide-induced antiallodynia. Data suggest that gabapentin-induced spinal antiallodynia could be due to activation of the NO-cyclic GMP-PKG-K+ channel pathway.

Amines↗

PubMed1998

Force, membrane potential and cytoplasmic Ca2+ responses to cyclic nucleotides in rat anococcygeus muscle.

Simultaneous recordings of membrane potential and force, and cytoplasmic calcium ([Ca2+]i) and force were made in rat anococcygeus to determine whether membrane hyperpolarisation plays a role in cyclic nucleotide-induced relaxation. In the presence of phenylephrine (0.2 microM), which evoked sustained contraction, an elevation in [Ca2+]i, and depolarisation, nitroprusside (5 microM) caused 96+/-3% relaxation, 77+/-3% decrease in suprabasal [Ca2+]i, and 16+/-2 mV hyperpolarisation. Forskolin (1 microM) caused 98+/-1% relaxation, 92+/-2% decrease in suprabasal [Ca2+]i, and 18+/-1 mV hyperpolarisation. These responses persisted in the presence of a variety of K+ channel blockers or in ouabain. The decrease in [Ca2+]i preceded the commencement of relaxation whereas the onset of hyperpolarisation lagged behind. Thus, cyclic nucleotide-mediated relaxation in rat anococcygeus is not dependent on hyperpolarisation mediated by the opening of K+ channels. Rather, it is suggested that the decrease in [Ca2+]i gives rise to hyperpolarisation, which reflects a decline in the Ca2+ dependent conductance(s) activated by phenylephrine.

Animals↗

PubMed2002

The T wave as a marker of dispersion of ventricular repolarization in premature infants before and while on treatment with the I(Kr) channel blocker cisapride.

AIMS: Measurement of electrocardiographic intervals to assess dispersion in ventricular repolarization may be helpful in the assessment of the risk of ventricular arrhythmia. We measured QTc, QT dispersion, and T wave intervals in premature infants before and while on treatment with the I(Kr) blocker cisapride as markers for dispersion in ventricular repolarization. METHODS AND RESULTS: We enrolled 15 non-ventilated premature infants with a mean gestational age of 30.5 weeks, ranging from 26.5 to 33.5 weeks, and mean postnatal age of 24 days, with a range from 5 to 51 days. A digital 12 lead electrocardiogram was recorded prior to and 3 days after administering cisapride at a dose of 0.8 mg/kg/day. Serum electrolytes were simultaneously measured. Electrocardiographic measurements before and after included: QT, QTc Bazett, QT dispersion, R-R, T wave interval peak to end, T wave interval peak to end/onset Q to T wave peak, T wave axis, T wave maximum voltage and QRS-T angle. A paired t test and analysis of variance was used to compare the variables before and during treatment. The QTc, T wave interval peak to end and the ratio T wave interval peak to end/onset Q to T peak increased significantly following treatment with cisapride. Results expressed as before and during treatment were for QTc: 429 (65) ms versus 454 (29) ms p < 0.02; for T wave interval peak to end: 65 (11) ms versus 103 (24) p <0.01, for the ratio T wave interval peak to end/onset Q to T peak: 0.32 (0.06) versus 0.55 (0.16) p < 0.001. Treatment with the I(Kr) blocker did not significantly alter the QT dispersion, T wave voltage, angle or QRS-T angle. CONCLUSION: The interval from the peak to the end of the T wave and the ratio of this value to the onset Q to T peak interval, represents regional dispersion of repolarization across the ventricular wall. This is a potentially useful clinical index in the assessment of arrhythmic risk in premature infants being treated by blockade of the I(Kr) channels.

Belgium↗

PubMed2001

Capsaicin-induced relaxation in rabbit coronary artery.

In the present study mechanism of inhibitory effects of capsaicin on the contractility of rabbit coronary artery were studied by measurement of isometric tension and intracellular Ca2+ concentration. Capsaicin (1 microM to 30 microM) relaxed the coronary artery pre-contracted with prostaglandin (PG) F2alpha (1 microM) in a concentration-dependent manner. The PGF2alpha-induced increase in intracellular Ca2+ concentration was also inhibited. The effects of capsaicin were readily reversed by washing capsaicin from the bath. Capsaicin-induced relaxation was not attenuated by pretreatment with capsazepine (1 microM), a blocker of vanilloid receptor or ruthenium red (1 microM), a blocker of non-selective cation channel. Previous exposure to a high concentration of capsaicin (100 microM) or repeated application of capsaicin did not eliminate the relaxation response to subsequent application of capsaicin. Increasing the external K+ concentration to 80 mM significantly attenuated the capsaicin-induced relaxation with simultaneous change in intracellular Ca2+ concentration. Pretreatment with iberiotoxin (100 nM), a blocker of Ca2+-activated K+ channel, only partially inhibited the capsaicin-induced relaxation. However, application of 4-aminopyridine (4-AP, 1 mM), a blocker of delayed rectifier K+ current significantly inhibited the capsaicin-induced relaxation with concomitant attenuation of the effect on intracellular Ca2+ concentration. These results indicate that capsaicin may have a direct relaxing effect on the smooth muscle contractility, and relaxation may be due to activation of the 4-AP-sensitive, delayed rectifier K+ channels in the rabbit coronary artery.

4-Aminopyridine↗

PubMed1997

Ex vivo study of the increased sensitivity to NO of endothelium-denuded thoracic aortas isolated from dietary magnesium-deficient rats.

The mechanisms underlying the enhanced relaxant responses to sodium nitroprusside (SNP) associated with magnesium (Mg) deficiency were examined using endothelium-denuded thoracic aortas isolated from rats with dietary Mg deficiency. This enhancement of SNP-induced relaxation was abolished or depressed in the presence of methylene blue (a guanylate cyclase inhibitor). The relaxant responses to 8-bromo cyclic GMP (8-Br cGMP; a membrane-permeable cGMP) of thoracic aortas isolated from Mg-deficient rats were enhanced like those to SNP. These enhanced relaxant responses were depressed by tetraethylammonium (a non-specific K+ channel blocker). Charybdotoxin, a large conductance Ca2+-activated K+ (K[Ca]) channel blocker, inhibited 8-Br cGMP-induced relaxations of aortas from Mg-deficient and control rats. Apamin, a small conductance K(Ca) channel blocker, inhibited 8-Br cGMP-induced relaxations of aortas from Mg-deficient, but not control rats. The relaxant responses to cromakalim (an ATP-sensitive K+ channel opener) of the two groups were not significantly different. These ex vivo results show that dietary Mg deficiency in rats leads to increased sensitivity to NO of endothelium-denuded thoracic aortas in vitro and K(Ca) channel activation via cGMP may be involved in this enhancement.

Animals↗

PubMed2006

Possible activation of the NO-cyclic GMP-protein kinase G-K+ channels pathway by gabapentin on the formalin test.

The effect of modulators of the nitric oxide-cyclic GMP-protein kinase G-K+ channels pathway on the local peripheral antinociceptive action induced by gabapentin was assessed in the rat 1% formalin test. Local peripheral administration of gabapentin produced a dose-dependent antinociception in the second phase of the test. Gabapentin-induced antinociception was due to a local action as its administration in the contralateral paw was ineffective. Local peripheral pretreatment of the paws with NG-L-nitro-arginine methyl ester (L-NAME, a nitric oxide synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor) and KT-5823 (a protein kinase G inhibitor) dose-dependently reduced gabapentin-induced antinociception. Likewise, glibenclamide or tolbutamide (ATP-sensitive K+ channel inhibitors), 4-aminopyridine or tetraethylammonium (non-selective inward rectifier K+ channel inhibitors) or charybdotoxin (large-conductance Ca2+-activated-K+ channel blocker), but not apamin (small-conductance Ca2+-activated-K+ channel blocker) or naloxone (opioid receptor antagonist), reduced the antinociception induced by gabapentin. Our data suggest that gabapentin could activate the nitric oxide-cyclic GMP-protein kinase G-K+ channels pathway in order to produce its peripheral antinociceptive effect in the rat 1% formalin test.

4-Aminopyridine↗

PubMed1997

Effects of K+ channel blockers on K+ channels, membrane potential, and aldosterone secretion in rat adrenal zona glomerulosa cells.

The hypothesis that angiotensin II (ANG II)-induced aldosterone secretion is mediated through inhibition of plasma membrane K+ channels was examined by measuring the effects of K+ channel blockers on K+ currents, membrane potential, and aldosterone secretion in rat adrenal glomerulosa cells. Effective K+ channel blockers were identified and studied using patch clamp methods on isolated glomerulosa cells in cell culture. Extracellular Cs+ (2-20 mm) caused a voltage-dependent inhibition of macroscopic K+ currents, exhibiting an apparent Kd of 2 mM for blockade of K+ current at membrane potentials near the K+ equilibrium potential. Outward K+ current opposed the Cs+ block, imparting a steep voltage dependence to this block. In single channel studies Cs blocked inward, but not outward, unitary currents through ANG II-regulated weakly voltage-dependent K+ channels, which are thought to control resting membrane potential. Cs+ reversibly depolarized the resting membrane potential at concentrations greater than or equal to the apparent Kd for K+ conductance inhibition (> or =2 mM). Depolarization consisted of a slow, maintained phase proportional to Cs+ concentration superimposed with 2- to 5-mV transient depolarizing events. Cs+ induced a Ca2+-dependent stimulation of aldosterone secretion in acutely dissociated cells, exhibiting an EC50 of approximately 3 mM. Maximal Cs+-induced secretion was quantitatively similar to 1 nM ANG II- or 8 mM K+-induced secretion. Cs+-induced secretion was not additive with that of ANG II. K+ channel blockers that did not inhibit weakly voltage-dependent K+ channels at rest (quinidine, apamin, and charybdotoxin) did not cause depolarization or stimulate aldosterone secretion. Furthermore, charybdotoxin did not significantly affect ANG II-induced aldosterone secretion, indicating that Ca2+-dependent maxi-K+ channels did not contribute to the control of aldosterone secretion in acutely dissociated cells. These data strongly support involvement of weakly voltage-dependent K+ channels in ANG II-induced aldosterone secretion, but also implicate roles for other channel classes in controlling membrane potential during ANG II-induced aldosterone secretion.

Aldosterone↗

PubMed2002

Involvement of K+ channels in adenosine A2A and A2B receptor-mediated hyperpolarization of porcine coronary artery endothelial cells.

This study investigated the effects of the following adenosine agonists: 5;-ethylcarboxamidoadenosine (NECA), N6-cyclopentyadenosine (CPA) 2-[p-(2-carboxyethyl)]phenylamino-5;N-ethylcarboxamidoadenosine (CGS-21680), and 2-chloroadenosine (CAD) and its antagonist, 4-(2-[7-amino-2-[2-furyl]]1,2,4-triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-241385), a selective A2A adenosine receptor antagonist, and the involvement of the K+ATP and KCa channels on the resting membrane potential (RMP) of confluent monolayers of cultured porcine coronary artery endothelial cells (PCAECs). Adenosine agonists and K+ATP channel openers (pinacidil, cromakalim) hyperpolarized cultured PCAECs. The average RMP was -32.31 +/- 1.2 mV. Adenosine agonists at 10-5 M caused a significant increase in RMP to -65.0 +/- 1.5 mV for CAD (a nonselective adenosine receptor agonist) to -75.9 +/- 1.6 mV for CGS-21680 (a selective A2A receptor agonist) and to -87.0 +/- 3.5 mV for NECA (a nonselective A1/A2A/A2B receptor agonist). Pinacidil and cromakalim at 10 microM increased the membrane potential to -76.2 +/- 1.2 mV and -75.22 +/- 0.12 mV, respectively. The hyperpolarization induced by adenosine receptor agonists and KATP openers was inhibited by an application of the K+ATP channel blocker glibenclamide (10 microM), indicating the involvement of the K+ATP channel in the adenosine-mediated hyperpolarization of PCAECs. Moreover, 1-EB10, a selective opener of the maxi-KCa channel, hyperpolarized PCAECs, and the effect of 1-EB10 was completely blocked by a selective, irreversible blocker of the high conductance KCa (maxi-K) channels (penitrem A), but it only partially blocked the effect of NECA. ZM-241385 has no effect on hyperpolarization elicited by K+ATP and KCa channel openers. However, ZM-241385 significantly blocked the hyperpolarization effect of CAD and CGS-21680. ZM-241385 partially blocked the hyperpolarizing effect of NECA, and a combination of ZM-241385 and penitrem A further blocked the hyperpolarizing effect of NECA. These results further support the involvement of K+ channels in adenosine A2A and A2B receptor-mediated hyperpolarization of PCAECs.

Animals↗

PubMed2004

Effect of blockers of potential-dependent and calcium-activated K+-channels on facilitation of neuromuscular transmission.

Rhythmic stimulation of nerve-muscle preparation of frog sternal muscle bathed in low-Ca(2+) saline increased the release of neurotransmitter (facilitation) and modified the shape of extracellular response of nerve terminal (decreased phase III amplitude). Iberiotoxin and 4-aminopyridine modified the dynamics these processes. We conclude that inactivation of potential-dependent K(+)-channels and activation of calcium-dependent K(+)-channels in frog motor nerve terminals during rhythmic activity modulate Ca(2+) influx into nerve terminals and contribute into facilitation of neurotransmitter secretion. The degree of these mechanisms depends on the rate of synaptic rhythmic activity.

4-Aminopyridine↗

PubMedDate not supplied

[The effect of K(ATP)-channel activation on the electrical stability of myocardium in rats with postinfarction cardiosclerosis].

Opening of the ATP-dependent K-channels (K(ATP) channels) upon intravenous administration of the cardioselective activator BMS 180448 (3 mg/kg) decreased the ventricular fibrillation threshold (VFT) in rats with postinfarction cardiosclerosis (PIC). Preliminary injection of the selective K(ATP) channel blocker glibenclamide (0.3 mg/kg, i.v.) completely abolished the profibrillatory effect of BMS 180448. At the same time, the mitochondrial K(ATP) channel blocker 5-hydroxydecanoic acid (5 mg/kg) did not influence the proarrhythmogen activity of BMS 180448. Simultaneous administration of the sarcoK(ATP) channel inhibitor HMR 1098 (3 mg/kg) and BMS 180448 increased the VFT up to a level in intact animals. Administration of the mitoK(ATP) channel activator diazoxide (5 mg/kg) after preliminary treatment with guanethidine (50 mg/kg) increased the VFT in rats with PIC. It is concluded that opening of the mitoK(ATP) channels increases the cardiac electrical stability in rats with PIC.

Adenosine Triphosphate↗

PubMed1997

Role of inward K+ channel located at carrot plasma membrane in signal cross-talking of cAMP with Ca2+ cascade.

Treatment of cultured carrot cells with dibutyryl cAMP or forskolin resulted in the appreciable decrease in extracellular K+ concentration. This decrease was found to be transient and the concentration of the ion in the culture medium restored to the original level within few minutes. The cAMP-induced decrease in K+ level in the medium was almost completely inhibited when carrot cells were incubated in the presence of K+ channel blockers, CsCl and tetraethylammonium chloride. Appreciable amounts of 45Ca2+ were discharged from 45Ca2+-loaded inside-out vesicles of carrot plasma membrane by the stimulation with cAMP, however, the release of the ion was significantly inhibited in the presence of the K+ channel blockers. The release of 45Ca2+ from the vesicles was also observed when K+ current was evoked with an ionophore, valinomycin, even in the absence of cAMP. These results suggest that the gating of some of the inward K+ channels located at plasma membrane of cultured carrot cells is controlled by cytoplasmic concentration of cAMP and the inward K+ current across the plasma membrane induced by the nucleotide elicits Ca2+ influx into the cells possibly by the activation of voltage-dependent Ca2+ channels.

Bucladesine↗

PubMed2004

Vasorelaxation and hyperpolarisation of rat small mesenteric artery by the quaternary anion tetraphenylboron.

This study characterises the vasorelaxation and hyperpolarisation effects of the negatively charged quaternary compound tetraphenylboron (TPB) in the rat small mesenteric artery. Segments of rat small mesenteric artery were mounted in a myograph and vessel tone and membrane potential were measured simultaneously. In vessels pre-contracted with vasopressin (0.3-0.6 nM), U46619 (30-90 nM) or methoxamine (0.3-3 microM), TPB (0.1-100 microM) produced a marked endothelium-independent relaxation. However, vasorelaxation responses to TPB were abolished in tissues pre-contracted with K(+) (50 mM), and significantly inhibited by glibenclamide (glib, 10 microM). In the absence of tone, TPB (1-30 microM) caused a concentration-dependent membrane hyperpolarisation of rat mesenteric artery smooth muscle cells, which was not dependent on the endothelium, but sensitive to glibenclamide (10 microM). In methoxamine (0.3-3 microM) pre-contracted vessels, the relaxation response was associated with a marked hyperpolarisation, which was also sensitive to glibenclamide (10 microM), further inhibited by a combination of K(+) channel blockers (glib [10 microM], charybdotoxin [100 nM], apamin [100 nM], 4-aminopyridine [1 mM] and Ba(2+) [30 microM]) and abolished by 50 mM K(+). The results of this study show that TPB causes a vasorelaxation and hyperpolarisation response in the rat small mesenteric artery through a direct action on the vascular smooth muscle. TPB exerts its effects partially via the activation of K(ATP) channels, but also by another mechanism involving K(+)-dependent hyperpolarisation.

Animals↗

PubMed2003

Evidence for a function-specific mutation in the neurotoxin, parabutoxin 3.

Parabutoxin 3 (PBTx3), a short-chain alpha-K+ neurotoxin from the scorpion, Parabuthus transvaalicus, is a 37-residue polypeptide cross-linked by three disulphide bridges. The affinity towards Kv1 channels is very weak (Kd approximately 79 micro m for Kv1.1 channels), or moderate (Kd approximately 500 nm for Kv1.2 and Kv1.3 channels). In an effort to generate a more potent K+ channel blocker, we recombinantly produced a mutant PBTx3 by the introduction of an aromatic amino acid, fenylalanine in close proximity of the crucial lysine 26 residue, to create a functional diad similar to subfamily three alpha-K+ toxins. The mutant was tested for his ability to block Kv1.1, Kv1.2 and Kv1.3 channels in Xenopus laevis oocytes: a hundred-fold higher affinity towards Kv1.1 channels and a fivefold increase in affinity towards Kv1.3 channels was observed, when compared to the wild-type toxin. The effect on Kv1.2 channels was similar to the wild-type toxin, indicating a specific interaction site for the mutated residue onto the different Kv-type channels.

Amino Acid Sequence↗

PubMed1997

Mechanism of capsaicin-induced relaxation in equine tracheal smooth muscle.

The effects of capsaicin and neuropeptides were examined in equine tracheal smooth muscle (TSM). Neither capsaicin nor substance P (SP) contracted TSM. Capsaicin (100 microM) elicited relaxation in TSM contracted with methacholine. This relaxation was not mimicked by SP or calcitonin gene-related peptide (CGRP). Relaxation was not attenuated by removal of the epithelium or by pretreatment of tissue with meclofenamate or the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine. Previous exposure of TSM to capsaicin did not eliminate the relaxation responses to subsequent capsaicin. Although vasoactive intestinal peptide (VIP) elicited marked relaxation that was attenuated by alpha-chymotrypsin, alpha-chymotrypsin did not affect the capsaicin-induced relaxation. Capsaicin-induced relaxation was abolished by charybdotoxin, a blocker of large-conductance Ca(2+)-activated K+ channels. These results indicate that capsaicin-induced equine TSM relaxation is not mediated either by neuropeptides such as SP or CGRP released from capsaicin-sensitive sensory nerves or by prostanoids, NO, or VIP. Relaxation is due to the effect of capsaicin on large-conductance Ca(2+)-activated K+ channels. The peptidergic nerves play no important role in the regulation of TSM tone in horse airways.

Animals↗

PubMed2004

NH2-terminal inactivation peptide binding to C-type-inactivated Kv channels.

In many voltage-gated K(+) channels, N-type inactivation significantly accelerates the onset of C-type inactivation, but effects on recovery from inactivation are small or absent. We have exploited the Na(+) permeability of C-type-inactivated K(+) channels to characterize a strong interaction between the inactivation peptide of Kv1.4 and the C-type-inactivated state of Kv1.4 and Kv1.5. The presence of the Kv1.4 inactivation peptide results in a slower decay of the Na(+) tail currents normally observed through C-type-inactivated channels, an effective blockade of the peak Na(+) tail current, and also a delay of the peak tail current. These effects are mimicked by addition of quaternary ammonium ions to the pipette-filling solution. These observations support a common mechanism of action of the inactivation peptide and intracellular quaternary ammonium ions, and also demonstrate that the Kv channel inner vestibule is cytosolically exposed before and after the onset of C-type inactivation. We have also examined the process of N-type inactivation under conditions where C-type inactivation is removed, to compare the interaction of the inactivation peptide with open and C-type-inactivated channels. In C-type-deficient forms of Kv1.4 or Kv1.5 channels, the Kv1.4 inactivation ball behaves like an open channel blocker, and the resultant slowing of deactivation tail currents is considerably weaker than observed in C-type-inactivated channels. We present a kinetic model that duplicates the effects of the inactivation peptide on the slow Na(+) tail of C-type-inactivated channels. Stable binding between the inactivation peptide and the C-type-inactivated state results in slower current decay, and a reduction of the Na(+) tail current magnitude, due to slower transition of channels through the Na(+)-permeable states traversed during recovery from inactivation.

Cell Line↗

PubMed1995

Critical role of endothelium in sustained arterial contraction during prolonged hypoxia.

Acute anoxia or severe hypoxia causes an initial transient contraction followed by marked relaxation of vascular tissues. We observed a spontaneous gradual sustained contraction of rat aortic rings following relaxation when hypoxia was prolonged. Deendothelialization as well as treatment of the endothelium-intact rings with nitric oxide synthase inhibitors or oxyhemoglobin abolished the late hypoxic contraction despite prolonged hypoxia. The prolonged hypoxia-induced sustained contraction was not affected by adenosine receptor blockade, cyclooxygenase inhibition, free radical scavengers, or the endothelin receptor antagonists. The ATP-sensitive K+ channel blocker glibenclamide abbreviated the duration of hypoxic relaxation and potentiated the magnitude of late hypoxic contraction. These data suggest that the late-sustained hypoxic contraction of arterial tissues is dependent on the presence of intact functional endothelium. Activation of ATP-sensitive K+ channels may participate in the genesis of hypoxic relaxation. However, cyclooxygenase products, free oxygen radicals, adenosine, and endothelin are not involved in the regulation of hypoxia-mediated events in rat aortic rings.

Adenosine Triphosphate↗