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Results for “Potassium Channel Blockers”

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PubMed2006

Potassium ion channels of Chlorella viruses cause rapid depolarization of host cells during infection.

Previous studies have established that chlorella viruses encode K(+) channels with different structural and functional properties. In the current study, we exploit the different sensitivities of these channels to Cs(+) to determine if the membrane depolarization observed during virus infection is caused by the activities of these channels. Infection of Chlorella NC64A with four viruses caused rapid membrane depolarization of similar amplitudes, but with different kinetics. Depolarization was fastest after infection with virus SC-1A (half time [t(1/2)], about 9 min) and slowest with virus NY-2A (t(1/2), about 12 min). Cs(+) inhibited membrane depolarization only in viruses that encode a Cs(+)-sensitive K(+) channel. Collectively, the results indicate that membrane depolarization is an early event in chlorella virus-host interactions and that it is correlated with viral-channel activity. This suggestion was supported by investigations of thin sections of Chlorella cells, which show that channel blockers inhibit virus DNA release into the host cell. Together, the data indicate that the channel is probably packaged in the virion, presumably in its internal membrane. We hypothesize that fusion of the virus internal membrane with the host plasma membrane results in an increase in K(+) conductance and membrane depolarization; this depolarization lowers the energy barrier for DNA release into the host.

Cell Membrane↗

PubMed1997

K+ channel inactivation mediated by the concerted action of the cytoplasmic N- and C-terminal domains.

We have examined the molecular mechanism of rapid inactivation gating in a mouse Shal K+ channel (mKv4.1). The results showed that inactivation of these channels follows a complex time course that is well approximated by the sum of three exponential terms. Truncation of an amphipathic region at the N-terminus (residues 2-71) abolished the rapid phase of inactivation (r = 16 ms) and altered voltage-dependent gating. Surprisingly, these effects could be mimicked by deletions affecting the hydrophilic C-terminus. The sum of two exponential terms was sufficient to describe the inactivation of deletion mutants. In fact, the time constants corresponded closely to those of the intermediate and slow phases of inactivation observed with wild-type channels. Further analysis revealed that several basic amino acids at the N-terminus do not influence inactivation, but a positively charged domain at the C-terminus (amino acids 420-550) is necessary to support rapid inactivation. Thus, the amphipathic N-terminus and the hydrophilic C-terminus of mKv4.1 are essential determinants of inactivation gating and may interact with each other to maintain the N-terminal inactivation gate near the inner mouth of the channel. Furthermore, this inactivation gate may not behave like a simple open-channel blocker because channel blockade by internal tetraethylammonium was not associated with slower current decay and an elevated external K+ concentration retarded recovery from inactivation.

Animals↗

PubMed2000

Extracellular K(+) and opening of voltage-gated potassium channels activate T cell integrin function: physical and functional association between Kv1.3 channels and beta1 integrins.

Elevated extracellular K(+) ([K(+)](o)), in the absence of "classical" immunological stimulatory signals, was found to itself be a sufficient stimulus to activate T cell beta1 integrin moieties, and to induce integrin-mediated adhesion and migration. Gating of T cell voltage-gated K(+) channels (Kv1.3) appears to be the crucial "decision-making" step, through which various physiological factors, including elevated [K(+)](o) levels, affect the T cell beta1 integrin function: opening of the channel leads to function, whereas its blockage prevents it. In support of this notion, we found that the proadhesive effects of the chemokine macrophage-inflammatory protein 1beta, the neuropeptide calcitonin gene-related peptide (CGRP), as well as elevated [K(+)](o) levels, are blocked by specific Kv1.3 channel blockers, and that the unique physiological ability of substance P to inhibit T cell adhesion correlates with Kv1.3 inhibition. Interestingly, the Kv1.3 channels and the beta1 integrins coimmunoprecipitate, suggesting that their physical association underlies their functional cooperation on the T cell surface. This study shows that T cells can be activated and driven to integrin function by a pathway that does not involve any of its specific receptors (i.e., by elevated [K(+)](o)). In addition, our results suggest that undesired T cell integrin function in a series of pathological conditions can be arrested by molecules that block the Kv1.3 channels.

Cell Adhesion↗

PubMed2004

Role of ATP-sensitive K+ channels in relaxation of penile resistance arteries.

OBJECTIVES: To investigate the functional presence of adenosine triphosphate (ATP)-sensitive potassium (K+) channels (K(ATP)) in penile resistance arteries by evaluating the relaxant effects of the selective K(ATP) channel openers, cromakalim and levcromakalim, and also the involvement of K(ATP) channels in the relaxation of two drugs currently used in the treatment of erectile dysfunction (ie, prostaglandin E1 [PGE1] and sildenafil). METHODS: Penile resistance arteries were dissected from the horse corpus cavernosum and mounted in microvascular myographs for isometric tension recording. The arteries were precontracted with phenylephrine, and the responses to several vasodilators were tested in the absence and presence of K+ channel blockers. RESULTS: Cromakalim and levcromakalim evoked complete concentration-dependent relaxations that were blocked by 3 microm of the selective K(ATP) channel inhibitor glibenclamide. Raising extracellular K+ (25 mM) inhibited the relaxations to PGE1 and to the selective inhibitor of the cyclic adenosine monophosphate-specific phosphodiesterase (PDE4) rolipram. At a concentration selective for calcium-activated K+(K(Ca)) channels (3 mM), tetraethylammonium inhibited rolipram responses but not those of PGE1. However, glibenclamide significantly reduced the relaxation to both PGE1 and rolipram, but not those induced by the selective inhibitor of the type 5 cyclic guanosine monophosphate-specific phosphodiesterase (PDE5). CONCLUSIONS: The present results suggest a functional role for K(ATP) channels in the relaxation of penile resistance arteries, as well as their differential involvement in the vasodilation to drugs used in the treatment of organic erectile dysfunction. They mediated relaxation to PGE1 and cyclic adenosine monophosphate-elevating agents, but not those of cyclic guanosine monophosphate-elevating agents such as sildenafil.

Adenosine Triphosphate↗

PubMed2005

A functional role for small-conductance calcium-activated potassium channels in sensory pathways including nociceptive processes.

We investigated the role of small-conductance calcium-activated potassium (SK) and intermediate-conductance calcium-activated potassium channels in modulating sensory transmission from peripheral afferents into the rat spinal cord. Subunit-specific antibodies reveal high levels of SK3 immunoreactivity in laminas I, II, and III of the spinal cord. Among dorsal root ganglion neurons, both peripherin-positive (C-type) and peripherin-negative (A-type) cells show intense SK3 immunoreactivity. Furthermore, dorsal root-stimulated sensory responses recorded in vitro are inhibited when SK channel activity is increased with 1-ethyl-2-benzimidazolinone (1-EBIO). In vivo electrophysiological recordings show that neuronal responses to naturally evoked nociceptive and nonnociceptive stimuli increase after application of the selective SK channel blocker 8,14-diaza-1,7(1,4)-diquinolinacyclotetradecaphanedium di-trifluoroacetate (UCL 1848), indicating that SK channels are normally active in moderating afferent input. Conversely, neuronal responses evoked by mechanical stimuli are inhibited when SK channel activity is increased with 1-EBIO. These effects are reversed by the subsequent application of UCL 1848. Our data demonstrate that SK channels have an important role in controlling sensory input into the spinal cord.

Animals↗

PubMed1998

Inhibition of cholinergic neurotransmission in guinea pig trachea by NS1619, a putative activator of large-conductance, calcium-activated potassium channels.

Indirect functional studies suggest that large-conductance calcium-activated potassium channels (BKCa channels) are involved in the control of ACh release from postganglionic, parasympathetic nerve terminals in the airways. The role of BKCa channels in regulating cholinergic neurotransmission was assessed by 1) investigating the effect of the putative BKCa channel opener NS1619 on cholinergic contractile responses and ACh output evoked by electrical field stimulation (EFS: 40 V, 0.5 ms, 4 Hz for 15 s every 4 min) and comparing the effect obtained with the inhibition of EFS-evoked ACh release by oxotremorine M, a muscarinic agonist, and 2) evaluating the sensitivity of these responses to the BKCa channel blocker iberiotoxin (IbTX). NS1619 (30 microM) inhibited cholinergic contractile responses by 60.0%. In contrast, NS1619 had no effect on contractile responses evoked by exogenous ACh (1 microM), which indicated that it was acting prejunctionally. NS1619 (30 microM) significantly inhibited EFS-induced ACh release by 33.9%. Oxotremorine M suppressed EFS-evoked ACh release in a concentration-dependent manner (at 1 microM, 77.4% inhibition). In neither case was the inhibition reversed by IbTX (100 nM). Collectively, the mechanical data suggest that NS1619 inhibits cholinergic contractile responses by interacting prejunctionally. The failure of IbTX to reverse the inhibitory action of NS1619 and oxotremorine M on ACh release indicates that activation of muscarinic autoinhibitory receptors is not coupled to the opening of IbTX-sensitive BKCa channels. Therefore, we propose that caution be exercised when using NS1619 as an activator of BKCa channels.

Acetylcholine↗

PubMed2005

Moderate glucose deprivation preconditions myocardium against infarction.

Glucose-free perfusion preconditions myocardium against the consequences of subsequent ischemia. We investigated whether mitochondrial ATP-sensitive potassium (mK (ATP)) channels are involved in preconditioning by glucose deprivation, and whether moderate glucose deprivation also preconditions myocardium. Isolated rat hearts underwent 30 min of no-flow ischemia followed by 1 h reperfusion. Controls were not further treated. Three groups were preconditioned by perfusion with 0, 40 or 80 mg/dl (0, 2.22, 4.44 mmol/l) glucose (correction of osmotic pressure by addition of urea) for 10 min followed by 10 min perfusion with normal buffer (150 mg/dl, or 8.33 mmol/l glucose) before the ischemia reperfusion protocol. In one group, 100 micromol/l of the mK (ATP) channel blocker 5-HD was added to the glucose-free perfusate. Two groups were treated with 5-HD or urea before ischemia without preconditioning. Left ventricular developed pressure and maximum ischemic contracture (82 +/- 21 mmHg) were similar in all groups. Mean left ventricular developed pressure was 100 +/- 16 mm Hg under baseline conditions, and poorly recovered to 8 +/- 11 mm Hg during reperfusion. Preconditioning with 0 and 40 mg/dl glucose containing buffer reduced infarct size from 41 +/- 10% (control) to 23 +/- 12% (p = 0.02) and 26 +/- 8% (p = 0.011). The 5-HD blocked preconditioning by glucose deprivation (38 +/- 9%, p = 0.04) while 80 mg/dl glucose, 5-HD and urea had no effect on infarct size (39 +/- 9%; 38 +/- 13%; 37 +/- 8%; p = 1.0 each). We conclude that transient severe glucose deprivation and moderate glucose deprivation preconditions the isolated rat heart. Preconditioning by complete glucose deprivation depends on the opening of mK (ATP) channels.

Animals↗

PubMed1999

Cardiac ion channels and antihistamines: possible mechanisms of cardiotoxicity.

Despite the enormous success of second generation antihistamines, in the mid-1980s, about 10 years after their introduction in the market, several reports appeared in the literature indicating the rare occurrence of a form of polymorphic ventricular dysrhythmia, the 'torsade de pointes', after the administration of astemizole or terfenadine. This cardiac side-effect has been interpreted as a consequence of the interference of these drugs with cardiac K+ channels involved in action potential repolarization, and in particular with the IKr component of the cardiac repolarizing current. As the K+ channels encoded by the human ether-a-gogo-related gene (HERG) seem to represent the molecular basis of IKr, this cardiac K+ channel was soon recognized as a primary target for second generation antihistamine-induced proarrhythmic effects. In fact, both terfenadine and astemizole have been shown to block HERG K+ channels in a concentration range similar to that found in the plasma of subjects with cardiotoxic manifestations. However, no correlation can be found between the ability to prolong the cardiac action potential duration and the H1-antagonistic activity by several antihistamines, suggesting that HERG blockade and cardiotoxic potential are not class properties of second generation antihistamines. In fact, other molecules such as cetirizine, loratadine, acrivastine, and fexofenadine seem to lack both cardiotoxic potential and HERG-blocking ability at therapeutically relevant concentrations. The marked heterogeneity displayed by second generation antihistamines in their ability to prolong the cardiac action potential duration and to block HERG K+ channels might be of considerable therapeutical significance for those patients at risk of developing cardiac dysrhythmias and in need of therapy with H1-receptor blockers; it also emphasizes the importance of an evaluation of the possible blockade of HERG K+ channels during the early developmental phases of novel compounds belonging to this therapeutical class.

Cation Transport Proteins↗

PubMed2000

Fentanyl protects the heart against ischaemic injury via opioid receptors, adenosine A1 receptors and KATP channel linked mechanisms in rats.

We have investigated if fentanyl protects against myocardial ischaemic injury and if so, if the mechanism of this protection is mediated via opioid and adenosine A1 receptors, and KATP channels. Langendorff rat hearts were subjected to global ischaemia (30 min) and reperfusion (60 min). The drugs were administered before induction of ischaemia and maintained throughout the experiment. Treatment with fentanyl 740 nmol litre-1 improved post-ischaemic mechanical function, assessed as developed pressure, +dP/dtmax and -dP/dtmin, compared with controls after 60 min of reperfusion. These effects were abolished by naloxone 1 mumol litre-1, DPCPX 10 mumol litre-1, a selective adenosine A1 antagonist and sodium 5-hydroxydecanoate 100 mumol litre-1, a K+ATP channel blocker. We conclude that fentanyl protected the heart against post-ischaemic injury by a mechanism which was blocked by an opioid and an adenosine A1 receptor antagonist and also by a KATP channel antagonist.

Adenosine Triphosphate↗

PubMed1997

Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride.

Cisapride, a gastrointestinal prokinetic agent, is known to cause long Q-T syndrome and ventricular arrhythmias. The cellular mechanism is not known. The human ether-á-go-go-related gene (HERG), which encodes the rapidly activating delayed rectifier K+ current and is important in cardiac repolarization, may serve as a target for the action of cisapride. We tested the hypothesis that cisapride blocks HERG. The whole cell patch-clamp recording technique was used to study HERG channels stably expressed heterologously in HEK293 cells. Under voltage-clamp conditions, cisapride block of HERG is dose dependent with a half-maximal inhibitory concentration of 6.5 nM at 22 degrees C (n = 25 cells). Currents rapidly recovered with drug washout. The onset of block by cisapride required channel activation indicative of open or inactivated state blockage. Block of HERG with cisapride after channel activation was voltage dependent. At -20 mV, 10 nM cisapride reduced HERG tail-current amplitude by 5%, whereas, at + 20 mV, the tail-current amplitude was reduced by 45% (n = 4 cells). At -20 and + 20 mV, 100 nM cisapride reduced tail-current amplitude by 66 and 90%, respectively. We conclude that cisapride is a potent blocker of HERG channels expressed in HEK293 cells. This effect may account for the clinical occurrence of Q-T prolongation and ventricular arrhythmias observed with cisapride.

Cation Transport Proteins↗

PubMed1999

Pharmacological and histochemical distinctions between molecularly defined sarcolemmal KATP channels and native cardiac mitochondrial KATP channels.

A variety of direct and indirect techniques have revealed the existence of ATP-sensitive potassium (KATP) channels in the inner membranes of mitochondria. The molecular identity of these mitochondrial KATP (mitoKATP) channels remains unclear. We used a pharmacological approach to distinguish mitoKATP channels from classical, molecularly defined cardiac sarcolemmal KATP (surfaceKATP) channels encoded by the sulfonylurea receptor SUR2A and the pore-forming subunit Kir6.2. SUR2A and Kir6.2 were expressed in human embryonic kidney (HEK)293 cells, and their activities were measured by patch-clamp recordings of membrane current. SurfaceKATP channels are activated potently by 100 microM pinacidil but only weakly by 100 microM diazoxide; in addition, they are blocked by 10 microM glibenclamide, but are insensitive to 500 microM 5-hydroxydecanoate. This pharmacology, which was confirmed with patch-clamp recordings in intact rabbit ventricular myocytes, contrasts with that of mitoKATP channels as indexed by flavoprotein oxidation. MitoKATP channels in myocytes are activated equally by 100 microM diazoxide and 100 microM pinacidil. In contrast to its lack of effect on surfaceKATP channels, 5-hydroxydecanoate is an effective blocker of mitoKATP channels. Glibenclamide's effects on mitoKATP channels are difficult to assess, because it independently activates flavoprotein fluorescence, consistent with a previously described primary uncoupling effect. Confocal imaging of the subcellular distribution of expressed fluorescent Kir6.2 in HEK cells and in myocytes revealed no targeting of mitochondrial membranes. The differences in drug sensitivity and subcellular localization indicate that mitoKATP channels are distinct from surface KATP channels at a molecular level.

Animals↗

PubMed2002

Potassium channels and human corporeal smooth muscle cell tone: further evidence of the physiological relevance of the Maxi-K channel subtype to the regulation of human corporeal smooth muscle tone in vitro.

PURPOSE: Recent evidence indicates that the large conductance, voltage dependent, Ca2+ sensitive K channel or Maxi-K has an important role in the modulation of human corporeal smooth muscle tone and, thus, in erectile capacity. We further clarified the contribution of the Maxi-K channel subtype to the generation of contractile responses in isolated human corporeal tissue strips. MATERIALS AND METHODS: We performed pharmacological studies of phenylephrine contracted isolated corporeal tissue strips in the presence and absence of the 2 Maxi-K channel blockers tetraethylammonium chloride (TEA) and charybdotoxin, and the Maxi-K opener NS1619. K channel treatment effects were evaluated using 2 parameters, including 1) the steady state parameter of the empirically determined peak magnitude of the steady state contractile response and 2) the kinetic parameter of time required to achieve half of the peak steady state contractile response or half-time. Electrophysiological studies in freshly isolated and cultured myocytes were performed in parallel to corroborate findings further at the tissue level. RESULTS: Pre-incubating isolated human corporeal tissue strips with 1 mM. TEA and 1 microM. charybdotoxin was associated with an approximate 20% increase in the peak steady state contractile response and a corresponding approximate 20% decrease in the half-time of the phenylephrine induced contractile response. Conversely, pre-incubation with 10 microM. NS1619 produced a significant, approximately 20% decrease in the peak steady state contractile response and an approximate 38% increase in the half-time of the phenylephrine induced contractile response. Adding 30 to 180 microM. NS1619 to phenylephrine pre-contracted smooth muscle strips resulted in a 30% to 50% reduction in steady state contractile tension. No detectable effect of NS1619 was observed in 120 mM. KCl or 100 mM. TEA pre-contracted corporeal tissue strips. Whole cell recordings of freshly isolated and cultured corporeal myocytes confirmed that 30 microM. NS1619 induced a charybdotoxin sensitive hyperpolarizing current mediated by the Maxi-K channel. CONCLUSIONS: These in vitro studies confirm and extend previous observations indicating the importance of the Maxi-K channel for regulating human corporeal smooth muscle tone, and by extension, erectile capacity and function.

Benzimidazoles↗

PubMed2004

Role of G protein-gated inwardly rectifying potassium channels in P2Y12 receptor-mediated platelet functional responses.

The role of the G(i)-coupled platelet P2Y(12) receptor in platelet function has been well established. However, the functional effector or effectors contributing directly to alphaIIbbeta3 activation in human platelets has not been delineated. As the P2Y(12) receptor has been shown to activate G protein-gated, inwardly rectifying potassium (GIRK) channels, we investigated whether GIRK channels mediate any of the functional responses of the platelet P2Y(12) receptor. Western blot analysis revealed that platelets express GIRK1, GIRK2, and GIRK4. In aspirin-treated and washed human platelets, 2 structurally distinct GIRK inhibitors, SCH23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride) and U50488H (trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(pyrrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate), inhibited adenosine diphosphate (ADP)-, 2-methylthioADP (2-MeSADP)-, U46619-, and low-dose thrombin-mediated platelet aggregation. However, the GIRK channel inhibitors did not affect platelet aggregation induced by high concentrations of thrombin, AYPGKF, or convulxin. Furthermore, the GIRK channel inhibitors reversed SFLLRN-induced platelet aggregation, inhibited the P2Y(12)-mediated potentiation of dense granule secretion and Akt phosphorylation, and did not affect the agonist-induced G(q)-mediated platelet shape change and intracellular calcium mobilization. Unlike AR-C 69931MX, a P2Y(12) receptor-selective antagonist, the GIRK channel blockers did not affect the ADP-induced adenlylyl cyclase inhibition, indicating that they do not directly antagonize the P2Y(12) receptor. We conclude that GIRK channels are important functional effectors of the P2Y(12) receptor in human platelets.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2006

The adenosine 5'-triphosphate-sensitive potassium channel in endocrine cells of the human ovary: role in membrane potential generation and steroidogenesis.

CONTEXT: ATP-sensitive potassium (K(ATP)) channels couple the metabolic state with the membrane potential in several cell types, and recently evidence for K(ATP) channels was given in rat corpus luteum, a fast-growing and metabolically highly active tissue. OBJECTIVE: We studied whether K(ATP) channels are present in the human ovary and luteinized granulosa cells (GCs). Human GCs were examined regarding functionality and physiological role of the channel. PATIENTS AND INTERVENTION: Human GCs were obtained from in vitro fertilization patients. RESULTS: K(ATP) channels are involved in membrane potential generation in human GCs because application of the K(ATP) blocker glibenclamide resulted in depolarization as monitored by fluorescence microscopy. Furthermore, glibenclamide significantly attenuated human chorionic gonadotropin-induced progesterone production. The channel pore is composed of K(ir)6.1, but not K(ir)6.2, as indicated by RT-PCR. K(ir)6.1 subunit protein was detected in human follicular and luteal cells by immunohistochemistry and localized to the plasma membrane of human GCs by immunogold staining. RT-PCR experiments revealed the sulfonylurea receptor subunit SUR2B as part of the K(ATP) channel. In addition, mRNAs encoding SUR1 and SUR2A were detected in some preparations. There is no evidence for mitochondrial K(ATP) channels in human GCs because we detected neither K(ir)6.1 protein in mitochondrial membranes nor alterations of mitochondrial membrane potential by glibenclamide or the K(ATP) opener diazoxide. CONCLUSIONS: Endocrine cells of the human ovary possess functional K(ATP) channels, which are linked to both plasma membrane potential generation and progesterone production. Our results may provide new insights into human ovarian physiology and raise the possibility of pharmacological targeting.

ATP-Binding Cassette Transporters↗

PubMed2001

Role of K+ -channels in homotaurine-induced analgesia.

In previous articles, antinociceptive activity for homotaurine has been demonstrated to be mediated by opioid, GABAergic and cholinergic mechanisms. GABAB-agonists affect K+-channels and it is known that K+-channels modulate specific activation of opioid receptors. In this study, we examined the involvement of K+-channels in the antinociceptive activity of homotaurine (22-445 mg/kg). Antinociceptive response was obtained after icv pretreatment with the channel specific blockers 4-aminopyridine (voltage-dependent channels), tetraethylammonium (Ca++ and voltage-dependent) and gliquidone (ATP-dependent). The nociceptive tests performed were acetic acid induced abdominal constriction (mice) and tail flick (rats) tests. Acetic acid responses to homotaurine were inhibited by tetraethylammonium (5 microg) and gliquidone (16 microg). Tail flick response to homotaurine was inhibited by tetraethylammonium (50 microg), gliquidone (40 and 80 microg) and 4-aminopyridine (25 and 250 ng). These results suggest an involvement of the three types of K+-channels in antinociception by homotaurine, depending on specific homotaurine and blocker doses. At a spinal level, they appear to be involved together with GABAB and opioid mechanisms. Peripherally, only tetraethylammonium channels would be substantially activated during homotaurine antinociceptive effect.

4-Aminopyridine↗

PubMed2004

Role of potassium channels in the nitric oxide-independent vasodilator response to acetylcholine.

Stimulation of vascular endothelial muscarinic receptors by acetylcholine (ACh) leads to the formation of an endothelium-derived relaxing factor (EDRF), which is generally accepted to be nitric oxide (NO). Recent evidence, however, suggests that NO may be only one of several EDRFs mediating the vasodilator response to ACh. Since this NO-independent vasodilator response to ACh has been hypothesized to be dependent upon K(+) channel activation, the current study was undertaken to investigate the role of K(+) channels in mediating the hindlimb vasodilator responses to ACh in vivo. Additionally, since variations in vascular tone can complicate the analysis of responses, the level of vascular tone was maintained at a similar level throughout the study so that responses could be compared directly. The results of the present study demonstrate that the vasodilator response to ACh possesses a significant component that is independent of NO production. The K(Ca) channel blockers charybdotoxin and apamin, but not K(+)-ATP channel blocker U37883A or the COX antagonist meclofenamate, attenuated the NO-independent component of the vasodilator response to ACh. This suggests that K(Ca) channels, but not K(+)-ATP channels or COX products, are involved in mediating the L-NAME resistant response to ACh. Further, the inhibition of the ACh vasodilator response by the K(+)-ATP opener BRL55834 suggests that the response is dependent upon membrane hyperpolarization. These data suggest that the mechanism mediating ACh responses in the hindlimb vascular bed of the rat are complex and may involve several signaling pathways.

Acetylcholine↗

PubMed1994

Role of calcium-activated potassium channels in the relaxation of tracheal smooth muscles by forskolin.

1. The role of calcium-activated potassium (KCa) channels in bronchodilation produced by a direct adenylyl cyclase activator, forskolin, was investigated. The involvement of intracellular cyclic AMP (cAMP) in the process was also examined. 2. The isometric tension records from guinea-pig tracheal smooth muscles indicated that application of charybdotoxin (ChTX), a selective inhibitor of large conductance KCa channels, led to a suppression of the relaxant effect of forskolin in the precontracted tissue by carbachol (CCh). However, the inhibitory action by ChTX had a much greater effect on the relaxation caused by isoproterenol than by forskolin. 3. In contrast to the effect of ChTX, glybenclamide, a cromakalim-sensitive K+ channel inhibitor and apamin, a small conductance KCa channel blocker, had no effects on the bronchodilation produced by forskolin. 4. The effects of forskolin and nifedipine on tone produced by high K+ was compared. Concentration-inhibition curves in guinea-pig trachealis precontracted by 20 mmol/L K+ solution were similar for forskolin and nifedipine. Conversely, relaxation by forskolin was significantly diminished when tissues were contracted with 40 mmol/L K+ solution, whereas nifedipine relaxations were unaffected. 5. A single channel record from a cell-attached patch in a porcine tracheal myocyte demonstrated that forskolin stimulates reversibly KCa channels without affecting the unitary amplitude. 6. The results are consistent with forskolin-induced relaxation occurring at least in part through the opening of ChTX-sensitive KCa channels, by means of a cAMP-dependent channel modulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Inhibition of adenosine-induced coronary vasodilation by block of large-conductance Ca(2+)-activated K+ channels.

The aim of the present study was to investigate the contribution of large-conductance calcium-activated potassium (large-conductance KCa) channels to adenosine (Ado)- and nitroprusside-mediated relaxation in small coronary arteries. Canine subepicardial arteries (170 +/- 23 microns at 120 mmHg) were studied as in vitro pressurized vessels. Pressure-diameter experiments showed myogenic tone over a physiological range of pressures. Tone was increased with the thromboxane A2 analogue 9,11-dideoxy-11 alpha,9 alpha-epoxy-methanoprostaglandin F2 alpha (U-46619). Tetraethylammonium (TEA+; 1 mM) significantly inhibited Ado-induced [and by implication, adenosine 3',5'-cyclic monophosphate (cAMP)-induced] relaxations at Ado concentrations ranging from 0.1 to 10 microM with maximal inhibition (61 +/- 8%) at 1 microM Ado. The large-conductance KCa-channel blocker iberiotoxin (IbTX; 0.01-0.1 microM) inhibited Ado-mediated relaxation in a concentration-dependent manner. Inhibition by IbTX increased with increasing vessel pressure (i.e., 45 +/- 12% at 40 mmHg and 83 +/- 20% at 120 mmHg). TEA+ had a minimal effect (8 +/- 3%) on relaxation induced by nitroprusside. Similar results were found with acetylcholine and bradykinin. These results suggest that (in dog coronary arteries with diameter < 200 microns) large-conductance KCa-channel modulation may play a major role in cAMP-mediated relaxation but is not significant in guanosine 3',5'-cyclic monophosphate-mediated relaxation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗