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Results for “Potassium Channel Blockers”

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At least 253 records · Page 14Linked to original sources

PubMed2005

Patch clamped single pancreatic zymogen granules: direct measurements of ion channel activities at the granule membrane.

BACKGROUND/AIM: Pancreatic acinar cells are involved in the secretion of digestive enzymes. Digestive enzymes in pancreatic acinar cells are stored in membrane-bound secretory vesicles called zymogen granules (ZGs). The swelling of ZGs is implicated in the regulation of the expulsion of intravesicular contents during secretion. The molecular mechanism of ZG swelling has been previously elucidated. It has been further demonstrated that the water channel aquaporin-1, the potassium channel IRK-8, and the chloride channel CLC-2, are present in the ZG membrane and involved in ZG swelling. However, a direct measurement of these ion channels at the ZG membrane in intact ZGs had not been performed. The aim of this study was to investigate the electrical activity of single ZGs and verify the types of channels found within their membrane. METHODS: ZGs from pancreatic acinar cells were isolated from the pancreas of Sprague-Dawley rats. Direct measurements of whole vesicle currents, in the presence and absence of ion channel blockers (quinine, glyburide and DIDS), were recorded following successful patching of single ZGs. CONCLUSION: In this study, we were able, for the first time, to patch single ZGs and study ion channels in their membrane. We were able to record currents across the ZG membrane and, utilizing ion channel blockers, confirm the presence of the chloride channels CLC-2 and the potassium channel IRK-8 (Kir6.1), and additionally demonstrate the presence of a second chloride channel CLC-3.

ATP-Binding Cassette Transporters↗

PubMed2002

Multiple channel interactions explain the protection of sympathetic neurons from apoptosis induced by nerve growth factor deprivation.

We investigated the neuroprotective properties of two M-type K+ channel blockers, linopirdine and its analog XE991, in rat sympathetic neurons deprived of nerve growth factor (NGF). Linopirdine and XE991 promoted sympathetic neuronal survival 48-72 hr after NGF withdrawal in a concentration-dependent manner. Both drugs prevented neuronal apoptosis by blocking the pathway leading to the release of cytochrome c and development of "competence-to-die" after NGF deprivation. Fura-2 Ca2+ imaging showed no significant difference in intracellular free Ca2+ ([Ca2+]i) in the presence or absence of NGF; linopirdine and XE991, on the other hand, caused membrane depolarization and increases in [Ca2+]i. Whole-cell recordings showed that linopirdine and XE991 selectively blocked the M current at neuroprotective concentrations, although they additionally inhibited other K+ currents at high concentrations. Membrane depolarization and [Ca2+]i increases induced by linopirdine and XE991 were blocked by the Na+ channel blocker tetrodotoxin (TTX) or by the L-type Ca2+ channel antagonist nifedipine. TTX and nifedipine also prevented the neuroprotection elicited by linopirdine or XE991. We propose that Na+ channel activation amplifies the membrane depolarization produced by M channel blockade and is essential for subsequent Ca2+ entry via the L-type Ca2+ channel. The interaction of these three classes of ion channels highlights an integrated anti-apoptosis mechanism in sympathetic neurons.

Animals↗

PubMed2005

Orexins cause depolarization via nonselective cationic and K+ channels in isolated locus coeruleus neurons.

The locus coeruleus (LC) contains noradrenergic neurons that are innervated by orexin (ORX)-like immunoreactive axons and express both orexin receptor-1 and -2. We studied effects of ORX-A and -B (ORX-A/B) on dissociated LC neurons by using whole-cell patch clamp techniques. In current-clamp mode, LC neurons were depolarized by application of ORX-A (10(-7) M) [53% of neurons tested; 9.0+/-0.2 mV (n=5)], or ORX-B (10(-7) M) [38% of neurons tested; 4.0+/-0.1 mV (n=5)]. Firing frequencies of action potentials increased during application [1.1+/-0.2 Hz (n=5) in ORX-A; 0.8+/-0.2 Hz (n=5) in ORX-B] and returned to the control level [0.2+/-0.1 Hz (n=5)] after removal. The ORX-A/B-induced depolarization was well maintained in the presence of TTX (3x10(-7) M), CNQX (10(-6) M) and AP5 (10(-5) M). In voltage-clamp mode, removal of external Na+ suppressed both ORX-A/B-induced currents and shifted their reversal potentials from approximately -45 mV to -60 mV. In addition, ORX-A/B inhibited sustained K+ currents. These results suggest that ORX-A/B increase the firing frequency of LC neurons through the depolarization probably produced by both augmentation of the nonselective cationic conductance and inhibition of the sustained K+ conductance.

2-Amino-5-phosphonovalerate↗

PubMed2003

Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action?

Levetiracetam (ucb L059; Keppra) is a novel antiepileptic drug. Its effects on action potential generation and voltage-operated potassium currents were studied in acutely isolated hippocampal CA1 neurones from rat and guinea pig, using the patch-clamp technique in the whole-cell configuration. (i) Levetiracetam reduced repetitive action potential generation and affected the single action potential. Levetiracetam, 100 microM, decreased the total number of action potentials and reduced the total depolarisation area of repetitive action potentials by 21%. Furthermore, levetiracetam increased the duration of the first action potential slightly, prolonged that of the second action potential by 13% and decreased the slope of rise by 23%. (ii) Levetiracetam decreased the voltage-operated potassium current. Without effect on sodium and A-type potassium currents, levetiracetam, 100 microM, reduced the delayed rectifier current by 26%. The concentration of half-maximal block was 47 microM for guinea pig and 6 microM for rat neurones. Thus, the reduction of repetitive action potential generation by levetiracetam can be attributed, unexpectedly, to a moderate reduction of the delayed rectifier potassium current, as supported by a simulation of action potential generation. This suggests that a reduction of potassium currents may contribute to the antiepileptic effect(s) of levetiracetam.

4-Aminopyridine↗

PubMed2000

Odorants suppress voltage-gated currents in retinal horizontal cells in goldfish.

Odorants are known to suppress non-selectively voltage-gated currents in olfactory receptor cells. We found that odorants also suppress voltage-gated currents in neurons of outside of the olfactory system. Under voltage clamp, odorants such as amyl acetate, limonene, and acetophenone suppressed non-selectively voltage-gated currents (a Ca(2+) current, a delayed rectifier K(+) current, a fast transient K(+) current, and an anomalous rectifier K(+) current) in horizontal cells from the goldfish retina. An amyl acetate puff completely and immediately suppressed the Ca(2+) current (I(Ca)) and the delayed rectifier K(+) current induced by repetitive depolarizations, suggesting that amyl acetate is a closed-channel blocker. Odorants did not change significantly the activation curve of I(Ca), but made the slope of inactivation curve of I(Ca) gentler and shifted its half-inactivation voltage toward a negative voltage. These results are similar to the effects of odorants on voltage-gated currents in olfactory receptor cells. This suggests that odorants may suppress the voltage-gated currents in retinal horizontal cells by the same mechanism described in olfactory receptor cells.

Acetophenones↗

PubMed2005

Blocking characteristics of hERG, hNav1.5, and hKvLQT1/hminK after administration of the novel anti-arrhythmic compound AZD7009.

INTRODUCTION: AZD7009 is a novel anti-arrhythmic compound under development for short- and long-term management of atrial fibrillation and flutter. Electrophysiological studies in animals have shown high anti-arrhythmic efficacy, predominant action on atrial electrophysiology, and low proarrhythmic activity. The main aim of this study was to characterize the blocking effects of AZD7009 on the human ether-a-go-go-related gene (hERG), the hNav1.5, and the hKvLQT1/hminK currents. METHODS AND RESULTS: hERG, hKvLQT1/hminK, and hNav1.5 were expressed in CHO K1 cells. Currents were measured using the whole-cell configuration of the voltage-clamp technique. AZD7009 inhibited the hERG current with an IC50 of 0.6 +/- 0.07 microM (n = 6). AZD7009 1 microM hyperpolarized the potential for half-maximal activation from -8.2 +/- 0.1 mV to -18.0 +/- 0.6 mV (P < 0.001, n = 14) and induced pre-pulse potentiation at potentials near the activation threshold. The hNav1.5 current was blocked with an IC50 of 4.3 +/- 1.20 microM at 10 Hz (n = 6) and block developed use-dependently. Recovery from use-dependent block was slow, tau= 131 seconds. AZD7009 inhibited the hKvLQT1/hminK current only at high concentrations (IC50= 193 +/- 20 microM, n = 6). CONCLUSION: AZD7009 inhibits both the hERG and the hNav1.5 current, and it is most likely this combined current block that underlies the prolongation of the refractoriness and the low proarrhythmic activity demonstrated in animals in vivo.

Action Potentials↗

PubMed1998

Electrophysiological properties of human astrocytic tumor cells In situ: enigma of spiking glial cells.

To better understand physiological changes that accompany the neoplastic transition of astrocytes to become astrocytoma cells, we studied biopsies of low-grade, pilocytic astrocytomas. This group of tumors is most prevalent in children and the tumor cells maintain most antigenic features typical of astrocytes. Astrocytoma cells were studied with the use of whole cell patch-clamp recordings in acute biopsy slices from 4-mo- to 14-yr-old pediatric patients. Recordings from 53 cells in six cases of low-grade astrocytomas were compared to either noncancerous peritumoral astrocytes or astrocytes obtained from other surgeries. Astrocytoma cells almost exclusively displayed slowly activating, sustained, tetraethylammonium (TEA)-sensitive outward potassium currents (delayed rectifying potassium currents; IDR) and transient, tetrodotoxin (TTX)-sensitive sodium currents (INa). By contrast, comparison glial cells from peritumoral regions or other surgeries showed IDR and INa, but in addition these cells also expressed transient "A"-type K+ currents and inwardly rectifying K+ currents (IIR), both of which were absent in astrocytoma cells. IIR constituted the predominant conductance in comparison astrocytes and was responsible for a high-resting K+ conductance in these cells. Voltage-activated Na+ currents were observed in 37 of 53 astrocytoma cells. Na+ current densities in astrocytoma cells, on average, were three- to fivefold larger than in comparison astrocytes. Astrocytoma cells expressing INa could be induced to generate slow action potential-like responses (spikes) by current injections. The threshold for generating such spikes was -34 mV (from a holding potential of -70 mV). The spike amplitude and time width were 52.5 mV and 12 ms, respectively. No spikes could be elicited in comparison astrocytes, although some of them expressed Na+ currents of similar size. Comparison of astrocytes to astrocytoma cells suggests that the apparent lack of IIR, which leads to high-input resistance (>500 MOmega), allows glioma cells to be sufficiently depolarized to generate Na+ spikes, whereas the high resting K+ conductance in astrocytes prevents their depolarization and thus generation of spikes. Consistent with this notion, Na+ spikes could be induced in spinal cord astrocytes in culture when IIR was experimentally blocked by 10 microM Ba2+, suggesting that the absence of IIR in astrocytoma cells is primarily responsible for the unusual spiking behavior seen in these glial tumor cells. It is unlikely that such glial spikes ever occur in vivo.

Action Potentials↗

PubMed2001

ATP-Sensitive potassium channels modulate glucose transport in cultured human skeletal muscle cells.

Several lines of evidence suggest that ATP-sensitive potassium (KATP) channels are involved in glucose uptake by insulin target tissues. The aim of the present study was to prove directly the effect of KATP channel activity on glucose transport into cultured human skeletal muscle cells. We used potassium channel openers PCO-400 and nicorandil alone or in combination with channel blockers glibenclamide and gliclazide to examine their effects on insulin- or high glucose concentration-induced glucose uptake using 2-deoxy-D-3H-glucose or 3-O-methyl-D-3H-glucose as tracer, respectively. PCO-400 inhibited the basal (non-stimulated) uptake of 2-DG or 3-OMG at the glucose concentration of 5 mM. PCO-400 and nicorandil dose-dependently inhibited insulin-stimulated glucose uptake, and their inhibitory effects were reversed by glibenclamide or gliclazide. In addition, PCO-400 inhibited high glucose concentration-facilitated glucose transport in the absence of insulin, and this effect was also antagonized by both sulfonylurea drugs. Regarding the mechanism by which KATP channels modulate glucose transport, we focused on protein kinase C (PKC), because PKC has been supposed to participate in both insulin- and high glucose concentration-stimulated glucose transport. PMA (phorbol 12-myristate 13-acetate) dose-dependently reversed the PCO-400-induced suppression of insulin-stimulated glucose uptake. On the other hand, PCO-400 at the concentration that inhibited glucose uptake caused no alteration of membrane-associated PKC activity in the presence of insulin or PMA. From these results we conclude that KATP channels modulate the basal and insulin-or high glucose level-stimulated glucose transport in skeletal muscle through a mechanism independent of PKC.

3-O-Methylglucose↗

PubMed2000

Effects of tetraethylammonium analogs on apoptosis and membrane currents in cultured cortical neurons.

Tetraethylammonium (TEA), the quaternary ammonium ion and nonselective K(+) channel blocker, is protective against neuronal apoptosis. We now tested two TEA analogs, tetrapentylammonium (TPeA) and tetrahexylammonium (THA), for their effects on apoptotic neuronal death and for their pharmacological profiles on membrane currents in cultured mouse cortical neurons. TPeA and THA (0.1-1.0 microM) attenuated staurosporine-induced caspase-3 activation and neuronal apoptosis. TPeA and THA blocked the outward delayed rectifier K(+) (I(K)) current in concentration-dependent manners with IC(50) values of 2.7 and 1.9 microM, respectively. I(K) was blocked by TPeA in a use-dependent manner, whereas THA blocked I(K) regardless of activation state of the channel. TPeA at 1 microM inhibited the high voltage-activated (HVA) Ca(2+) current and the A-type K(+) current (I(A)). TPeA (1-10 microM) also blocked the fast inactivating Na(+) current. The ligand-gated N-methyl-D-aspartate (NMDA) receptor current was not affected by up to 20 microM TPeA. THA at 1 microM showed inhibitory effects on I(A), HVA Ca(2+), and Na(+) currents. THA (10 microM) suppressed NMDA currents. The data suggest that, as K(+) channel blockers and apoptosis antagonists, TPeA and THA are much more potent than TEA; however, they have nonspecific actions on several voltage-gated or ligand-gated channels.

Animals↗

PubMed2004

Methylamine, but not ammonia, is hypophagic in mouse by interaction with brain Kv1.6 channel subtype.

Ammonia and methylamine (MET) are endogenous compounds increased during liver and renal failure, Alzheimer's disease, vascular dementia and diabetes, where they alter some neurobehavioural functions probably acting as potassium channel blockers. We have already described that potassium channel blockers including tetraethylammonium (TEA), ammonia and MET are hypophagic in mice. Antisense oligonucleotides (aODNs) against Shaker-like Kv1.1 gene abolished the effect of TEA but not of ammonia and MET. The central effects elicited in fasted mice by ammonia and MET were further studied. For MET, an ED(50) value 71.4+/-1.8 nmol mouse(-1) was calculated. The slope of the dose-response curves for these two compounds and the partial hypophagic effect elicited by ammonia indicated a different action mechanism for these amines. The aODNs pretreatments capable of temporarily reducing the expression of all seven known subtypes of Shaker-like gene or to inactivate specifically the Kv1.6 subtype abolished the hypophagic effect of MET but not that of ammonia. Reverse transcription-polymerase chain reaction, Western blot and immunohistochemical results indicate that a full expression in the brain of Kv1.6 is required only for the activity of MET, and confirms the different action mechanism of ammonia and MET.

Ammonia↗

PubMed2003

The structure and ion channel activity of 6-benzylamino-3-hydroxyhexa-cyclo[6.5.0.0(3,7).0(4,12).0(5,10).0(9,13]tridecane.

A novel compound, 6-benzylamino-3-hydroxyhexacyclo [6.5.0.0(3, 7).0(4, 12).0(5, 10).0(9, 13)]-tridecane, was synthesized as part of an ongoing study to explore the ion channel activity of polycyclic cage amines. The known polycyclic calcium channel antagonist, 8-benzylamino-8, 11-oxapentacyclo [5.4.0.0(2, 6).0(3, 10).0(5, 9)]undecane (NGP 1-01) served as the lead compound and as a positive control for channel activity. The title compound inhibited calcium currents at test concentrations of 10 microM at depolarized membrane potentials (in the potential range where the L-type calcium channel inactivates). At the test concentrations modulating effects were also observed for sodium and the delayed rectifier potassium currents. Due to its activity at both Ca(2+) and Na(+) channels, this compound may offer utility as a cardiovascular and/or neuroprotecting agent.

Animals↗

PubMed2002

Differential blockade of neuronal voltage-gated Na(+) and K(+) channels by antidepressant drugs.

The effects of a range of antidepressants were investigated on neuronal voltage-gated Na(+) and K(+) channels. With the exception of phenelzine, all antidepressants inhibited batrachotoxin-stimulated 22Na(+) uptake, most likely via negative allosteric inhibition of batrachotoxin binding to neurotoxin receptor site-2 on the Na(+) channel. Imipramine also produced a differential action on macroscopic Na(+) and K(+) channel currents in acutely dissociated rat dorsal root ganglion neurons. Imipramine produced a use-dependent block of Na(+) channels. In addition, there was a hyperpolarizing shift in the voltage-dependence of steady-state Na(+) channel inactivation and slowed repriming kinetics consistent with imipramine having a higher affinity for the inactivated state of the Na(+) channel. At higher concentrations, imipramine also blocked delayed-rectifier and transient outward K(+) currents in the absence of alterations to the voltage-dependence of activation or the kinetics of inactivation. These actions on voltage-gated ion channels may underlie the therapeutic and toxic effects of these drugs.

Algorithms↗

PubMed2003

Contrasting roles of a novel K+ channel blocker and a K+ channel opener on electro-mechanical activity in canine heart tissue.

We tested the effects of a potassium channel opener diazoxide on the action potential duration (APD) and contractile force changes in canine Purkinje tissue induced by a novel class III anti-arrhythmic agent (C3A), KCB-328 (0.5 microM) with 3,4-dimethoxyphenethyl ring structure (0.5 microM). KCB-328 shortened APD(25) by 8.3+/-2.1%, prolonged APD(50) and APD(90) by 31.2+/-5.3 and 50.0+/-7.1%, respectively. Diazoxide (0.1 mM) shortened APD at all levels by 58.3+/-8.1, 54.1+/-6.1, and 42.8+/-5.8%, respectively. In the presence of diazoxide, KCB-328 still prolonged APD(50) and APD(90) (12.5+/-3.8 and 26.8+/-5.9%, respectively). KCB-328 increased force of contraction in a dose-dependent manner. KCB-328 increased force less in the presence of diazoxide. Administration of diazoxide only, reduced force of contraction. We conclude that APD prolongation by KCB-328 may occur even in the presence of diazoxide. It is not sufficient for the restoration of already diminished contractile force and that such an APD prolongation may be unrelated to the restoration of force of contraction even though both are most often seen to occur simultaneously.

Action Potentials↗

PubMed1999

Voltage-activated currents from adult honeybee (Apis mellifera) antennal motor neurons recorded in vitro and in situ.

Voltage-activated currents from adult honey bee antennal motor neurons were characterized with in vitro studies in parallel with recordings taken from cells in situ. Two methods were used to ensure unequivocal identification of cells as antennal motor neurons: 1) selective backfilling of the neurons with fluorescent markers before dissociation for cell culture or before recording from cells in intact brains, semiintact brains, or in brain slices or 2) staining with a fluorescent marker via the patch pipette during recordings and identifying antennal motor neurons in situ on the basis of their characteristic morphology. Four voltage-activated currents were isolated in these antennal motor neurons with pharmacological, voltage, and ion substitution protocols. The neurons expressed at least two distinct K+ currents, a transient current (IA) that was blocked by 4-aminopyridine (4-5 x 10(-3) M), and a sustained current (IK(V)) that was partially blocked by tetraethylammonium (2-3 x 10(-2) M) and quinidine (5 x 10(-5) M). IA activated above -40 to -30 mV and the half-maximal voltages for steady-state activation and inactivation were -8.8 and -43.2 mV, respectively. IK(V) activated above -50 to -40 mV and the midpoint of the steady-state activation curve was +11.2 mV. IK(V) did not show steady-state inactivation. Additionally, two inward currents were isolated: a tetrodotoxin (10(-7) M)-sensitive, transient Na+ current (INa) that activated above -35 mV, with a maximum around -5 mV and a half-maximal voltage for inactivation of -72.6 mV, and a CdCl2 (5 x 10(-5) M)-sensitive Ca2+ current that activated above -45 to -40 mV, with a maximum around -15 mV. This study represents the first step in our effort to analyze the cellular and ionic mechanisms underlying the intrinsic properties and plasticity of antennal motor neurons.

Algorithms↗

PubMed2002

Postnatal development of membrane excitability in taste cells of the mouse vallate papilla.

The mammalian peripheral taste system undergoes functional changes during postnatal development. These changes could reflect age-dependent alterations in the membrane properties of taste cells, which use a vast array of ion channels for transduction mechanisms. Yet, scarce information is available on the membrane events in developing taste cells. We have addressed this issue by studying voltage-dependent Na+, K+, and Cl- currents (I(Na), I(K), and I(Cl), respectively) in a subset of taste cells (the so-called "Na/OUT" cells, which are electrically excitable and thought to be sensory) from mouse vallate papilla. Voltage-dependent currents play a key role during taste transduction, especially in the generation of action potentials. Patch-clamp recordings revealed that I(Na), I(K), and I(Cl) were expressed early in postnatal development. However, only I(K) and I(Cl) densities increased significantly in developing Na/OUT cells. Consistent with the rise of I(K) density, we found that action potential waveform changed markedly, with an increased speed of repolarization that was accompanied by an enhanced capability of repetitive firing. In addition to membrane excitability changes in putative sensory cells, we observed a concomitant increase in the occurrence of glia-like taste cells (the so called "leaky" cells) among patched cells. Leaky cells are likely involved in dissipating the increase of extracellular K+ during action potential discharge in chemosensory cells. Thus, developing taste cells of the mouse vallate papilla undergo a significant electrophysiological maturation and diversification. These functional changes may have a profound impact on the transduction capabilities of taste buds during development.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMedDate not supplied

Effects of glyburide on renal tubule transport and potassium-channel activity.

Renal clearance, microperfusion and patch-clamp techniques were used to investigate the effects of the K-channel blocker glyburide on electrolyte excretion, the transport properties of the thick ascending limb (TAL) of Henle and K-channel activity in the apical membrane of the TAL and of the cortical collecting tubule. Our data suggest that the K-channel blocker glyburide can inhibit transport of Na and K in the TAL by blocking K recycling across the apical membrane. Additionally, inhibition of K secretion in the collecting ducts occurs by decreasing the activity of apical K channels and prevents kaliuresis.

Animals↗

PubMed1999

Sodium influx plays a major role in the membrane depolarization induced by oxygen and glucose deprivation in rat striatal spiny neurons.

BACKGROUND AND PURPOSE: Striatal spiny neurons are selectively vulnerable to ischemia, but the ionic mechanisms underlying this selective vulnerability are unclear. Although a possible involvement of sodium and calcium ions has been postulated in the ischemia-induced damage of rat striatal neurons, the ischemia-induced ionic changes have never been analyzed in this neuronal subtype. METHODS: We studied the effects of in vitro ischemia (oxygen and glucose deprivation) at the cellular level using intracellular recordings and microfluorometric measurements in a slice preparation. We also used various channel blockers and pharmacological compounds to characterize the ischemia-induced ionic conductances. RESULTS: Spiny neurons responded to ischemia with a membrane depolarization/inward current that reversed at approximately -40 mV. This event was coupled with an increased membrane conductance. The simultaneous analysis of membrane potential changes and of variations in [Na+]i and [Ca2+]i levels showed that the ischemia-induced membrane depolarization was associated with an increase of [Na+]i and [Ca2+]i. The ischemia-induced membrane depolarization was not affected by tetrodotoxin or by glutamate receptor antagonists. Neither intracellular BAPTA, a Ca2+ chelator, nor incubation of the slices in low-Ca2+-containing solutions affected the ischemia-induced depolarization, whereas it was reduced by lowering the external Na+ concentration. High doses of blockers of ATP-dependent K+ channels increased the membrane depolarization observed in spiny neurons during ischemia. CONCLUSIONS: Our findings show that, although the ischemia-induced membrane depolarization is coupled with a rise of [Na+]i and [Ca2+]i, only the Na+ influx plays a prominent role in this early electrophysiological event, whereas the increase of [Ca2+]i might be relevant for the delayed neuronal death. We also suggest that the activation of ATP-dependent K+ channels might counteract the ischemia-induced membrane depolarization.

Adenosine Triphosphate↗

PubMed2006

In vivo evidence for nitric oxide-mediated calcium-activated potassium-channel activation during human endotoxemia.

BACKGROUND: During septic shock, the vasoconstrictor response to norepinephrine is seriously blunted. Animal experiments suggest that hyperpolarization of smooth muscle cells by opening of potassium (K) channels underlies this phenomenon. In the present study, we examined whether K-channel blockers and/or nitric oxide (NO) synthase inhibition could restore norepinephrine sensitivity during experimental human endotoxemia. METHODS AND RESULTS: Volunteers received 2 ng/kg Escherichia coli endotoxin intravenously. Forearm blood flow (FBF) was measured with venous occlusion plethysmography. Infusion of 4 dose steps of norepinephrine into the brachial artery decreased the FBF ratio (ratio of FBF in the experimental arm to FBF in the control arm) to 84 +/- 4%, 70 +/- 4%, 55 +/- 4%, and 38 +/- 4% (mean +/- SEM) of its baseline value. After endotoxin administration, norepinephrine-induced vasoconstriction was attenuated (FBF ratio, 101 +/- 4%, 92 +/- 4%, 83 +/- 6%, and 56 +/- 7%; n = 30; P = 0.0018; pooled data). Intrabrachial infusion of the K-channel blocker tetraethylammonium (TEA) completely restored the vasoconstrictor response to norepinephrine from 104 +/- 5%, 93 +/- 7%, 93 +/- 12%, and 69 +/- 12% to 89 +/- 9%, 73 +/- 4%, 59 +/- 5%, and 46 +/- 8% (n = 6; P = 0.045). Other K-channel blockers did not affect the response to norepinephrine. The NO synthase inhibitor N(G)-monomethyl-l-arginine (L-NMMA; 0.2 mg x min(-1) x dL(-1) intra-arterially) also restored the norepinephrine sensitivity. In the presence of L-NMMA, TEA did not have an additional effect on the norepinephrine-induced vasoconstriction (n = 6; P = 0.9). CONCLUSIONS: The K-channel blocker TEA restores the attenuated vasoconstrictor response to norepinephrine during experimental human endotoxemia. Coadministration of L-NMMA abolishes this potentiating effect of TEA, suggesting that NO mediates the endotoxin-induced effect on vascular K channels. In the absence of an effect of the selective adenosine triphosphate-dependent K-channel blocker tolbutamide, we conclude that the blunting effect of endotoxin on norepinephrine-induced vasoconstriction is caused by NO-mediated activation of calcium-activated K channels in the vascular wall.

Adult↗