SEARCH · PubMed Health

Results for “Potassium Channel Blockers”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 739 records · Page 41Linked to original sources

PubMed2003

Effect of the sarcolemmal K(ATP) channel blocker HMR1098 on arrhythmias induced by programmed electrical stimulation in canine old myocardial infarction model: comparison with glibenclamide.

The blockade of myocardial K(ATP) channels may be antiarrhythmic for ischemic arrhythmias. A new sulfonylthiourea, HMR1098 (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenylsulfonyl]-3-methylthiourea, sodium salt), was demonstrated to be a cardioselective K(ATP)-channel antagonist and to suppress arrhythmias during acute ischemia. We investigated effects of HMR1098 on the arrhythmias induced by programmed electrical stimulation (PES) in a canine old myocardial infarction model. HMR1098 (3 mg/kg, i.v.) significantly improved the scores of PES-induced ventricular arrhythmias, without changing the blood glucose concentrations. A classical sulfonylurea, glibenclamide (1 mg/kg, i.v.), had no significant effects on these arrhythmias, but reduced the blood glucose and increased the plasma insulin concentrations.

Adenosine Triphosphate↗

PubMed1996

Transmembrane potential responses during HL-60 promyelocyte differentiation.

Myeloid cells, including granulocytes and monocyte/macrophages, are important in disease-associated inflammatory reactions. These cells come from a common progenitor, the promyelocyte. The human promyelocytic cell line, HL-60, can be induced to terminally differentiate into granulocytes or monocyte/ macrophages in a controlled fashion providing a model to study various aspects of myelomonocytic differentiation. The expression of several ion channels is controlled in HL-60 cells in a differentiation specific pattern. The purpose of this study was to determine if lineage-specific ion channel expression during HL-60 differentiation resulted in differences in functional responses to external stimuli. This was investigated by examining transmembrane potential responses in HL-60 promyelocytes, HL-60-derived polymorphonuclear cells (PMNs), and monocytes to various stimuli using the transmembrane potential sensitive dye, diSBAC2-(3). Exposure of HL-60 promyelocytes to ionomycin or ATP produced a membrane hyperpolarization. Studies using ion substitutions and ion channel blockers indicate that the hyperpolarization was mediated by KCa channels. During HL-60 promyelocyte differentiation to PMNs, the membrane potential response to ionomycin and ATP shifted from a hyperpolarization to a depolarization over 7 days. Conversely, HL-60-derived monocytes exhibited a membrane hyperpolarization in response to ionomycin and ATP. HL-60-derived monocytes also exhibit a Cl- conductance specifically induced by ATP. Lineage-specific expression of ion channels during HL-60 cell differentiation is important in determining the transmembrane potential response of these cells. This may be translated into functional responses of various myelomonocytic cells during disease-associated inflammatory reactions.

Calcium↗

PubMed1995

The pulmonary vascular response to propofol in the isolated perfused rat lung.

This study investigated the effect of propofol on the pulmonary vascular bed of the rat. Propofol (5 x 10(-6) to 5 x 10(-4) M) did not alter the basal perfusion pressure in isolated rat lungs perfused at a constant flow (0.03 mL g body wt-1 min-1) with Krebs-Henseleit solution. When perfusion pressure was elevated by raising the K+ concentration to 30 mM (depolarizing Krebs-Henseleit solution), propofol decreased it in a concentration-dependent manner. Indomethacin (3 x 10(-6) M) and NG-nitro-L-arginine methyl ester (10(-4) M) did not affect the response to propofol, which excluded the role of cyclo-oxygenase metabolites and nitric oxide, respectively. The ATP-sensitive K+ (K+ATP) channel blocker glibenclamide (3 x 10(-6) and 10(-5) M) inhibited the vasodilator effect of propofol. When lungs were perfused with Ca(2+)-free depolarizing Krebs-Henseleit solution, 0.1-2.5 mM Ca+2 produced a concentration-dependent pressor response. Propofol (5 x 10(-5) M) attenuated the vasopressor response to Ca2+ significantly. In conclusion, the activation of K+ATP channels is probably the major mechanism of the vasodilator effect of propofol, at clinically relevant concentrations, in the rat lung. The Ca2+ antagonistic property of propofol is evident only at higher concentrations.

Anesthetics, Intravenous↗

PubMed2000

The peripheral antinociceptive effect induced by morphine is associated with ATP-sensitive K(+) channels.

The effect of several K(+) channel blockers such as glibenclamide, tolbutamide, charybdotoxin (ChTX), apamin, tetraethylammonium (TEA), 4-aminopyridine (4-AP) and cesium on the peripheral antinociceptive effect of morphine was evaluated by the paw pressure test in Wistar rats. The intraplantar administration of a carrageenan suspension (250 microg) resulted in an acute inflammatory response and a decreased threshold to noxious pressure. Morphine administered locally into the paw (25, 50, 100 and 200 microg) elicited a dose-dependent antinociceptive effect which was demonstrated to be mediated by a peripheral site up to the 100 microg dose. The selective blockers of ATP-sensitive K(+) channels glibenclamide (20, 40 and 80 microg paw(-1)) and tolbutamide (40, 80 and 160 microg paw(-1)) antagonized the peripheral antinociception induced by morphine (100 microg paw(-1)). This effect was unaffected by ChTX (0. 5, 1.0 and 2.0 microg paw(-1)), a large conductance Ca(2+)-activated K(+) channel blocker, or by apamin (2.5, 5.0 and 10.0 microg paw(-1)), a selective blocker of a small conductance Ca(2+)-activated K(+) channel. Intraplantar administration of the non-specific K(+) channel blockers TEA (160, 320 and 640 microg), 4-AP (10, 50 and 100 microg) and cesium (125, 250 and 500 microg) also did not modify the peripheral antinociceptive effect of morphine. These results suggest that the peripheral antinociceptive effect of morphine may result from activation of ATP-sensitive K(+) channels, which may cause a hyperpolarization of peripheral terminals of primary afferents, leading to a decrease in action potential generation. In contrast, large conductance Ca(2+)-activated K(+) channels, small conductance Ca(2+)-activated K(+) channels as well as voltage-dependent K(+) channels appear not to be involved in this transduction pathway. British Journal of Pharmacology (2000) 129, 110 - 114

4-Aminopyridine↗

PubMed1998

ATP-sensitive K+ channels in smooth muscle cells of guinea-pig mesenteric lymphatics: role in nitric oxide and beta-adrenoceptor agonist-induced hyperpolarizations.

1. Intracellular microelectrode recordings were performed to investigate the membrane K+ conductances involved in smooth muscle hyperpolarization of lymphatic vessels in the guinea-pig mesentery. 2. Nitric oxide (NO), released either by the endothelium after acetylcholine (ACh; 10 microM) stimulation or by sodium nitroprusside (SNP; 50-100 microM), hyperpolarized lymphatic smooth muscle. These responses were inhibited with the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole [4,3-a]quinoxalin-1-one (ODQ, 10 microM). 3. ACh and SNP-induced hyperpolarizations were inhibited (by about 90%) upon application of the ATP-sensitive K+(K(ATP)) channel blocker, glibenclamide (10 microM), or with 4-aminopyridine (2.5 mM), but were not affected by the Ca2+-activated K+ channels blocker, penitrem A (100 nM). 4. Hyperpolarization caused by the K+ channel opener, cromakalim (0.1-10 microM), isoprenaline (0.1 microM) or forskolin (0.5 microM) were all significantly blocked by glibenclamide. 5. Hyperpolarization evoked by ACh and SNP were inhibited with N-[2-(p-bromociannamylamino)-ethyl]-5-isoquinolinesulfonamide-dich loride (H89, 10 microM), suggesting the involvement of cyclic AMP dependent protein kinase (PKA). 6. These results suggest that K(ATP) channels play a central role in lymphatic smooth muscle hyperpolarization evoked by a NO-induced increase in cyclic GMP synthesis, as well as by beta-adrenoceptor-mediated production of cyclic AMP. Interestingly, both pathways lead to K(ATP) channels opening through the activation of PKA.

Adenosine Triphosphate↗

PubMed1999

The role of BK-type Ca2+-dependent K+ channels in spike broadening during repetitive firing in rat hippocampal pyramidal cells.

1. The role of large-conductance Ca2+-dependent K+ channels (BK-channels; also known as maxi-K- or slo-channels) in spike broadening during repetitive firing was studied in CA1 pyramidal cells, using sharp electrode intracellular recordings in rat hippocampal slices, and computer modelling. 2. Trains of action potentials elicited by depolarizing current pulses showed a progressive, frequency-dependent spike broadening, reflecting a reduced rate of repolarization. During a 50 ms long 5 spike train, the spike duration increased by 63.6 +/- 3.4 % from the 1st to the 3rd spike. The amplitude of the fast after-hyperpolarization (fAHP) also rapidly declined during each train. 3. Suppression of BK-channel activity with (a) the selective BK-channel blocker iberiotoxin (IbTX, 60 nM), (b) the non-peptidergic BK-channel blocker paxilline (2-10 microM), or (c) calcium-free medium, broadened the 1st spike to a similar degree ( approximately 60 %). BK-channel suppression also caused a similar change in spike waveform as observed during repetitive firing, and eliminated (occluded) most of the spike broadening during repetitive firing. 4. Computer simulations using a reduced compartmental model with transient BK-channel current and 10 other active ionic currents, produced an activity-dependent spike broadening that was strongly reduced when the BK-channel inactivation mechanism was removed. 5. These results, which are supported by recent voltage-clamp data, strongly suggest that in CA1 pyramidal cells, fast inactivation of a transient BK-channel current (ICT), substantially contributes to frequency-dependent spike broadening during repetitive firing.

Action Potentials↗

PubMed1995

The ACh-induced whole-cell currents in sheep parotid secretory cells. Do BK channels really carry the ACh-evoked whole-cell K+ current?

As in other salivary glands, the secretory cells of the sheep parotid have a resting K+ conductance that is dominated by BK channels, which are activated by acetylcholine (ACh) and are blocked by tetraethylammonium (TEA). Nevertheless, perfusion studies indicate that TEA does not inhibit ACh-evoked fluid secretion or K+ efflux from intact sheep parotid glands. In the present study, we have used whole-cell patch clamp techniques to show that ACh activates K+ and Cl- conductances in sheep parotid secretory cells by increasing intracellular free Ca2+, and we have compared the blocker sensitivity of the ACh-evoked whole-cell K+ current to the previously reported blocker sensitivity of the BK channels seen in these cells. The ACh-induced whole-cell K+ current was not blocked by TEA (10 mmol/l) or verapamil (100 mumol/l), both of which block the resting K+ conductance and inhibit BK channels in these cells. Quinine (1 mmol/l) and quinidine (1 mmol/l), although only weak blockers of the resting K+ conductance, inhibited the ACh-evoked current at 0 mV (K+ current), by 68% and 78%, respectively. 4-Aminopyridine (10 mmol/l) partially inhibited the ACh-induced K+ current and caused it to fluctuate. It also caused the resting membrane currents to fluctuate, possibly by altering cytosolic free Ca2+. Ba2+ (100 mumol/l), a blocker of the inwardly rectifying K+ conductance in sheep parotid cells, had no effect on the ACh-induced K+ current. We conclude that the ACh-induced K+ conductance in sheep parotid cells is pharmacologically distinct from both the outwardly rectifying (BK) K+ conductance and the inwardly rectifying K+ conductance seen in unstimulated cells. Given that in vitro perfusion and K+ efflux studies on other salivary glands in which BK channels dominate the resting conductance (e.g., the rat mandibular, rat parotid and mouse mandibular glands) have revealed an insensitivity to TEA, suggesting that BK channels do not carry the ACh-evoked K+ current, we propose that BK channels do not contribute substantially to the K+ current evoked by ACh in the secretory cells of most salivary glands.

4-Aminopyridine↗

PubMed2003

Computational modelling of the open-state Kv 1.5 ion channel block by bupivacaine.

Binding of R(+)-bupivacaine to open-state homology models of the mammalian K(v)1.5 membrane ion channel is studied using automated docking and molecular dynamics (MD) methods. Homology models of K(v)1.5 are built using the 3D structures of the KcsA and MthK channels as a template. The packing of transmembrane (TM) alpha-helices in the KcsA structure corresponds to a closed channel state. Opening of the channel may be reached by a conformational transition yielding a bent structure of the internal S6 helices. Our first model of the K(v) open state involves a PVP-type of bending hinge in the internal helices, while the second model corresponds to a Gly-type of bending hinge as found in the MthK channel. Ligand binding to these models is probed using the common local anaesthetic bupivacaine, where blocker binding from the intracellular side of the channel is considered. Conformational properties and partial atomic charges of bupivacaine are determined from quantum mechanical HF/6-31G* calculations with inclusion of solvent effects. The automated docking and MD calculations for the PVP-bend model predict that bupivacaine could bind either in the central cavity or in the PVP region of the channel pore. Linear interaction energy (LIE) estimates of the binding free energies for bupivacaine predict strongest binding to the PVP region. Surprisingly, no binding is predicted for the Gly-bend model. These results are discussed in light of electrophysiological data which show that the K(v)1.5 channel is unable to close when bupivacaine is bound.

Amino Acid Sequence↗

PubMed2003

Determinants of renal microvascular response to ACh: afferent and efferent arteriolar actions of EDHF.

The renal microvascular actions of ACh were investigated using the in vitro perfused hydronephrotic rat kidney. ACh reversed ANG II-induced vasoconstriction in the afferent and efferent arteriole by 106 +/- 2 and 75 +/- 5%, respectively. Inhibition of nitric oxide synthase [NOS; 100 micromol/l N(G)-nitro-L-arginine methyl ester (L-NAME)] and cyclooxygenase (COX; 10 micromol/l ibuprofen) prevented the sustained response of the afferent arteriole but did not reduce the magnitude of the initial dilation (97 +/- 7%). However, NOS/COX inhibition abolished the response of the efferent arteriole. The underlying mechanisms mediating this endothelium-derived hyperpolarizing factor (EDHF)-like response were characterized using K channel blockers. Ba (100 micromol/l), tetraethylammonium (1 mmol/l), and ouabain (3 mmol/l) had no effect, arguing against a role of an inward rectifier K channel, large-conductance Ca-activated K channel, or Na,K-ATPase. Charybdotoxin (10 nmol/l) and apamin (1.0micromol/l) attenuated the response when administered alone (63 +/- 7% and 37 +/- 5%, respectively) and abolished the response when coadministered (0.1 +/- 1.0%). These findings indicate that, as in other vascular beds, the renal EDHF-like response to ACh involves K channels that are sensitive to a combination of apamin and charybdotoxin. Our finding that EDHF modulates preglomerular, but not postglomerular, tone is consistent with the evolving concept that vasomotor mechanisms in cortical efferent arterioles do not involve voltage-gated Ca entry.

4-Aminopyridine↗

PubMed2004

NPPB block of the intermediate-conductance Ca2+-activated K+ channel.

We have shown that the Cl(-) channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) also blocks the intermediate-conductance Ca(2+)-activated K(+) (IK(Ca)) current in human leukemic HL-60 and glioblastoma GL-15 cell lines. The macroscopic IK(Ca) current was activated by ionomycin plus 1-EBIO, and identified as intermediate conductance by being fully blocked by charybdotoxin, clotrimazole, nitrendipine (L-type Ca(2+) channel blocker), and NS1619 (BK(Ca) channel opener), but not by D-tubocurarine or TEA. The IK(Ca) current was blocked by NPPB in a reversible dose-dependent manner, with an IC(50) of 39 microM in HL-60 and 125 microM in GL-15 cells. The block of the IK(Ca) current was also recorded at the single channel level in excised inside-out patches. As expected, NPPB also blocked the volume-activated Cl(-) current expressed by GL-15 cells, with an IC(50) of 44 microM. The functional implications of IK(Ca) current block by NPPB are discussed.

Cell Line, Tumor↗

PubMed2003

Apoptosis repressor with caspase domain inhibits cardiomyocyte apoptosis by reducing K+ currents.

Cell shrinkage is an early prerequisite in programmed cell death, and cytoplasmic K(+) is a dominant cation that controls intracellular ion homeostasis and cell volume. Blockade of K(+) channels inhibits apoptotic cell shrinkage and attenuates apoptosis. We examined whether apoptotic repressor with caspase recruitment domain (ARC), an antiapoptotic protein, inhibits cardiomyocyte apoptosis by reducing K(+) efflux through voltage-gated K(+) (Kv) channels. In heart-derived H9c2 cells, whole cell Kv currents (I(K(V))) were isolated by using Ca(2+)-free extracellular (bath) solution and including 5 mM ATP and 10 mM EGTA in the intracellular (pipette) solution. Extracellular application of 5 mM 4-aminopyridine (4-AP), a blocker of Kv channels, reversibly reduced I(K(V)) by 50-60% in H9c2 cells. The remaining currents during 4-AP treatment may be generated by K(+) efflux through 4-AP-insensitive K(+) channels. Overexpression of ARC in heart-derived H9c2 cells significantly decreased I(K(V)), whereas treatment with staurosporine, a potent apoptosis inducer, enhanced I(K(V)) in wild-type cells. The staurosporine-induced increase in I(K(V)) was significantly suppressed and the staurosporine-mediated apoptosis was markedly inhibited in cells overexpressing ARC compared with cells transfected with the control neomycin vector. These results suggest that the antiapoptotic effect of ARC is, in part, due to inhibition of Kv channels in cardiomyocytes.

4-Aminopyridine↗

PubMed2003

Evidence for the primary role for 4-aminopyridine-sensitive K(v) channels in beta(3)-adrenoceptor-mediated, cyclic AMP-independent relaxations of guinea-pig gastrointestinal smooth muscles.

Gastrointestinal smooth muscles exhibit relaxation in response to the stimulation of beta-adrenoceptors with catecholamines. Subtypes of beta-adrenoceptors which mediate catecholamine-elicited relaxations in gastrointestinal smooth muscles are predominantly atypical beta-adrenoceptors including beta(3)-adrenoceptors. Gastrointestinal smooth muscle relaxations mediated via beta(3)-adrenoceptors can occur independently of intracellular cyclic adenosine monophosphate (AMP) elevation. One of the mechanisms responsible for cyclic AMP-independent smooth muscle relaxation following activation of G(s) protein-coupled receptors could be activation of voltage-gated K(+) channels. In the present study, possible contribution of two types of K(+) (large-conductance, Ca(2+)-sensitive and voltage-gated K(+), BK(Ca); voltage-gated, K(v)) channels to beta(3)-adrenoceptor-mediated, cyclic AMP-independent relaxations was compared in gastric fundus and duodenum smooth muscles isolated from the guinea-pig. In these gastrointestinal smooth muscles, three catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline) and two beta(3)-adrenoceptor agonists ((R(*), R(*))-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium (BRL37344) and (+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy] -1,3-dihydro-2H-benzimidazol-2-one] hydrochloride ((+/-)-CGP12177A)) elicited a concentration-dependent relaxation in the presence of beta(1)- and beta(2)-adrenoceptor antagonists. The relaxations were unaffected by an adenylyl cyclase inhibitor, SQ-22536 (100 microM), which indicates their characteristic of cyclic AMP-independency. On the other hand, the SQ-22536-resistant, beta(3)-adrenoceptor-mediated relaxant components were potently attenuated when the tone was raised using high-KCl (80 mM) or in the presence of a K(v) channel blocker, 4-aminopyridine (4-AP, 1-3 mM). Iberiotoxin (100 nM), a selective blocker of BK(Ca) channels which significantly contribute to cyclic AMP-independent vascular smooth muscle relaxations induced through activation of G(s) protein-coupled receptors, did not apparently show any inhibitory effects on SQ-22536-resistant, beta(3)-adrenoceptor-mediated relaxations in these gastrointestinal smooth muscles. The present results indicate that 4-AP-sensitive K(v) channels play a primary role in beta(3)-adrenoceptor-mediated, cyclic AMP-independent relaxations of guinea-pig gastrointestinal smooth muscles. In these smooth muscles, BK(Ca) channels seem to apparently contribute insignificantly to cyclic AMP-independent relaxations following stimulation of beta(3)-type of adrenoceptors.

4-Aminopyridine↗

PubMed1999

Ionic mechanism of isoflurane's actions on thalamocortical neurons.

We studied the actions of isoflurane (IFL) applied in aqueous solutions on ventrobasal neurons from thalamic brain slices of juvenile rats. By using the whole cell, patch-clamp method with current- and voltage-clamp recording techniques, we found that IFL increased a noninactivating membrane conductance in a concentration-dependent reversible manner. In an eightfold concentration range that extended into equivalent in vivo lethal concentrations, IFL did not produce a maximal effect on the conductance; this is consistent with a nonreceptor-mediated mechanism of action. TTX eliminated action potential activity but did not alter IFL effects. The effects on the membrane potential and current induced by IFL were voltage independent but depended on the external [K+], reversing near the equilibrium potential for K+. External Ba2+ or internal Cs+ applications, which block K+ channels, suppressed the conductance increase caused by IFL. External applications of the Ca2+ channel blockers Co2+ or Cd2+ or internal application of the Ca2+ chelator 1,2-bis-(2-aminophenoxy)-ethane-N,N, N',N'-tetraacetic acid did not prevent the effects of IFL, implying little involvement of Ca2+-dependent K+ currents. A contribution of inwardly rectifying K+ channels to the increased steady-state conductance seemed unlikely because IFL decreased inward rectification. An involvement of ATP-mediated K+ channels also was unlikely because application of the ATP-mediated K+ channel blocker glibenclamide (1-80 microM) did not prevent IFL's actions. In contrast to spiking cells, IFL depolarized presumed glial cells, consistent with an efflux of K+ from thalamocortical neurons. The results imply that a leak K+ channel mediated the IFL-induced increase in postsynaptic membrane conductance in thalamic relay neurons. Thus a single nonreceptor-mediated mechanism of IFL action was responsible for the hyperpolarization and conductance shunt of voltage-dependent Na+ and Ca2+ spikes, as reported in the preceding paper. Although anesthetics influence various neurological systems, an enhanced K+ leak generalized in thalamocortical neurons alone could account for anesthesia in vivo.

4-Aminopyridine↗

PubMed1995

Modulation of the inwardly rectifying K+ channel in isolated human atrial myocytes by alpha 1-adrenergic stimulation.

We have examined the alpha 1-adrenergic modulation of the inwardly-rectifying K+ channel (IK1) in isolated human atrial myocytes using the patch clamp technique. alpha 1-Adrenergic agonist methoxamine produced action potential prolongation and a depolarization of the resting membrane potential. Under whole-cell voltage-clamp conditions, bath application of methoxamine can inhibit macroscopic IK1. The methoxamine-induced inhibition was reversible and concentration dependent, with the concentration for half-maximal inhibition being 18 microM. The methoxamine-induced inhibition of IK1 was prevented by bath application of alpha 1-adrenergic blocker prazosin. The current was similarly inhibited by phorbol ester (PMA), an activator of protein kinase C (PKC). In contrast, methoxamine failed to inhibit the current in the presence of a specific PKC inhibitor H-9, suggesting that PKC is involved in the methoxamine-induced inhibition of IK1. In single channel recording from cell-attached patches, bath-applied methoxamine could suppress IK1 channels by decreasing the frequency and duration of bursting without affecting unitary amplitude. Direct application of purified PKC to excised inside-out patches inhibited channel activity similar to methoxamine in cell-attached patches. The PKC selective inhibitor, PKC19-36, prevented the PKC-induced inhibition of the channel. We conclude that human atrial IK1 can be inhibited by alpha 1-adrenergic stimulation via PKC-dependent pathways.

Adrenergic alpha-Agonists↗

PubMed2001

Involvement of adenosine in vascular contractile preconditioning.

Measurements of isometric tensions of rat aortic rings revealed the fact that when aortic rings with intact endothelium were precontracted (preconditioned) for 20 min by the alpha1-adrenergic agonist phenylephrine (10 microM), the tonic level of subsequent contraction by the same agonist was depressed and/or declined regardless of the presence or absence of endothelium during the second contraction. The removal of endothelium before preconditioning showed no such phenomenon. With the use of specific blockers, involvements of adenosine or of ATP-sensitive K+ (K(ATP)) channels during preconditioning or second contraction, respectively, were evaluated. Actions of nitric oxide synthase, cyclooxygenase, P(2) ATP purinoceptors, or K(ATP) channels during preconditioning appear not to be involved. Exogenous adenosine (up to 100 microM) without endothelium could mimic the preconditioning; however, contractile preconditioning by phenylephrine, mechanical stretching, or activation of protein kinase C needed to be done. The release of adenosine and adenine nucleotides from aortic rings was augmented by phenylephrine or by mechanical stretching of the rings with intact endothelium. Our results suggest that during vasocontraction, endothelium-derived adenosine acquires an ability to protect vascular tone against subsequent repeated contractions by mediating a delayed, possibly indirect, opening of K(ATP) channels.

Adenine Nucleotides↗

PubMed2000

Cardioprotection by K(ATP) channels in wild-type hearts and hearts overexpressing A(1)-adenosine receptors.

We studied the role of mitochondrial ATP-sensitive K(+) (K(ATP)) channels in modifying functional responses to 20 min global ischemia and 30 min reperfusion in wild-type mouse hearts and in hearts with approximately 250-fold overexpression of functionally coupled A(1)-adenosine receptors (A(1)ARs). In wild-type hearts, time to onset of contracture (TOC) was 303 +/- 24 s, with a peak contracture of 89 +/- 5 mmHg. Diastolic pressure remained elevated at 52 +/- 6 mmHg after reperfusion, and developed pressure recovered to 40 +/- 6% of preischemia. A(1)AR overexpression markedly prolonged TOC to 517 +/- 84 s, reduced contracture to 64 +/- 6 mmHg, and improved recovery of diastolic (to 9 +/- 4 mmHg) and developed pressure (to 82 +/- 8%). 5-Hydroxydecanoate (5-HD; 100 microM), a mitochondrial K(ATP) blocker, did not alter ischemic contracture in wild-type hearts, but increased diastolic pressure to 69 +/- 8 mmHg and reduced developed pressure to 10 +/- 5% during reperfusion. In transgenic hearts, 5-HD reduced TOC to 348 +/- 18 s, increased postischemic contracture to 53 +/- 4 mmHg, and reduced recovery of developed pressure to 22 +/- 4%. In summary, these data are the first to demonstrate that endogenous activation of K(ATP) channels improves tolerance to ischemia-reperfusion in murine myocardium. This functional protection occurs without modification of ischemic contracture. The data also support a role for mitochondrial K(ATP) channel activation in the pronounced cardioprotection afforded by overexpression of myocardial A(1)ARs.

Adenosine Triphosphate↗

PubMed2005

Possible mechanism of the vasodepressor effect of endokinin a/b in anesthetized rats.

We investigated the mechanism of the vasodepressor effect of endokinin A/B. An intravenous (IV) bolus of endokinin A/B (0.05-0.3 nmol/kg) dose-dependently decreased mean arterial pressure in thiobutabarbital-anesthetized rats. The magnitude of the response was unaffected by IV pretreatment with NG-nitro-L-arginine methyl ester (L-NAME, inhibitor of nitric oxide synthase), methylene blue (inhibitor of soluble guanylyl cyclase), indomethacin (cyclooxygenase inhibitor), or tetraethylammonium (TEA, nonspecific K+ channel blocker). L-NAME reduced the half-recovery time of the vasodepressor effect of endokinin A/B relative to responses in rats pretreated with either saline or norepinephrine, which caused a similar pressor effect as did L-NAME. Methylene blue, but not TEA or indomethacin, reduced the recovery time of the vasodepressor effect of endokinin A/B. Therefore, the vasodepressor effect of endokinin A/B is mediated via the nitric oxide/L-arginine pathway and activation of soluble guanylyl cyclase but not by production of prostanoids or opening of TEA-sensitive K+ channels.

Anesthesia↗

PubMed2004

Sevoflurane-induced preconditioning of rat brain in vitro and the role of KATP channels.

In the present study we tested the ability of the inhalation anesthetic sevoflurane to induce preconditioning against hypoxia in vitro. Rat hippocampal slices were prepared using established procedures. After 90 min of incubation, slices were exposed for 30 min to 0, 1, 2 or 3 minimum alveolar concentration (MAC) of sevoflurane under normoxic conditions (95% O2/5% CO2). Fifteen minutes later, slices were exposed to 13-min hypoxia (95% N2/5% CO2) followed by 30-min reoxygenation. The amplitude of extracellularly recorded, orthodromically evoked, CA1 population spikes (neuronal function) at the end of the reoxygenation period was measured and used to quantify the degree of recovery of neuronal function posthypoxia. To assess the role that the mitochondrial KATP channel plays in preconditioning, its blocker, 5-hydroxydecanoic acid (5-HD), was added during sevoflurane exposure. Sevoflurane-preconditioning with 1, 2 and 3 MAC increased the degree of recovery of neuronal function after 13-min hypoxia and 30-min reoxygenation from 51 +/- 1% (0 MAC), to 55 +/- 3%, 63 +/- 3%, and 72 +/- 2%, respectively. The effect of 3 MAC sevoflurane was blocked by 5-HD (53 +/- 3%), whereas 5-HD alone had no effect (48 +/- 3%) on the recovery of neuronal function from hypoxia. It is concluded that sevoflurane is capable of inducing preconditioning in vitro in a dose-dependent fashion and involves activation of mitochondrial KATP channels.

Adenosine Triphosphate↗