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At least 613 records · Page 34Linked to original sources
PubMed2001

Pharmacological comparison of native mitochondrial K(ATP) channels with molecularly defined surface K(ATP) channels.

Many mammalian cells have two distinct types of ATP-sensitive potassium (K(ATP)) channels: the classic ones in the surface membrane (sK(ATP)) and others in the mitochondrial inner membrane (mitoK(ATP)). Cardiac mitoK(ATP) channels play a pivotal role in ischemic preconditioning, and thus represent interesting drug targets. Unfortunately, the molecular structure of mitoK(ATP) channels is unknown, in contrast to sK(ATP) channels, which are composed of a pore-forming subunit (Kir6.1 or Kir6.2) and a sulfonylurea receptor (SUR1, SUR2A, or SUR2B). As a means of probing the molecular makeup of mitoK(ATP) channels, we compared the pharmacology of native cardiac mitoK(ATP) channels with that of molecularly defined sK(ATP) channels expressed heterologously in human embryonic kidney 293 cells. Using mitochondrial oxidation to index mitoK(ATP) channel activity in rabbit ventricular myocytes, we found that pinacidil and diazoxide open mitoK(ATP) channels, but P-1075 does not. On the other hand, 5-hydroxydecanoic acid (5HD), but not HMR-1098, blocks mitoK(ATP) channels. Although pinacidil is a nonselective activator of expressed sK(ATP) channels, diazoxide did not open channels formed by Kir6.1/SUR2A, Kir6.2/SUR2A (known components of cardiac sK(ATP) channels) or Kir6.2/SUR2B. P-1075 activated all the K(ATP) channels, except Kir6.1/SUR1 channels. Glybenclamide potently blocked all sK(ATP) channels, but 5HD only blocked channels formed by SUR1/Kir6.1 or Kir6.2 (IC(50)s of 66 and 81 microM, respectively). This potency is similar to that for block of mitoK(ATP) channels (IC(50) = 95 microM). In addition, HMR-1098 potently blocked Kir6.2/SUR2A channels (IC(50) = 1.5 microM), but was 67 times less potent in blocking Kir6.1/SUR1 channels (IC(50) = 100 microM). Our results demonstrate that mitoK(ATP) channels closely resemble Kir6.1/SUR1 sK(ATP) channels in their pharmacological profiles.

ATP-Binding Cassette Transporters↗
PubMed1990

Selective inhibition of relaxation of guinea-pig trachea by charybdotoxin, a potent Ca(++)-activated K+ channel inhibitor.

Airway smooth muscle plasma membranes are rich in K+ channels of various types. Charybdotoxin (ChTX) is a potent blocker of the high-conductance Ca(++)-activated K+ channel in smooth muscle and produces a concentration-dependent contraction of guinea pig trachea. In the present study, pharmacologic experiments were performed on carbachol-contracted (0.34 microM) guinea-pig trachea contracted further with ChTX in order to determine if Ca(++)-activated K+ channels play a role in the responses to cAMP-dependent and cAMP-independent bronchodilators. Relaxation concentration response curves to the beta-agonists, isoproterenol and salbutamol; the phosphodiesterase inhibitor, aminophylline; the cAMP mimic, N6-2'-O-adenosine 3':5'-cyclic monophosphate the guanylate cyclase activator, sodium nitroprusside; and the K+ channel agonists, BRL-34915 and pinacidil, were obtained in the absence and presence of ChTX. The concentration response curves to isoproterenol and salbutamol were shifted to the right (approximately 27-fold and greater than 40-fold, respectively) by 180 nM ChTX, whereas concentration response curves to N6-2'-O-adenosine 3':5'-cyclic monophosphate and aminophylline were affected significantly less (shifted approximately 7.5-fold). Concentration response curves to the cGMP-dependent relaxant sodium nitroprusside were also altered by ChTX (17-fold rightward shift at 180 nM). In the presence of 60 nM ChTX, the concentration response curves to the above relaxants were shifted only 3- to 5-fold. In contrast, ChTX (60 and 180 nM) failed to produce a significant rightward shift in the concentration response curves to BRL-34915 or pinacidil. Relaxation to BRL-34915 was however, blocked by glybenclamide, suggesting differences in the mechanism of relaxation. Contraction of tissues with depolarizing concentrations of KCl (20-80 mM) inhibited responses to all bronchodilators. These results suggest that hyperpolarization of tracheal smooth muscle as a result of opening various types of K+ channels can lead to relaxation of carbachol-contracted tracheal smooth muscle.

Aminophylline↗
PubMed1989

Comparison of contractions to serotonin, carbamylcholine and prostaglandin F2 alpha in rat stomach fundus.

Contractile effects of serotonin were compared to those of carbamylcholine and prostaglandin (PG) F2 alpha in an effort to characterize serotonergic receptor activation in rat stomach fundus. All three agents elicited concentration-dependent contractions of fundal strips with serotonin (EC50 = 2 X 10(-10) M) being approximately 100-fold more potent than carbamylcholine (EC50 = 2 X 10(-8) M) and PGF2, (EC50 = 10(-8) M). The calcium channel blockers, diltiazem (5 X 10(-7) to 5 X 10(-5) M) and nitrendipine (10(-8) to 10(-5) M), attenuated responses markedly to serotonin and PGF2 alpha whereas having only minimal effects on carbamylcholine-induced contractions. Neither serotonin (10(-11) to 10(-5) M) nor PGF2 alpha (10(-9) to 10(-5) M) altered [3H]inositol monophosphate generation in fundus whereas carbamylcholine (10(-6) to 10(-5) M) increased significantly [3H]inositol monophosphate with 10(-5) M eliciting an 8-fold increase. Strips of fundus contracted submaximally with either serotonin, PGF2 alpha or carbamylcholine were compared for sensitivity to relaxants. Pinacidil (10(-8) to 10(-5) M) was equipotent (EC50 = 0.1 microM) in relaxing serotonin- and PGF2 alpha-contracted tissues. In contrast, pinacidil was 10-fold less potent in relaxing contractions produced by carbamylcholine. Likewise, nitroglycerin (10(-8) to 10(-4) M) and isoproterenol (10(-12) to 10(-7) M) were at least 10-fold more potent in relaxing serotonin- and PGF2 alpha- than carbamylcholine-induced contractions. Thus, in rat fundus, contractions associated with increased phosphoinositide hydrolysis may be more resistant to relaxation than are contractions not associated with altered phosphoinositide hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Role of calcium-activated K+ channels in vasodilation induced by nitroglycerine, acetylcholine and nitric oxide.

A comparative analysis was carried out of the sensitivities of in vitro vasorelaxations by nitroglycerine (NTG), acetylcholine (ACh) and nitric oxide (NO) to blockade by glyburide, a blocker of ATP-sensitive K+ channels (KATP), as well as to blockade by charybdotoxin (ChTX) and iberiotoxin (lbTX), potent blockers of calcium-activated K+ channels (KCa). In the isolated rabbit mesenteric artery (RMA) precontracted with 5 microM norepinephrine (NE), ACh (0.01-1 microM), NTG (0.01-5 microM) and NO (0.075-2.7 microM) produced a dose-dependent vasodilation. Glyburide (0.5 microM) had no significant effect on relaxation dose-response curves (DRCs) to ACh, NTG or NO. In contrast, glyburide completely abolished the relaxation DRC by pinacidil, a known KATP opener. ChTX (10 or 100 nM) caused an inhibition of relaxation DRCs to ACh, NTG and NO. In all cases, ChTX shifted the relaxation DRC to the right and depressed the maximal response. Another potent KCa blocker, lbTX (20 nM) also significantly inhibited relaxation DRCs to NTG, ACh and NO and inhibited maximal relaxation response to SNP. The effects of ChTX and lbTX were selective; they did not inhibit relaxations by pinacidil and forskolin. Finally, it was observed that the use of 80 mM K+ as a contractile stimulus inhibited NTG relaxations in a manner similar to the KCa blockers. Collectively, these data provide strong support for the hypothesis that the activation of KCa plays an important role in mediating the vasorelaxation caused by NTG, SNP, ACh and NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1995

Myogenic and agonist induced responses of coronary venules after cold hyperkalaemic cardioplegia.

OBJECTIVE: The aim was to examine agonist induced and myogenic venular responses after crystalloid cardioplegia in conditions simulating cardiopulmonary bypass. METHODS: Hearts of pigs were arrested with cold hyperkalaemic ([K+] = 25 mM) crystalloid cardioplegic solution for 1 h under conditions of cardiopulmonary bypass. In another group, hearts were arrested and then reperfused with warm blood for 1 h while being separated from cardiopulmonary bypass. In a third group, animals were supported on cardiopulmonary bypass for 75 min without diversion of coronary blood flow. Hearts from non-instrumented animals served as controls. Coronary venules (91-197 microns in internal diameter) were studied in vitro in a pressurised no flow state using video microscopy. Agonist induced responses were assessed in vessels precontracted with the thromboxane A2 analogue U46619. RESULTS: Endothelium dependent relaxations to adenosine diphosphate (ADP, P = 0.11 v control), or serotonin (P = 0.67), and endothelium independent relaxations to the beta adrenergic cyclic AMP mediated agonist isoprenaline (P = 0.20), adenosine (P = 0.98), or the KATP channel opener pinacidil (P = 0.40) were not significantly altered after cold cardioplegia alone. After cardioplegia followed by 1 h of warm blood reperfusion, venular responses to ADP (P = 0.003 v control), isoprenaline (P = 0.013), adenosine (P = < 0.001), and pinacidil (P = 0.005) were reduced compared to the respective control responses, while the response to serotonin (P = 0.97) remained unchanged. Endothelium independent cyclic GMP mediated relaxation to sodium nitroprusside was similar in all groups (P > 0.90). Myogenic reactivity was assessed after incremental increases in the intraluminal pressure from 2-40 mm Hg. As intraluminal pressure was increased, the diameter of control venules increased and reached a plateau. Following cardioplegia, the pressure-diameter relationship of venules was shifted upward (P = 0.04 v control) suggesting impaired myogenic tone. After reperfusion, myogenic tone partially recovered. Extracorporeal circulation without diversion of coronary perfusion did not significantly affect venular responses. CONCLUSIONS: Ischaemic cardioplegia using a cold hyperkalaemic solution under conditions of cardiopulmonary bypass does not significantly alter agonist induced venular responses, whereas myogenic contraction is slightly reduced. After 1 h of reperfusion, agonist induced relaxations of coronary venules are significantly impaired, whereas myogenic contraction recovers. These findings may have implications for the control of myocardial perfusion and diastolic properties of the heart after ischaemic cardioplegia under conditions of extracorporeal circulation.

Adenosine↗
PubMed1997

Effect of K+ channel openers on K+ channel in cultured human dermal papilla cells.

Minoxidil sulfate and pinacidil, well-known activators of the ATP-sensitive K+ (KATP) channel, induce hair growth in clinical studies. The opening of K+ channels is thought to be an important mechanism in the regulation of hair follicles. In the present study, we used the patch clamp technique to characterize the K+ channels and tested the effect of K+ channel openers on K+ channels in cultured human dermal papilla cells. In dermal papilla cells, the Ca(2+)-activated K+ (KCa) channel with large conductance (179.3 +/- 13.1 pS in symmetrical 150 mM K+ solutions, n = 9) was dominant and we could not observe KATP channels in cell-attached and inside-out patches. In addition, minoxidil and pinacidil failed to activate KATP or KCa channels. In inside-out membrane patches, the channel was blocked by 10 mM tetraethylammonium ion, 2 mM 4-aminopyridine to the cytosolic face of the membrane or by lowering Ca2+ using 10 mM EGTA, but not by glibenclamide. In the cell-attached patch configurations, extracellular application of 1 mM sodium nitroprusside, a nitrovasodilator, activated the KCa channel. Methylene blue (2 mM) inhibited channel activation by sodium nitroprusside. Extracellular application of 20 mM dibutyryl cGMP activated the KCa channel, suggesting that channel activation is mediated by cGMP. Nitrovasodilators, which have no effect on hair growth, now appear to activate KCa channels in dermal papilla cells. These results suggest that increased K+ permeability itself in dermal papilla cells may not be sufficient for promotion of hair growth.

Cells, Cultured↗
PubMed1991

Coenzyme Q10 attenuates cyanide-activation of the ATP-sensitive K+ channel current in single cardiac myocytes of the guinea-pig.

The effect of coenzyme Q10 (CoQ10) on the cyanide (CN-)-induced ATP-sensitive K+ channel current (KATP) was examined in single atrial myocytes, using the patch clamp technique. Superfusion of the cells with a CN-/low glucose bathing solution induced an outward current in the whole-cell clamp condition. Glibenclamide (1 microM) abolished this current, indicating that the current was carried through the KATP channel. After steady-state activation by CN-, pinacidil (a KATP channel opener, 300 microM) failed to further increase the current. In cell-attached patches, CN-, when applied to the bath, induced bursting openings of an 80 pS channel (the KATP channel). In cells preincubated for 30 min in a solution containing CoQ10 (100 micrograms/ml), CN(-)-activation of the KATP channel was markedly attenuated both at the whole cell and at the single channel level. At the steady-state effect of CN- in CoQ10-treated cells, pinacidil (300 microM) activated the current to the maximum level achieved by CN- in the control cells. These results suggest that CoQ10 reduces in the CN(-)-induced KATP current not by affecting the channel itself but by preventing depletion of intracellular ATP caused by CN-.

Adenosine Triphosphate↗
PubMed1988

Enhancement of muscle blood cell flux and pO2 by cromakalim (BRL 34915) and other compounds enhancing membrane K+ conductance, but not by Ca2+ antagonists or hydralazine, in an animal model of occlusive arterial disease.

The effect of Ca2+ antagonists, hydralazine and agents which enhance membrane K+ conductance (cromakalim, pinacidil and nicorandil) in smooth muscle cells, was compared on normal and hypoxic skeletal muscle blood cell flux and pO2. The K+ conductance enhancers and verapamil, diltiazem and nifedipine increased blood cell flux in normally perfused muscle. At equieffective blood pressure lowering dosages, the Ca2+ antagonists produced greater increases than the K+ channel openers. Hydralazine did not elevate blood cell flux in the normal muscle. In hypoxic skeletal muscle, the K+ conductance enhancers produced a marked increase in blood cell flux and in tissue oxygen tension, indicating that they had increased the nutritive blood flow in the muscle. The Ca2+ antagonists and hydralazine either did not change hypoxic muscle blood cell flux and pO2 or reduced them. The dissimilarity in the activity of the compounds may be due to differences in their site of action in the vascular bed. Ca2+ antagonists and hydralazine are known to reduce arteriolar vessel resistance and do not increase blood flow in hypoxic skeletal muscle. The positive effect of cromakalim, pinacidil and nicorandil may be due to relaxant activity on larger arterial blood vessels including collaterals. This effect could be related to their ability to enhance membrane K+ conductance in vascular smooth muscle cells.

Animals↗
PubMed1993

ATP-sensitive K+ channels in cardiac ischemia: an endogenous mechanism for protection of the heart.

The Role of ATP-sensitive K+ channels (KATP) in action potential shortening and protection of myocardium in ischemia were explored using isolated ventricular myocytes and arterially perfused right ventricular walls of guinea pigs. Conditions "simulating" some aspects of ischemia--(10.8 mM K+o, 6.9 pHo, 20 mM lactate, no glucose; 10 mM 2-deoxy-D-glucose; and either 1 mM cyanide or no O2 (bubbled with 95/5% N2/CO2)--caused a decline in action potential duration (APD) and the elaboration of time- and voltage-independent, steady-state outward conductance due to KATP, which could be inhibited with glibenclamide (50 microM) in myocytes studied via the perforated patch (nystatin) whole-cell technique. Right ventricular walls subjected to no-flow ischemia +/- glibenclamide (10 microM) to block, or +/- pinacidil (1 and 10 microM) to activate, KATP, respectively, exhibited varied ischemic injury. Glibenclamide caused a greater fall in resting membrane potential, inhibited the decline in APD, caused an early rise in resting tension, and inhibited recovery of contractile function upon reflow. Pinacidil caused a greater decline in APD, inhibited changes in resting tension, and improved recovery during reperfusion. These results indicate that KATP contributes to action potential shortening in isolated myocytes in simulated ischemia and intact myocardium in no-flow ischemia. Activation of this membrane current may be an important adaptive mechanism for protecting the myocardium when blood flow to the tissue is compromised.

Adenosine Diphosphate↗
PubMed1994

Partial contribution of the ATP-sensitive K+ current to the effects of mild metabolic depression in rabbit myocardium.

The object of the study was to compare the capability of glibenclamide to block the effects of K(+)-ATP channel activators on action potential duration and steady state whole cell current to its efficiency in counteracting the effects of hypoxia or metabolic poisons in the presence of glycolytic substrate. The modulation of action potential duration by 30 microM glibenclamide was tested in perfused hearts subjected to hypoxia or to the K(+)-ATP channel opener pinacidil. Similar protocols were used to study the modifications of the steady state whole cell current in isolated ventricular myocytes. It was found that glibenclamide did not prevent early action potential shortening induced by hypoxia but produced a partial recovery after 15 min of exposure. At the steady state the action potential duration had lengthened by 53 +/- 6% at plateau level and 42 +/- 3% at 95% repolarization. In contrast, action potential shortening induced by 100 microM pinacidil was fully reversed by glibenclamide within 2 min. Freshly dispersed ventricular myocytes were characterized in control conditions as for the properties of the steady state current. This current, measured at the end of 450 ms long pulses showed typical inward rectification that was abolished by 50 microM Ba2+. Cyanide (2 mM), carbonylcyanide m-chlorophenylhydrazone (CCCP, 200 nM) and BRL 38227 (30 microM) produced characteristic increases in time independent outward currents. Glibenclamide abolished the outward current induced by BRL 38227 and the concomitant action potential shortening. Addition of cyanide in the presence of glibenclamide and BRL 38227 produced a new increase in outward current accompanied by action potential shortening. In the absence of K(+)-ATP channel activators, glibenclamide partly inhibited the CCCP induced current. Our data suggested that the delayed onset of glibenclamide action in hypoxic hearts is not due to diffusion barriers. They rather support the view that mechanisms other than K(+)-ATP channel activation could determine the early action potential shortening in whole hearts. The partial recovery observed under glibenclamide may be due, in part, to channel desensitization but also reflect the contribution of more than one current system to the action potential shortening because the glibenclamide insensitive fraction of the CCCP induced current is partly blocked by low concentrations of Ba2+. Differences with other data in the literature are attributed to the degree of metabolic blockade, to species differences, and to the inherent heterogeneities of the whole heart model where non-muscle cells may modulate the response to hypoxia.

Action Potentials↗
PubMed1996

Reconstitution in lipid bilayers of an ATP-sensitive K+ channel from pig coronary smooth muscle.

A K+ channel with a main conductance of 29 pS was recorded after the incorporation of coronary artery membrane vesicles into lipid bilayers. This channel was identified as an ATP-sensitive K+ channel (KATP) because its activity was diminished by the internal application of 50-250 microM ATP-Na2. Moreover, it was opened when 10-50 microM pinacidil was externally applied. Single-channel records revealed the existence of several (sub)conductance states. At 0 mV and with a 5/250 KCl gradient, the main conductance of the KATP channel was 29 pS. The other (sub)conductance states were less frequent and had discrete values of 12, 17 and 22 pS. Pinacidil stabilized the channel open state primarily in the 29 pS conductance level; whereas ATP inhibited all the conductance levels. In general, KATP channels were characterized by brief openings followed by long closings (open probability, Po approximately 0.02); only occasionally (3 out of 12 experiments) did the KATP channels have a high open probability (Po >/= 0.7). Channel activity could be increased or rescued by adding 2.5-10 mM UDP-TRIS and 0.5-2 mM MgCl2 to the internal side of the channel.

Adenosine Triphosphate↗
PubMed1989

Pharmacological modulation of 86Rb efflux from aortic endothelial cells.

The ATP-induced efflux of 86Rb from prelabelled bovine aortic endothelial cells was inhibited by quinine (50 microM) but not by a tetraethylammonium (5 mM) or apamin (50 nM). Neither sulfonylureas nor pinacidil had a significant effect on the rate of 86Rb efflux from the endothelial cells. These data are consistent with the presence of intermediate conductance Ca2(+)-activated K+ channels in endothelial cells. ATP-dependent K+ channels, sensitive to sulfonylureas and pinacidil, could not be detected.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

The effect of K+ channel openers on submucosal gland function and epithelial transport of the ferret trachea, in vitro.

The effects of three K+ channel openers on lysozyme output from submucosal gland serous cells and epithelial albumin transport following maintained submaximal stimulation by the secretagogues methacholine and phenylephrine were examined in the ferret trachea in vitro preparation. The K+ channel openers Ro 31-6930, 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-pyridine 1-oxide (10 nM-10 microM), levcromakalim, BRL38227 (10 nM-10 microM) and pinacidil (100 nM-10 microM) produced a concentration dependent inhibition of (20 microM) methacholine-induced lysozyme output, with pD2 values of 7.64, 7.72 and 7.28 respectively. Ro 31-6930 (10 nM-10 microM), levcromakalim (10 nM-10 microM) and pinacidil (1 nM-10 microM) also produced a concentration dependent inhibition of (100 microM) phenylephrine-induced lysozyme output, with pD2 values of 7.64, 6.55 and 9.16 respectively. Furthermore, glibenclamide (1 microM) produced a modest attenuation of the K+ channel opener effects on secretagogue-induced lysozyme output. All three K+ channel openers failed to produce any significant change in either methacholine or phenylephrine-induced albumin outputs. The K+ channel openers exerted marked effects on airway secretion processes, suggesting that these compounds may have an antisecretory effect. The relevance of the use of the K+ channel openers in airway disease remains to be determined.

Albumins↗
PubMed2004

Potassium-specific effects of levosimendan on heart mitochondria.

In this study, we evaluated levosimendan, a new drug developed for the treatment of acute and decompensated heart failure, as a potential activator of ATP-sensitive potassium flux to the matrix of cardiac mitochondria. We estimated the KATP channel openers-induced increase in mitochondrial inner membrane permeability for potassium by registering changes in membrane potential of heart mitochondria, oxidizing endogenous substrates. We compared the effect of levosimendan with the effects of the known KATP channel openers diazoxide and pinacidil. Levosimendan (1 microM) accelerated potassium-specific DeltaPsi decrease by 0.15%/s, whereas 50 microM diazoxide by 0.10%/s, and 50 microM pinacidil by 0.08%/s, respectively. These results were confirmed by swelling experiments of non-respiring mitochondria in potassium nitrate medium. We found that levosimendan with an EC50 of 0.83 +/- 0.24 microM activates potassium flux to the mitochondrial matrix. This effect is discussed as a possible explanation of the anti-ischemic action of levosimendan.

Animals↗
PubMed2004

Some arylacridine derivatives possessing potassium channel opening activity.

In this study, six new 2,2,7,7-tetramethyl-9-aryl-2,3,4,5,6,7,9,10-octahydro-1,8-acridinedione derivatives (1-6) were synthesised and their functional effects on vascular potassium channels and mechanism of induced relaxations on phenylephrine-induced contractile responses in isolated rat mesenteric arteries were investigated. Pinacidil was used as standard potassium channel opener. Compounds 1, 2, 5, 6 and pinacidil induced concentration-dependent relaxation response of vessel rings previously contracted with phenylephrine.

Acridines↗
PubMed1999

Pharmacological and molecular characterization of ATP-sensitive K+ channels in the TE671 human medulloblastoma cell line.

ATP-sensitive K+ (K(ATP)) channels in the human medulloblastoma TE671 cell line were characterized by membrane potential assays utilizing a potentiometric fluorescent probe, bis-(1,3-dibutylbarbituric acid)trimethine oxonol (DiBAC4(3)), and by mRNA analysis. Membrane potential assays showed concentration-dependent and glyburide-sensitive changes in fluorescence upon addition of (-)-cromakalim, pinacidil, diazoxide and P1075. The rank order of potency for these openers was P1075 > (-)-cromakalim approximately = pinacidil > diazoxide. Additionally, glyburide and glipizide inhibited P1075-evoked responses in TE671 cells with half-maximal inhibitory concentrations of 0.22 and 14 microM, respectively. The rank order potencies of both openers and inhibitors were similar to those observed in the rat smooth muscle A-10 cell line. In contrast, in the rat pancreatic insulinoma RIN-m5F cell line, only diazoxide was effective as an opener. Reverse transcription-polymerase chain reaction (RT-PCR) studies detected sulfonylurea receptors SUR2B and SUR1 mRNA in TE671 cells whereas only SUR2B and SUR1 mRNA were, respectively, detected in A-10 and RIN-m5F cells. The inward rectifier Kir6.2 mRNA was detected in all three cell types whereas Kir6.1 was detected only in A-10 cells. Collectively, the molecular and pharmacologic studies suggest that K(ATP) channels endogenously expressed in TE671 medulloblastoma resemble those present in the smooth muscle.

Adenosine Triphosphate↗
PubMed2001

Inhibitory effect of tetrabutylammonium ions on endothelium/nitric oxide-mediated vasorelaxation.

Apart from the well-described K+ channel blocking effects in vascular smooth muscle cells, monovalent quaternary ammonium ions may also interact with endothelial cells in the endothelium-intact mammalian arteries. The present study was aimed to examine the effect of tetrabutylammonium ions on endothelium-dependent and -independent relaxation in the rat isolated aortic rings. Pretreatment with tetrabutylammonium concentration dependently reduced the endothelium-dependent relaxation induced by acetylcholine, cyclopiazonic acid and ionomycin. Tetrabutylammonium also inhibited endothelium-independent relaxation induced by hydroxylamine or nitroprusside. Pretreatment of endothelium-denuded rings with tetrabutylammonium did not affect relaxation induced by NS1619 or by diltiazem. In contrast, tetrabutylammonium significantly reduced the pinacidil- or cromakalim-induced relaxation. Tetrabutylammonium also inhibited the acetylcholine- but not nitroprusside-induced increase of tissue content of cyclic GMP in the aortic rings. The present study indicates that tetrabutylammonium ions could inhibit endothelial and exogenous nitric oxide-mediated aortic relaxation while it had no effect on relaxation induced by activation of Ca2+-activated K+ channels (by NS1619) or by inhibition of voltage-gated Ca2+ channels (by diltiazem). The inhibitory effect on pinacidil- and cromakalim-induced relaxation suggests that tetrabutylammonium ions also inhibit ATP-sensitive K+ channels in aortic smooth muscle cells.

Animals↗
PubMed2002

Ageing is associated with a decrease in the number of sarcolemmal ATP-sensitive K+ channels in a gender-dependent manner.

The opening of sarcolemmal K(ATP) channels is considered to be an important endogenous cardioprotective mechanism. On the other hand, age-dependent changes in the myocardial susceptibility to ischemia and hypoxia have been observed in different species, including humans. Here, we have hypothesized that aging might be associated with the changes in sarcolemmal K(ATP) channels. Therefore, the main objective of the present study was to establish whether aging changes expression of cardiac sarcolemmal ATP-sensitive K+ (K(ATP)) channels. RT-PCR using primers specific for K(ATP) channel subunits, Kir6.2, Kir6.1 and SUR2A subunits was performed using total RNA from guinea-pig ventricular tissue. Whole cell electrophysiology was done on isolated guinea-pig ventricular cardiomyocytes. Western blotting using anti-Kir6.2 and anti-SUR2A antibodies was performed on cardiac membrane fraction. Tissue and cells were harvested from young and old, male and female guinea-pigs. RT-PCR analysis did not reveal significant age-related changes in levels of Kir6.1 or Kir6.2 mRNAs. However, levels of SUR2A were significantly lower in old than in young females. Such age-differences were not observed with cardiac tissue from male animals. In both old and young males, pinacidil (100 microM) induced outward currents. The difference between current density of pinacidil-sensitive component in females, but not males, was statistically significant. Western blotting analysis revealed higher levels of Kir6.2 and SUR2A proteins in cardiac membrane fraction from young than old females. The present study demonstrates that in females, but not males, aging is associated with decrease in number of cardiac K(ATP) channels which is due to decrease in levels of the SUR2A subunit.

Adenosine Triphosphate↗