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PubMed1997

K(ATP) channels do not mediate vasodilation by 3-morpholinosydnonimine in goat coronary artery.

The present study investigated the role of ATP-sensitive potassium (K(ATP)) channels in mediating relaxation to the nitric oxide (NO) donor, 3-morpholinosydnonimine (SIN-1) in goat coronary arteries. SIN-1 (10(-8)-10(-5) M) caused concentration-dependent relaxations of the coronary artery ring segments contracted with K+ (30 mM) with an EC50 of 6.61 x 10(-7) M. Methylene blue (3 x 10(-6) M) caused a rightward shift in the concentration-response curve of SIN-1 (10(-8)-3 X 10(-5) M) with a corresponding increase in the EC50 (3.62 x 10(-6) M) of the nitrovasodilator. While the K(ATP) channel blocker, glibenclamide (1 and 3 x 10(-6) M) caused dose-dependent inhibition of vasorelaxations produced by pinacidil (10(-8)-10(-4) M), it had no effect on the vasodilations elicited by SIN-1 (10(-8)-10(-5) M) in the coronary arterial smooth muscle. Increasing the extracellular K+ concentration from 30 mM to 80 mM to reduce the K+ gradient across the cell membrane, inhibited the relaxations elicited by pinacidil (10(-8)-10(-4) M). On the other hand, SIN-1 (10(-8)-10(-5) M)-induced relaxations were potentiated in high K+ (80 mM) compared to those observed at K+ (30 mM). These results suggest that goat coronary artery vasodilations caused by the NO donor, SIN-1, do not involve K(ATP) channels.

Adenosine Triphosphate↗
PubMed1997

Endothelium and cannabinoid receptor involvement in levcromakalim vasorelaxation.

Levcromakalim was more potent at relaxing rat small mesenteric arteries with endothelium (EC50, 84+/-10 nM) than denuded vessels (EC50, 779+/-101 nM). The cannabinoid receptor antagonist SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride; 1 microM) shifted the levcromakalim concentration/response curve 7.6-fold rightwards in intact vessels but had no effect in de-endothelialised vessels. Similar effects occurred with pinacidil. Combination of the K+ channel blockers apamin (1 microM) and charybdotoxin (100 nM) shifted the levcromakalim concentration/response curve 3-fold rightwards only in intact vessels. It is concluded that levcromakalim and pinacidil relax mesenteric arteries partly by releasing a relaxing factor from endothelium, possibly an endogenous cannabinoid.

Animals↗
PubMed1999

Influence of increase in osmotic pressure with sucrose on relaxation and cyclonucleotides levels in isolated rat aorta.

The influence of increases in osmolarity by addition of sucrose were investigated on relaxation and changes in adenosine 3':5'-cyclic monophosphate (cyclic AMP) and guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels in isolated rat aortic rings. Isoprenaline-mediated relaxations were attenuated in hypertonic (341+/-0.4 mOsmol) (mean+/-S.E.M.) solution. The concentration-response curve to isoprenaline was displaced to the right. The EC(50) (0.16+/-0.05 vs. 1.14+/-0.5 microM) significantly (n=6; P<0.05) increased without any changes to the maximum response. Hypertonic solution also attenuated methacholine-mediated relaxations resulting in a significant increase in the EC(50) (0. 28+/-0.04 vs. 0.52+/-0.04 microM) and reduced the maximal response (73+/-5% vs. 51+/-8%). In contrast, an increase in tonicity did not have any influence on sodium nitroprusside, forskolin or pinacidil concentration-response curves. Hypertonic solution also did not affect either basal cyclic AMP or cyclic GMP production. In addition, an increase in osmolarity did not affect isoprenaline-stimulated increases in the levels of cyclic AMP. However, an increase in the tonicity of Krebs solution significantly inhibited methacholine-stimulated (58%-34%) accumulation of cyclic GMP. The present data indicated that an increase in the tonicity of Krebs solution impaired endothelium-dependent relaxation and the associated increase in cyclic GMP production without affecting basal levels of this nucleotide. The inhibitory effects of high osmolarity on beta-adrenoceptor-mediated relaxation did not appear to be due to a reduction in cyclic AMP generation, or the result of inhibition of pinacidil-sensitive K(ATP)(+) channels. Moreover, an increase in the tonicity of Krebs solution did not influence relaxation induced by direct activation of adenylate cyclase or guanylate cyclase by forskolin and sodium nitroprusside, respectively.

Adrenergic beta-Agonists↗
PubMed2001

Gender-specific difference in cardiac ATP-sensitive K(+) channels.

OBJECTIVES: The main objective of this study was to establish whether gender regulates expression and/or properties of cardiac ATP-sensitive K(+) (K(ATP)) channels. BACKGROUND: Recently, evidence has been provided that differing cardiac responses in males and females to metabolic stress may result from gender-specific difference(s) in the efficiency of endogenous cardioprotective mechanism(s) such as K(ATP) channels. METHODS: A reverse transcription polymerase chain reaction (RT-PCR) using primers specific for Kir6.2, Kir6.1 and SUR2A subunits was performed on total RNA from guinea pig ventricular tissue. Western blotting using anti-Kir6.2 and anti-SUR2A antibodies was performed on cardiac membrane fraction. Whole-cell, single-channel electrophysiology and digital epifluorescent Ca(2+) imaging were performed on isolated guinea pig ventricular cardiomyocytes. RESULTS: The RT-PCR revealed higher levels of SUR2A, but not Kir6.1 and Kir6.2, messenger RNA in female tissue relative to male tissue, while much higher levels of both Kir6.2 and SUR2A proteins in cardiac membrane fraction in female tissue compared with male tissue were found. In both male and female tissue, pinacidil (100 microM), a K(ATP) channel opener, induced outward whole-cell currents. The current density of the pinacidil-sensitive component was significantly higher in female tissue than it was in male tissue, while no differences in single K(ATP) channel properties between genders were observed. Ischemia-reperfusion challenge induced significant intracellular Ca(2+) loading in male, but not female, cardiomyocytes. To test the hypothesis that SUR2A expression is the limiting factor in K(ATP) channel formation, we took different volumes of Kir6.2 and SUR2A complementary DNA (cDNA) from the same cDNA pool and subjected them to PCR. In order to obtain a band having 50% of the maximal intensity, a volume of SUR2a cDNA approximately 20 times the volume of Kir6.2 cDNA was required. CONCLUSIONS: This study has demonstrated that female tissue expresses higher levels of functional cardiac K(ATP) channels than male tissue due to the higher expression of the SUR2A subunit, which has an impact on cardiac response to ischemia-reperfusion challenge.

Adenosine Triphosphate↗
PubMed1994

Novel potassium channel openers: synthesis and pharmacological evaluation of new N-(substituted-3-pyridyl)-N'-alkylthioureas and related compounds.

This report describes the synthesis and pharmacological evaluation of a series of novel potassium channel openers related to the pinacidil-type compounds. Thioureas, cyanoguanidines, and pyridine N-oxides were systematically evaluated for their effects on both the inhibition of spontaneous mechanical activity in rat portal vein (in vitro) and their antihypertensive activity (in vivo), and the structure-activity relationship for this series of compounds was discussed. Good correlation between in vitro and iv antihypertensive activity was observed for these compounds. Among them, cyanoguanidines bearing a conformationally rigid unit such as a norbornyl group generally possessed potent activity in both in vitro and in vivo studies. Especially, N-(6-amino-3-pyridyl)-N'-cyano-N"-(1-methyl-2-norbornyl)guanidine (23d) was identified as a more potent potassium channel opener in vitro (EC100 = 3 x 10(-8) M) than pinacidil (EC100 = 10(-7) M).

4-Aminopyridine↗
PubMed1994

Cloning and functional expression of a rat heart KATP channel.

Potassium channels that are ATP-sensitive (KATP) couple membrane potential to the metabolic status of the cell. KATP channels are inhibited by intracellular ATP and are stimulated by intracellular nucleotide diphosphates. KATP channels are important regulators of secretory processes and muscle contraction, and are targets for therapeutic treatment of type II diabetes by the inhibitory sulphonylureas and for hypertension by activators such as pinacidil. In cardiac tissue, KATP channels are central regulators of post-ischaemic cardioprotection. Electrophysiological and pharmacological characteristics vary among KATP channels recorded from diverse tissues suggesting extensive molecular heterogeneity. A complementary DNA encoding a KATP channel was isolated from rat heart using the polymerase chain reaction. We report here that the expressed channels possess all of the essential features of native cardiac KATP channels, including sensitivity to intracellular nucleotides. In addition the cloned channels are activated by the potassium channel opener, pinacidil, but are not inhibited by the sulphonylurea, glibenclamide.

Adenosine Triphosphate↗
PubMed1997

Evidence against a role of cytochrome P450-derived arachidonic acid metabolites in endothelium-dependent hyperpolarization by acetylcholine in rat isolated mesenteric artery.

1. In rat mesenteric artery, acetylcholine (ACh) causes endothelium-dependent hyperpolarization by releasing endothelium-derived hyperpolarizing factor (EDHF). Recent evidence suggests that EDHF may be a cytochrome P450-derived arachidonic acid metabolite. The aim of the present study was to investigate whether such a metabolite is indeed contributing to ACh-induced hyperpolarization observed in rat mesenteric artery. 2. The phospholipase A2 inhibitor quinacrine (30 microM) nearly completely eliminated ACh-induced hyperpolarization. However, the hyperpolarizing effect of pinacidil was also abolished in the presence of quinacrine. 3. The imidazole antimycotic agents ketoconazole (50 microM), clotrimazole (30 microM) and miconazole (10 microM), which bind to the heme moiety of cytochrome P450, eliminated not only ACh-induced hyperpolarizations but also those induced by pinacidil. SKF525A (30 microM), a prototype inhibitor of the enzyme, also abolished the hyperpolarizing responses to both agents. In contrast, neither 17-octadecynoic acid (10 microM), a mechanism-based inhibitor of cytochrome P450 metabolism of fatty acids, nor eicosatetraynoic acid (20 microM), an inhibitor of all arachidonic acid metabolic pathways, altered ACh-induced hyperpolarization. Furthermore, the hyperpolarization was unaffected by the preferential inhibitors of specific cytochrome P450 isozymes, alpha-naphtoflavone (1 microM), diedthyldithiocarbamate (50 microM), metyrapone (20 microM) and troleandomycin (10 microM). 4. Pretreatment of rats with lipopolysaccharide (2 mg kg-1) and exposure to nitroprusside (10 microM), both of which are expected to inhibit cytochrome P450 activity due to nitric oxide overproduction, were without effect on ACh-induced hyperpolarization. Pretreatment of rats for 3 days with pentobarbitone (80 mg kg-1 day-1), a cytochrome P450 inducer, also did not affect the hyperpolarizing response to ACh. 5. Arachidonic acid in concentrations up to 100 microM had no detectable effect on smooth muscle membrane potential. 11, 12-Epoxyeicosatrienoic acid (EET, 10 microM), one of cytochrome P450-derived epoxygenase metabolites of arachidonic acid, elicited a small endothelium-independent membrane hyperpolarization. The hyperpolarizing response to EET was blocked by glibenclamide (30 microM), in contrast to the response to ACh. 6. These results suggest that the contribution of a cytochrome P450-derived metabolite of arachidonic acid to ACh-induced hyperpolarization via EDHF release is minimal or absent in rat mesenteric artery.

Acetylcholine↗
PubMed1998

Direct effects of diazoxide on mitochondria in pancreatic B-cells and on isolated liver mitochondria.

1. The direct effects of diazoxide on mitochondrial membrane potential, Ca2+ transport, oxygen consumption and ATP generation were investigated in mouse pancreatic B-cells and rat liver mitochondria. 2. Diazoxide, at concentrations commonly used to open adenosine 5'-triphosphate (ATP)-dependent K+-channels (K(ATP) channels) in pancreatic B-cells (100 to 1000 microM), decreased mitochondrial membrane potential in mouse intact perifused B-cells, as evidenced by an increase of rhodamine 123 fluorescence. This reversible decrease of membrane potential occurred at non-stimulating (5 mM) and stimulating (20 mM) glucose concentrations. 3. A decrease of mitochondrial membrane potential in perifused B-cells was also caused by pinacidil, but no effect could be seen with levcromakalim (500 microM each). 4. Measurements by a tetraphenylphosphonium-sensitive electrode of the membrane potential of rat isolated liver mitochondria confirmed that diazoxide decreased mitochondrial membrane potential by a direct action. Pretreatment with glibenclamide (2 microM) did not antagonize the effects of diazoxide. 5. In Fura 2-loaded B-cells perifused with the Ca2+ channel blocker, D 600, a moderate, reversible increase of intracellular Ca2+ concentration could be seen in response to 500 microM diazoxide. This intracellular Ca2+ mobilization may be due to mitochondrial Ca2+ release, since the reduction of membrane potential of isolated liver mitochondria by diazoxide was accompanied by an accelerated release of Ca2+ stored in the mitochondria. 6. In the presence of 500 microM diazoxide, ATP content of pancreatic islets incubated in 20 mM glucose for 30 min was significantly decreased by 29%. However, insulin secretion from mouse perifused islets induced by 40 mM K+ in the presence of 10 mM glucose was not inhibited by 500 microM diazoxide, suggesting that the energy-dependent processes of insulin secretion distal to Ca2+ influx were not affected by diazoxide at this concentration. 7. The effects of diazoxide on oxygen consumption and ATP production of liver mitochondria varied depending on the respiratory substrates (5 mM succinate, 10 mM alpha-ketoisocaproic acid, 2 mM tetramethyl phenylenediamine plus 5 mM ascorbic acid), indicating an inhibition of respiratory chain complex II. Pinacidil, but not levcromakalim, inhibited alpha-ketoisocaproic acid-fuelled ATP production. 8. In conclusion, diazoxide directly affects mitochondrial energy metabolism, which may be of relevance for stimulus-secretion coupling in pancreatic B-cells.

Adenosine Triphosphate↗
PubMed1998

Influence of potassium channel modulators on cognitive processes in mice.

1. The effect of i.c.v. administration of different potassium channel openers (minoxidil, pinacidil, cromakalim) and potassium channel blockers (tetraethylammonium, apamin, charybdotoxin, gliquidone, glibenclamide) on memory processes was evaluated in the mouse passive avoidance test. 2. The administration of minoxidil (10 microg per mouse i.c.v.), pinacidil (5-25 microg per mouse i.c.v.) and cromakalim (10-25 microg per mouse i.c.v.) immediately after the training session produced an amnesic effect. 3. Tetraethylammonium (TEA; 1-5 microg per mouse i.c.v.), apamin (10 ng per mouse i.c.v.), charybdotoxin (1 microg per mouse i.c.v.), gliquidone (3 microg per mouse i.c.v.) and glibenclamide (1 microg per mouse i.c.v.), administered 20 min before the training session, prevented the potassium channel opener-induced amnesia. 4. At the highest effective doses, none of the drugs impaired motor coordination, as revealed by the rota rod test, or modified spontaneous motility and inspection activity, as revealed by the hole board test. 5. These results suggest that the modulation of potassium channels plays an important role in the regulation of memory processes. On this basis, the potassium channel blockers could be useful in the treatment of cognitive deficits.

Amnesia↗
PubMed2004

Pharmacological activation of plasma-membrane KATP channels reduces reoxygenation-induced Ca(2+) overload in cardiac myocytes via modulation of the diastolic membrane potential.

1. The opening of cardiac plasma-membrane ATP-sensitive K(+) channels (pmK(ATP)) can protect the heart against ischaemia/reperfusion injury. We recently demonstrated that the resting membrane potential (E(m)) of ventricular myocytes strongly modulates reoxygenation-induced Ca(2+) overload. This led to the hypothesis that activation of pmK(ATP) can influence the extent of chemically induced hypoxia (CIH)/reoxygenation Ca(2+) overload via hyperpolarization of the diastolic membrane potential of ventricular myocytes. 2. The membrane potential (E(m)) of isolated rat myocytes was determined using the perforated patch-clamp technique and DiBac(4)(3) imaging. Intracellular Ca(2+) ([Ca(2+)](i)) was monitored using FURA-2 imaging. 3. CIH/reoxygenation caused a significant depolarization of E(m) and a substantial increase in [Ca(2+)](i). The K(ATP) opener pinacidil (100 microm) and the pmK(ATP) opener P-1075 (100 microm) hyperpolarized the E(m) of normoxic myocytes. Pinacidil (100 microm) and P-1075 (10 and 100 microm), applied during reoxygenation, hyperpolarized E(m) and prevented reoxygenation-induced increases in [Ca(2+)](i). 4. Myocyte hypercontracture and death increased in parallel with an E(m) depolarization of 10-15 mV and increases in [Ca(2+)](i). Under these conditions, the selective pmK(ATP) channel inhibitor HMR 1098 further depolarized myocyte membrane potential and increased hypercontracture. 5. In conclusion, activation of pmK(ATP) channels can prevent CIH/reoxygenation-induced Ca(2+) overload via a mechanism that is dependent on hyperpolarization of diastolic membrane potential. Hyperpolarization toward normal resting membrane potential favours the Ca(2+) extrusion mode of Na(+)/Ca(2+) exchange.

Animals↗
PubMed2006

Actions of ZD0947, a novel ATP-sensitive K+ channel opener, on membrane currents in human detrusor myocytes.

BACKGROUND AND PURPOSE: ATP-sensitive K+ channels (K(ATP) channels) play important roles in regulating the resting membrane potential of detrusor smooth muscle. Actions of ZD0947, a novel KATP channel opener, on both carbachol (CCh)-induced detrusor contractions and membrane currents in human urinary bladder myocytes were investigated. EXPERIMENTAL APPROACH: Tension measurements and patch-clamp techniques were utilized to study the effects of ZD0947 in segments of human urinary bladder. Immunohistochemistry was also performed to detect the expression of the sulphonylurea receptor 1 (SUR1) and the SUR2B antigens in human detrusor muscle. KEY RESULTS: ZD0947 (> or = 0.1 microM) caused a concentration-dependent relaxation of the CCh-induced contraction of human detrusor, which was reversed by glibenclamide. The rank order of the potency to relax the CCh-induced contraction was pinacidil > ZD0947 > diazoxide. In conventional whole-cell configuration, ZD0947 (> or = 1 microM) caused a concentration-dependent inward K+ current which was suppressed by glibenclamide at -60 mV. When 1 mM ATP was included in the pipette solution, application of pinacidil or ZD0947 caused no inward K+ current at -60 mV. Gliclazide (< or =1 microM), a selective SUR1 blocker, inhibited the ZD0947-induced currents (Ki = 4.0 microM) and the diazoxide-induced currents (high-affinity site, Ki1 = 42.4 nM; low-affinity site, Ki2 = 84.5 microM) at -60 mV. Immunohistochemical studies indicated the presence of SUR1 and SUR2B proteins, which are constituents of KATP channels, in the bundles of human detrusor smooth muscle. CONCLUSIONS AND IMPLICATIONS: These results suggest that ZD0947 caused a glibenclamide-sensitive detrusor relaxation through activation of glibenclamide-sensitive KATP channels in human urinary bladder.

ATP-Binding Cassette Transporters↗
PubMed1999

Characterization of ATP-sensitive potassium channels in human corporal smooth muscle cells.

Potassium (K) channels play a significant role in modulating human corporal smooth muscle tone, and thus, erectile capacity. Recent pharmacological studies indicate that the metabolically-regulated K channel (KATP) may be an important modulator of human penile erection with significant therapeutic potential. The goal of these initial studies, therefore, was to utilize patch clamp techniques to characterize the putative KATP subtype(s) present in cultured and freshly isolated human corporal smooth muscle cells. In the cell-attached patch mode, two distinct unitary K+ currents were identified whose respective conductance values were similar in cultured and freshly isolated smooth muscle cells. In cultured myocytes, the measured conductance values in symmetric KCl (140 mM) solutions were 59.1 +/- 2.7 pS and 18.4 +/- 2.1 pS (n = 5 cells). Under identical experimental conditions in freshly isolated myocytes, corresponding conductance values were 59.2 +/- 3.7 pS and 18.5 +/- 2.4 pS, respectively (n = 4 cells). I-V curves constructed during step depolarization (-60 to +80 mV), revealed a linear I-V relationship for both unitary conductances. Single channel records documented that both conductances were reversibly inhibited by the application of ATP (1-3 mM) to the bath solution in the inside-out attached patch configuration. The unitary activity of both K channel subtypes was significantly increased by the application of pinacidil (10 microM) and levcromakalim (10 microM). Whole cell patch recordings documented a glibenclamide-sensitive, pinacidil- and levcromakalim-induced increase in the whole cell outward K+ current during step depolarization (-70 mV to +130 mV) of 105 +/- 37%, 139 +/- 42%, respectively. These data confirm and extend our previous observations, and provide the first evidence for the presence of KATP channel subtypes in human corporal smooth muscle cells.

Adenosine Triphosphate↗
PubMed2006

Effects of systemic administration of iptakalim on extracellular neurotransmitter levels in the striatum of unilateral 6-hydroxydopamine-lesioned rats.

The function of ATP-sensitive potassium (KATP) channels in nigrostriatal pathway in Parkinson's disease (PD) was studied by employing a novel KATP channel opener iptakalim (Ipt). Apomorphine-induced rotation behavior test and microdialysis experiment were carried out in unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. Behavior test showed that systemic administration of Ipt failed to significantly alleviate apomorphine-induced rotation in unilateral 6-OHDA-lesioned PD model rats. However, using in vivo microdialysis in this PD model rats, it was found that Ipt could increase extracellular dopamine levels in the lesioned side of the striatum and decrease dopamine levels in the intact side of the striatum. Meanwhile, Ipt had no influence on glutamate levels in the intact side, but it did decrease glutamate levels in the lesioned side of the striatum of PD rats. Additionally, in primary cultured rat astrocytes, 6-OHDA decreased overall glutamate uptake activity, but this decrease was recovered and glutamate uptake activity was restored by the opening of KATP channels induced by Ipt and pinacidil. The classical KATP channel blocker glibenclamide completely abolished the effects of Ipt and pinacidil. The present study suggests that (i) the function of KATP channels in the lesioned and intact nigrostriatal pathway is different in unilateral 6-OHDA-lesioned PD model rats. (ii) KATP channels regulate extracellular neurotransmitter levels in the striatum of unilateral 6-OHDA-lesioned rats and may play neuroprotective roles due to their effects on glutamate transporters.

Adenosine Triphosphate↗
PubMed1996

Differentiated effects of vasodilators on myogenic reactivity during partial inhibition of myogenic tone in pressurized skeletal muscle small arteries of the rat.

Myogenic tone and reactivity were studied in isolated, cannulated and pressurized small branches of the femoral artery of the rat. Myogenic tone developed spontaneously under control conditions (1.5 mM Ca2+), reducing the diameter at 80 mmHg to 64 +/- 6% of the 'max 80', i.e. the diameter in Ca2+ free solution, which was 221 +/- 23 microns (mean +/- SD, n = 18). The calcium channel blockers verapamil and diltiazem, dose-dependently, decreased this myogenic tone with pIC50 values of 6.9 +/- 0.2 (n = 7) and 6.6 +/- 0.1 (n = 6), respectively. Myogenic reactivity was demonstrated under control conditions as a sustained decrease in diameter, by 5 +/- 3% of max 80 (after an initial, transient distension), in response to a step increase in transmural pressure from 80 to 140 mmHg. This response to the pressure increase was markedly inhibited when myogenic tone had been reduced by 50% with verapamil or diltiazem resulting, in fact, in an increased steady state diameter by 2 +/- 1 and 1 +/- 1% at 140 compared with 80 mmHg. However, if myogenic tone was reduced to the same extent by low extracellular Ca2+ (approximately 0.3 mM) the vessels constricted by 6 +/- 1% in response to the pressure increase, an effect comparable to that in control Ca2+. Moreover, 50% reductions in myogenic tone by ACh (approximately 0.1 microM) or pinacidil (approximately 0.3 microM) were associated with significantly enhanced reactivity; steady state diameter decreased by as much as 11 +/- 4 and 15 +/- 5% of max 80. These results suggest that voltage dependent L-type Ca2+ channels are involved both in myogenic tone and in the myogenic response to a rise in vascular transmural pressure in skeletal muscle arteries. Partial inhibition of myogenic tone by other pharmacological routes do not necessarily interfere with myogenic reactivity since the response was, in fact, enhanced in the presence of ACh or pinacidil.

Acetylcholine↗
PubMed1998

Comparison of the cellular electrophysiological characteristics of canine left ventricular epicardium, M cells, endocardium and Purkinje fibres.

Electrophysiological differences among M cells, epicardium, endocardium and Purkinje fibres of the canine ventricle were studied over a wide range of stimulation cycle lengths, and the pharmacological response of these cell types to the sodium channel blocker tetrodotoxin, calcium channel blocker nifedipine and ATP-sensitive potassium channel activator pinacidil was compared. The experiments were carried out by applying standard intracellular microelectrode technique in isolated dog left ventricular preparations. The results confirmed the existence of M cells in the canine ventricle, in addition, the distribution of the rate of rise of the action potential upstroke and action potential amplitude values reflecting probably the inhomogeneity of the fast sodium current in these cells was revealed. It was also demonstrated that M cells differ from Purkinje fibres in some aspects which were not expected from previous investigations: (1) The early portion of the action potential duration restitution curve in M cells is more similar to that of endocardial and epicardial cells than to Purkinje fibres. (2) The plateau phase of the action potentials in Purkinje fibres developed at a more negative potential range than that in the other cell types studied. (3) The pharmacological response to tetrodotoxin and pinacidil in M cells resembles to that in the endocardial and epicardial cells more than in the Purkinje fibres. Our results provide further evidence in support of the existence of M cells but also indicate that there are important electrophysiological as well as pharmacological differences between M cells and Purkinje fibres.

Action Potentials↗
PubMed1999

Post-partum prolongation of the atrial repolarization in rabbit.

Female sexual steroids are known to modify the expression of various K+ channels and thus they can alter cardiac repolarization. In the present work, using conventional microelectrode techniques, action potential characteristics were studied in atrial myocardium isolated from virgin, late pregnant, early (1-3 days) post-partum and late (2-3 weeks) post-partum rabbits. No changes in action potential configuration were observed during pregnancy. However, the duration, overshoot and amplitude of action potentials were significantly increased in the early (1-3 days) post-partum period. Resting potential and maximum rate of depolarization remained unchanged. The observed changes were transient, normal action potential characteristics were obtained at weeks 2-3 post-partum. 4-aminopyridine (1 mmol L(-1)). caused a marked lengthening of action potential duration in all preparations obtained from non-pregnant and pregnant rabbits, whereas this 4-aminopyridine-induced prolongation was moderate in those preparations excised from the hearts of early post-partum animals. Action potential configuration was not affected by pinacidil (10 micromol L(-1)) or glibenclamide (5 micromol L(-1)) in non-pregnant or pregnant animals. In preparations obtained from early post-partum rabbits, pinacidil significantly shortened action potential duration, which was reverted by glibenclamide. The lengthening of action potential duration together with the decreased sensitivity to 4-aminopyridine observed in early post-partum animals may probably be caused by reduction of the transient outward K+ current at this stage. The results also suggest that electrophysiological alterations in the early post-partum period may probably be more pronounced than those associated with pregnancy itself.

4-Aminopyridine↗
PubMed2000

KATP channels regulate mitogenically induced proliferation in primary rat hepatocytes and human liver cell lines. Implications for liver growth control and potential therapeutic targeting.

To determine whether K(ATP) channels control liver growth, we used primary rat hepatocytes and several human cancer cell lines for assays. K(ATP) channel openers (minoxidil, cromakalim, and pinacidil) increased cellular DNA synthesis, whereas K(ATP) channel blockers (quinidine and glibenclamide) attenuated DNA synthesis. The channel inhibitor glibenclamide decreased the clonogenicity of HepG2 cells without inducing cytotoxicity or apoptosis. To demonstrate the specificity of drugs for K(+) channels, whole-cell patch-clamp recordings were made. Hepatocytes revealed K(+) currents with K(ATP) channel properties. These K(+) currents were augmented by minoxidil and pinacidil and attenuated by glibenclamide as well as tetraethylammonium, in agreement with established responses of K(ATP) channels. Reverse transcription of total cellular RNA followed by polymerase chain reaction showed expression of K(ATP) channel-specific subunits in rat hepatocytes and human liver cell lines. Calcium fluxes were unperturbed in glibenclamide-treated HepG2 cells and primary rat hepatocytes following induction with ATP and hepatocyte growth factor, respectively, suggesting that the effect of K(ATP) channel activity upon hepatocyte proliferation was not simply due to indirect modulation of intracellular calcium. The regulation of mitogen-related hepatocyte proliferation by K(ATP) channels advances our insights into liver growth control. The findings have implications in mechanisms concerning liver development, regeneration, and oncogenesis.

ATP-Binding Cassette Transporters↗
PubMedDate not supplied

Electrotonic transmission within pericyte-containing retinal microvessels.

OBJECTIVE: Little is known about the electrotonic architecture of the pericyte-containing retinal microvasculature. Here, the authors focus on the cell-to-cell transmission of hyperpolarization, which can induce abluminal pericytes to relax and lumens to dilate. METHODS: With perforated-patch pipettes, the authors monitored the membrane potentials and ionic currents of pairs of pericytes located on freshly isolated rat retinal microvessels. Voltage changes were induced by administering electrical stimuli into pericytes, miniperfusing the KATP channel opener pinacidil, or using oxotremorine to activate chloride channels. RESULTS: Suggestive of extensive cell-to-cell communication, spontaneous voltage changes were strikingly similar in widely separated pericytes. In addition, injection of current into one of a pair of sampled pericytes always elicited a voltage response in the other sampled pericyte; the gap junction uncoupler, heptanol, blocked this transmission. In the dual recordings, hyperpolarization spreading from a current-injected pericyte decayed approximately 40% within 100 microm. In contrast, pinacidil-induced hyperpolarizations diminished by only approximately 2% in 100 microm. Depolarizations also appeared to spread with similar transmission efficacies. CONCLUSIONS: Based on the experiments, the authors propose that key features of the electrotonic architecture of retinal microvessels include highly efficient cell-to-cell communication within the endothelium and relatively inefficient transmission at pericyte/endothelial junctions. Thus, the endothelium is likely to provide an efficient pathway that functionally links contractile pericytes and thereby, serves to coordinate the vasomotor response of a retinal capillary.

Animals↗