Lidocaine and Mexiletine Inhibit Mitochondrial Oxidation in Rat Ventricular Myocytes

2001 ◽  
Vol 95 (3) ◽  
pp. 766-770 ◽  
Author(s):  
Yasuo Tsutsumi ◽  
Shuzo Oshita ◽  
Takashi Kawano ◽  
Hiroshi Kitahata ◽  
Yoshinobu Tomiyama ◽  
...  
Keyword(s):  
Antiarrhythmic Drugs ◽  
Ventricular Myocytes ◽  
Atp Synthesis ◽  
Dependent Manner ◽  
Mitochondrial Potential ◽  
Rat Ventricular Myocytes ◽  
Mitochondrial Redox State ◽  
Male Wistar Rats ◽  
Mitochondrial Oxidation ◽  
Dose Dependent

Background Accumulating evidence suggests that mitochondrial rather than sarcolemmal adenosine triphosphate-sensitive K+ (K(ATP)) channels may have an important role in the protection of myocardium during ischemia. Because both lidocaine and mexiletine are frequently used antiarrhythmic drugs during myocardial ischemia, it is important to investigate whether they affect mitochondrial K(ATP) channel activities. Methods Male Wistar rats were anesthetized with ether. Single, quiescent ventricular myocytes were dispersed enzymatically. The authors measured flavoprotein fluorescence to evaluate mitochondrial redox state. Lidocaine or mexiletine was applied after administration of diazoxide (25 microM), a selective mitochondrial K(ATP) channel opener. The redox signal was normalized to the baseline flavoprotein fluorescence obtained during exposure to 2,4-dinitrophenol, a protonophore that uncouples respiration from ATP synthesis and collapses the mitochondrial potential. Results Diazoxide-induced oxidation of flavoproteins and the redox changes were inhibited by 5-hydroxydecanoic acid, a selective mitochondrial K(ATP) channel blocker, suggesting that flavoprotein fluorescence can be used as an index of mitochondrial oxidation mediated by mitochondrial K(ATP) channels. Lidocaine (10(-3) to 10 mM) and mexiletine (10(-3) to 10 mM) reduced oxidation of the mitochondrial matrix in a dose-dependent manner with an EC50 of 98+/-63 microM for lidocaine and 107+/-89 microM for mexiletine. Conclusions Both lidocaine and mexiletine reduced flavoprotein fluorescence induced by diazoxide in rat ventricular myocytes, indicating that these antiarrhythmic drugs may produce impairment of mitochondrial oxidation mediated by mitochondrial K(ATP) channels.

Clinically Relevant Concentrations of Propofol Have No Effect on Adenosine Triphosphate–sensitive Potassium Channels in Rat Ventricular Myocytes

2002 ◽  
Vol 96 (6) ◽  
pp. 1472-1477 ◽  
Author(s):  
Takashi Kawano ◽  
Shuzo Oshita ◽  
Yasuo Tsutsumi ◽  
Yoshinobu Tomiyama ◽  
Hiroshi Kitahata ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Adenosine Triphosphate ◽  
Single Channel ◽  
Ventricular Myocytes ◽  
Dependent Manner ◽  
Open Probability ◽  
Concentration Dependent Manner ◽  
Rat Ventricular Myocytes ◽  
Mitochondrial Oxidation ◽  
Inside Out

Background Activation of adenosine triphosphate-sensitive potassium (K(ATP)) channels produces cardioprotective effects during ischemia. Because propofol is often used in patients who have coronary artery disease undergoing a wide variety of surgical procedures, it is important to evaluate the direct effects of propofol on K(ATP) channel activities in ventricular myocardium during ischemia. Methods The effects of propofol (0.4-60.1 microg/ml) on both sarcolemmal and mitochondrial K(ATP) channel activities were investigated in single, quiescent rat ventricular myocytes. Membrane currents were recorded using cell-attached and inside-out patch clamp configurations. Flavoprotein fluorescence was measured to evaluate mitochondrial oxidation mediated by mitochondrial K(ATP) channels. Results In the cell-attached configuration, open probability of K(ATP) channels was reduced by propofol in a concentration-dependent manner (EC(50) = 14.2 microg/ml). In the inside-out configurations, propofol inhibited K(ATP) channel activities without changing the single-channel conductance (EC(50) = 11.4 microg/ml). Propofol reduced mitochondrial oxidation in a concentration-dependent manner with an EC(50) of 14.6 microg/ml. Conclusions Propofol had no effect on the sarcolemmal K(ATP) channel activities in patch clamp configurations and the mitochondrial flavoprotein fluorescence induced by diazoxide at clinically relevant concentrations (< 2 microm), whereas it significantly inhibited both K(ATP) channel activities at very high, nonclinical concentrations (> 5.6 microg/ml; 31 microm).

scholarly journals Cobalt oxide nanoparticles induce oxidative stress and alter electromechanical function in rat ventricular myocytes

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Monia Savi ◽  
Leonardo Bocchi ◽  
Francesca Cacciani ◽  
Rocchina Vilella ◽  
Annamaria Buschini ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Intracellular Calcium ◽  
Cobalt Oxide ◽  
Ventricular Myocytes ◽  
Acute Exposure ◽  
Dependent Manner ◽  
Rat Ventricular Myocytes ◽  
Dose Dependent Decrease ◽  
Dose Dependent

Abstract Background Nanotoxicology is an increasingly relevant field and sound paradigms on how inhaled nanoparticles (NPs) interact with organs at the cellular level, causing harmful conditions, have yet to be established. This is particularly true in the case of the cardiovascular system, where experimental and clinical evidence shows morphological and functional damage associated with NP exposure. Giving the increasing interest on cobalt oxide (Co3O4) NPs applications in industrial and bio-medical fields, a detailed knowledge of the involved toxicological effects is required, in view of assessing health risk for subjects/workers daily exposed to nanomaterials. Specifically, it is of interest to evaluate whether NPs enter cardiac cells and interact with cell function. We addressed this issue by investigating the effect of acute exposure to Co3O4-NPs on excitation-contraction coupling in freshly isolated rat ventricular myocytes. Results Patch clamp analysis showed instability of resting membrane potential, decrease in membrane electrical capacitance, and dose-dependent decrease in action potential duration in cardiomyocytes acutely exposed to Co3O4-NPs. Motion detection and intracellular calcium fluorescence highlighted a parallel impairment of cell contractility in comparison with controls. Specifically, NP-treated cardiomyocytes exhibited a dose-dependent decrease in the fraction of shortening and in the maximal rate of shortening and re-lengthening, as well as a less efficient cytosolic calcium clearing and an increased tendency to develop spontaneous twitches. In addition, treatment with Co3O4-NPs strongly increased ROS accumulation and induced nuclear DNA damage in a dose dependent manner. Finally, transmission electron microscopy analysis demonstrated that acute exposure did lead to cellular internalization of NPs. Conclusions Taken together, our observations indicate that Co3O4-NPs alter cardiomyocyte electromechanical efficiency and intracellular calcium handling, and induce ROS production resulting in oxidative stress that can be related to DNA damage and adverse effects on cardiomyocyte functionality.

scholarly journals The Effect of the mGlu8 Receptor Agonist, S-3,4-DCPG on Acquisition and Expression of Morphine-induced Conditioned Place Preference in Male rats

2021 ◽  
Author(s):  
Nazanin Kahvandi ◽  
Zahra Ebrahimi ◽  
Seyed Asaad Karimi ◽  
Siamak Shahidi ◽  
Iraj Salehi ◽  
...  
Keyword(s):  
Conditioned Place Preference ◽  
Metabotropic Glutamate Receptors ◽  
Preference Test ◽  
Place Preference ◽  
Male Rats ◽  
Dependent Manner ◽  
Metabotropic Glutamate ◽  
Male Wistar Rats ◽  
Dose Dependent

Abstract Background: The nucleus accumbens (NAc) plays a principal role in drug reward. It has been reported that metabotropic glutamate receptors (mGlu receptors) play a key role in the rewarding pathway(s). Previous studies have shown the vast allocation of the different types of mGlu receptors, including mGlu8 receptors, in regions that are associated with opioid rewards, such as the NAc. The aim of the present study was to evaluate the role of mGlu8 receptors within the NAc in the acquisition and expression phases of morphine induced conditioned place preference (CPP). Adult male Wistar rats were bilaterally implanted by two cannulas' in the NAc and were evaluated in a CPP paradigm. Selective mGlu8 receptor allosteric agonist (S-3,4-DCPG) was administered at doses of 0.03, 0.3, and 3 μg/0.5 μL saline per side into the NAc on both sides during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase, or before place preference test, or post-conditioning (expression) phase of morphine-induced CPP. Results: The results revealed that intra-accumbal administration of S-3,4-DCPG (0.3 and 3 μg) markedly decreased the acquisition in a dose-dependent manner but had no effect on expression of morphine-induced CPP. Conclusions: The findings suggest that activation of mGlu8 receptors in the NAc dose-dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine which may be related to the glutamate activity into the NAc and in reward pathway(s). These data suggest that mGlu8 receptor may be involved in conditioned morphine reward.

Alpha 1b-adrenoceptor-mediated stimulation of Na-K pump current in adult rat ventricular myocytes

1993 ◽  
Vol 264 (4) ◽  
pp. H1315-H1318 ◽  
Author(s):  
A. P. Williamson ◽  
R. H. Kennedy ◽  
E. Seifen ◽  
J. P. Lindemann ◽  
J. R. Stimers
Keyword(s):  
Adrenergic Receptors ◽  
Ventricular Myocytes ◽  
Pump Current ◽  
Peak Effect ◽  
Patch Clamp Technique ◽  
Rat Ventricular Myocytes ◽  
Adult Rat ◽  
Whole Cell Patch Clamp ◽  
Dose Dependent ◽  
Stimulation Of

The purpose of this study was to determine if myocardial alpha 1a-and/or alpha 1b-adrenoceptors are involved in the increase in Na-K pump current (Ip) elicited by alpha 1-adrenergic agonists. Single rat ventricular myocytes were isolated by enzymatic disaggregation. The whole cell patch-clamp technique was used to examine dose-dependent effects of phenylephrine (PE) on holding current (Ih) and to determine whether observed actions were mediated via alpha 1a-or alpha 1b-adrenergic receptors. To minimize the contribution of transsar-colemmal currents other than Ip to Ih, membrane voltage was held constant -40 mV, and cells were maintained in a Ca-free perfusate containing 1 mM Ba and 0.1 mM Cd. All experiments were conducted in the presence of 3 microM nadolol. PE elicited dose-dependent increases in Ih, with a peak effect of 0.57 +/- 0.03 pA/pF observed at 30 microM. The response to PE was dose dependently inhibited by prazosin and chloroethylclonidine and was totally eliminated by 1 mM ouabain. When used at doses selective for the alpha 1a-subtype, WB4101 failed to significantly antagonize the action of PE. These data suggest that the observed alpha 1-adrenoceptor-mediated increase in Ih in isolated rat ventricular myocytes is the result of an increase in Ip effected via stimulation of alpha 1b-adrenergic receptors.

Blockade of Adenosine Triphosphate–sensitive Potassium Channels by Thiamylal in Rat Ventricular Myocytes

2000 ◽  
Vol 92 (4) ◽  
pp. 1154-1159 ◽  
Author(s):  
Yasuo Tsutsumi ◽  
Shuzo Oshita ◽  
Hiroshi Kitahata ◽  
Yasuhiro Kuroda ◽  
Takashi Kawano ◽  
...  
Keyword(s):  
Adenosine Triphosphate ◽  
Katp Channel ◽  
Single Channel ◽  
Ventricular Myocytes ◽  
Katp Channels ◽  
Dependent Manner ◽  
Open Probability ◽  
Rat Ventricular Myocytes ◽  
Inside Out ◽  
Cell Attached Configuration

Background The adenosine triphosphate (ATP)-sensitive potassium (KATP) channels protect myocytes during ischemia and reperfusion. This study investigated the effects of thiamylal on the activities of KATP channels in isolated rat ventricular myocytes during simulated ischemia. Methods Male Wistar rats were anesthetized with ether. Single, quiescent ventricular myocytes were dispersed enzymatically. Membrane currents were recorded using patch-clamp techniques. In the cell-attached configuration, KATP channel currents were assessed before and during activation of these channels by 2,4-dinitrophenol and after administration of 25, 50, and 100 mg/l thiamylal. The open probability was determined from current-amplitude histograms. In the inside-out configuration, the current-voltage relation was obtained before and after the application of thiamylal (50 mg/1). Results In the cell-attached configuration, 2,4-dinitrophenol caused frequent channel opening. 2,4-Dinitrophenol-induced channel activities were reduced significantly by glibenclamide, suggesting that the channels studied were KATP channels. Open probability of KATP channels was reduced by thiamylal in a concentration-dependent manner. KATP channels could be activated in the inside-out configuration because of the absence of ATP. Thiamylal inhibited KATP channel activity without changing the single-channel conductance. Conclusions The results obtained in this study indicate that thiamylal inhibits KATP channel activities in cell-attached and inside-out patches, suggesting a direct action of this drug on these channels.

Effects of Mg2+ on Ca2+ waves and Ca2+ transients of rat ventricular myocytes

1996 ◽  
Vol 270 (3) ◽  
pp. H907-H914 ◽  
Author(s):  
H. Terada ◽  
H. Hayashi ◽  
N. Noda ◽  
H. Satoh ◽  
H. Katoh ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Channel Blocker ◽  
Ventricular Myocytes ◽  
Inhibitory Effect ◽  
Antiarrhythmic Action ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Triggered Activity ◽  
Rat Ventricular Myocytes ◽  
High Concentrations

It has been shown that the occurrence of the transient inward current, which is responsible for triggered activity, was often associated with propagating regions of increased intracellular Ca2+ concentration ([Ca2+]i), i.e., the “Ca2+ wave.” To investigate the mechanism of antiarrhythmic action of Mg2+, we have studied effects of high concentrations of Mg2+ on Ca2+ waves in isolated rat ventricular myocytes. [Ca2+]i was estimated using the Ca(2+)-indicating probe indo 1. Ca2+ waves in myocytes, stimulated at 0.2 Hz, were induced by perfusion of isoproterenol (10(-7) M). High Mg2+ concentration suppressed Ca2+ waves in a concentration-dependent manner (36% at 4 mM, 70% at 8 mM, and 82% at 12 mM). The Ca2+ channel blocker verapamil also suppressed Ca2+ waves in a similar way. In contrast with marked depression of Ca2+ transients by verapamil, Ca2+ transients were not affected by high Mg2+ concentration (8 mM). High Mg2+ concentration also reduced frequencies of Ca2+ waves in the absence of electrical stimulation, whereas verapamil failed to reduce frequencies of Ca2+ waves. Reduction in frequency of Ca2+ waves by high Mg2+ concentration was associated with slowing of propagation velocity of Ca2+ waves. To examine whether suppressive effects of high Mg2+ concentration on Ca2+ waves were related to an increase in intracellular Mg2+ concentration ([Mg2+]i), the effect of high-Mg2+ solution on [Mg2+]i was examined in myocytes loaded with mag-fura 2. An increase in extracellular Mg2+ concentration from 1 to 12 mM increased [Mg2+]i from 1.06 +/- 0.16 to 1.87 +/- 0.22 mM (P < 0.01) in 30 min. To examine the effect of high Mg2+ concentration on amount of releasable Ca2+ in the sarcoplasmic reticulum, the effect of high Mg2+ concentration on the Ca2+ transient induced by a rapid application of caffeine was examined. High-Mg2+ solution increased the peak of the caffeine-induced Ca2+ transient. These results suggest that the inhibitory effect of Mg2+ on Ca2+ waves was not due to inhibition of the sarcolemmal Ca2+ channel but could be due to a decreased propensity for the sarcoplasmic reticulum to divest itself of excess Ca2+.

Inhibition of Succinic Dehydrogenase and F0F1-ATP Synthase by 4,4'-Diisothiocyanatostilbene-2,2'-disulfonic Acid (DIDS)

1997 ◽  
Vol 52 (11-12) ◽  
pp. 799-806 ◽  
Author(s):  
Celene F. Bernardes ◽  
Jose R. Meyer-Fernandes ◽  
Orlando B. Martins ◽  
Anibal E. Vercesi
Keyword(s):  
Succinic Dehydrogenase ◽  
Atp Synthesis ◽  
Liver Mitochondria ◽  
Disulfonic Acid ◽  
Rat Liver Mitochondria ◽  
Dependent Manner ◽  
Submitochondrial Particles ◽  
Succinate Oxidation ◽  
Hydrolytic Activities ◽  
Dose Dependent

Abstract This study shows that incubation of rat liver mitochondria in the presence of the thiol/ amino reagent 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DID S) is followed by inhibition of both succinate supported respiration and oxidative phosphorylation. Half-maximal inhibition of succinic dehydrogenase activity and succinate oxidation by mitochondria was attained at 55.3 and 60.8 μm DIDS, respectively. DIDS did inhibit the net ATP synthesis and ATP ⇔ [32P]Pi exchange reaction catalyzed by submitochondrial particles in a dose-dependent manner (Ki= 31.7 μm and Ki = 32.7 μm), respectively. The hydrolytic activities of uncoupled heart submitochondrial particles and purified F 1 -ATPase were also inhibited 50% by 31.9 and 20.9 μm DIDS, respectively.

scholarly journals Antinociceptive and Anti-edematous Activities of the Essential Oils of Two Balkan EndemicLaserpitium Species

2014 ◽  
Vol 9 (1) ◽  
pp. 1934578X1400900 ◽  
Author(s):  
Višnja Popović ◽  
Silvana Petrović ◽  
Maja Tomić ◽  
Radica Stepanović-Petrović ◽  
Ana Micov ◽  
...  
Keyword(s):  
Essential Oil ◽  
Essential Oils ◽  
Antinociceptive Effect ◽  
Dependent Manner ◽  
Paw Edema ◽  
Oral Gavage ◽  
Inflammatory Conditions ◽  
Pressure Test ◽  
Male Wistar Rats ◽  
Dose Dependent

In this paper antinociceptive and anti-edematous effects are examined of the essential oils of the underground parts of two Balkan endemic Laserpitium species (Apiaceae), L. zernyi and L. ochridanum. Furthermore, the essential oil of the underground parts of L. ochridanum is chemically characterised by GC and GC-MS. Antinociceptive and anti-edematous effects were measured in a rat model of localized inflammation, induced by carrageenan, using apparatus for the modified paw-pressure test, and plethysmometer, respectively. The effects of both Laserpitium essential oils were measured after oral gavage administration to male Wistar rats in doses of 25, 50 and 100 mg/kg. The main constituents of L. ochridanum essential oil were: α-pinene (33.2%), α-bisabolol (10.3%) and chamazulene (14.9%). The essential oil of L. zernyi was previously shown to be rich in α-pinene (31.6%) and α-bisabolol (30.9%). Both examined essential oils produced a significant dose-dependent antinociceptive effect. The corresponding ED50±SEM in producing antinociception were 45.9±4.9 mg/kg and 42.4±2.1 mg/kg for L. zernyi and L. ochridanum oil, respectively. Both essential oils also significantly reduced paw edema in a dose-dependent manner. The estimated ED50±SEM values for the anti-edematous effect were 36.3±4.5 mg/kg for L. zernyi oil and 45.1±11.3 mg/kg for L. ochridanum oil. These results suggest that the essential oils of both investigated Laserpitium species may be effective against pain and edema present in various inflammatory conditions.

scholarly journals Nesfatin-1 Suppresses Cardiac L-type Ca2+ Channels Through Melanocortin Type 4 Receptor and the Novel Protein Kinase C Theta Isoform Pathway

2015 ◽  
Vol 36 (2) ◽  
pp. 555-568 ◽  
Author(s):  
Jiaoqian Ying ◽  
Yuan Zhang ◽  
Shan Gong ◽  
Zhigang Chang ◽  
Xiaofeng Zhou ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Ventricular Myocytes ◽  
Dependent Manner ◽  
The Novel ◽  
Inotropic Effects ◽  
Kinase C ◽  
Melanocortin 4 Receptor ◽  
Dose Dependent ◽  
Ca2 Channels

Background/Aims: Nesfatin-1 (NF-1), an anorexic nucleobindin-2 (NUCB2)-derived hypothalamic peptide, acts as a peripheral cardiac modulator and it can induce negative inotropic effects. However, the mechanisms underlying these effects in cardiomyocytes remain unclear. Methods: Using patch clamp, protein kinase assays, and western blot analysis, we studied the effect of NF-1 on L-type Ca2+ currents (ICa,L) and to explore the regulatory mechanisms of this effect in adult ventricular myocytes. Results: NF-1 reversibly decreased ICa,L in a dose-dependent manner. This effect was mediated by melanocortin 4 receptor (MC4-R) and was associated with a hyperpolarizing shift in the voltage-dependence of inactivation. Dialysis of cells with GDP-β-S or anti-Gβ antibody as well as pertussis toxin pretreatment abolished the inhibitory effects of NF-1 on ICa,L. Protein kinase C (PKC) antagonists abolished NF-1-induced responses, whereas inhibition of PKA activity or intracellular application of the fast Ca2+-chelator BAPTA elicited no such effects. Application of NF-1 increased membrane abundance of PKC theta isoform (PKCθ), and PKCθ inhibition abolished the decrease in ICa,L induced by NF-1. Conclusion: These data suggest that NF-1 suppresses L-type Ca2+ channels via the MC4-R that couples sequentially to the βγ subunits of Gi/o-protein and the novel PKCθ isoform in adult ventricular myocytes.

scholarly journals Effect of 6-Gingerol on Growth Factors and Apoptosis Indices in Rats Exposed to Gold Nanoparticles

2021 ◽  
Author(s):  
Ghasem Majdi Yazdi ◽  
◽  
Gholamhasan Vaezi ◽  
Vida Hojati ◽  
Mohammad Mohammadzadeh ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Oxidative Dna Damage ◽  
Antioxidant Properties ◽  
Dependent Manner ◽  
Elisa Method ◽  
Dna Oxidative Damage ◽  
Physiological Processes ◽  
Male Wistar Rats ◽  
Dose Dependent ◽  
Time Injection

Introduction: Research has shown that gold nanoparticles (AuNPs) can damage brain tissue physiological processes. Given the antioxidant properties of gingerol (GING), the aim of this study was to determine the protective effect of 6-gingerol on hippocampal levels of brain-derived neurotrophic factor, nerve growth factor, DNA oxidative damage, and the amount of Bax and Bcl-2 Apoptosis indices of rats exposed to AuNPs. Methods: Forty two male Wistar rats were divided into four groups: control (30 days 0.5 ml saline), AuNPs (one time injection of 0.5 ml AuNPs, 200 ppm and 60 Nm + 30 days 0.5 ml saline), AuNPs+GING 50 (one time injection of 0.5 ml AuNPs, 200 ppm and 60 Nm + 30 days 0.5 ml density of gingerol 50 mg / kg), AuNPs+GING100 (one time injection of 0.5 ml AuNPs, 200 ppm and 60 Nm + 30 days 0.5 ml density of gingerol 100 mg / kg). At the end of the treatment period, the hippocampal levels of NGF, BDNF, 8-HodG and Apoptotic indices of Bax and Bcl-2 were assessed through ELISA method. Results: Compared with the AuNPs group, hippocampal levels of BDNF, NGF, and Bcl-2 in rats from AuNPs+GING 50 and AuNPs+GING 100 groups significantly increased depending on the dose of injection. The hippocampal levels of Bax and HOdG-8 significantly decreased in a dose-dependent manner (P < 0.05). Conclusion: According to obtained results, it may be suggested that gingerol improves hippocampal BDNF and NGF levels in rats exposed to AuNPs maybe by reducing apoptosis and oxidative DNA damage.

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