Halothane inhibits residual fast sodium channels in human atrial muscle.
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Halothane↗
Biomedical subjects
C I Lin
Publications and source records attributed to C I Lin.
Optical biosensor assay (OBA).
We describe a new biosensor immunoassay involving optical diffraction to detect clinically important analytes in human body fluids. A silicon wafer is used as a support for immobilization of antigen or antibody. The protein-coated surface is illuminated through a photo mask to create distinct periodic areas of active and inactive protein. When the surface is incubated with a positive sample, antigen-antibody binding occurs only on the active areas. Upon illumination with a light source such as a laser, the resulting biological diffraction grating diffracts the light. A negative sample does not result in diffraction because no antigen-antibody binding occurs to create the diffraction grating. The presence or absence of a diffraction signal differentiates between positive and negative samples, and the intensity of the signal provides a quantitative measure of the analyte concentration. The technique is demonstrated with a quantitative assay of choriogonadotropin in serum.
Biosensing Techniques↗
Extragenic suppressors of mar2(sir3) mutations in Saccharomyces cerevisiae.
The silent mating-type genes (HML and HMR) of Saccharomyces cerevisiae are kept under negative transcriptional control by four trans-acting MAR (or SIR) loci. We have isolated extragenic suppressors of the mar2-1 mutation which, based on genetic complementation tests, define two additional loci involved in regulating the expression of HML and HMR. A strain with the genotype HMLa MAT alpha HMRa mar2-1 is sterile due to the simultaneous expression of a and alpha information. Two mutants exhibiting an alpha phenotype (which may result from the restoration of MAR/SIR repression) were isolated and genetically characterized. The mutations in these strains: (1) are recessive, (2) are capable of suppressing a mar2-deletion mutation, (3) are unlinked to MAT, (4) complement one another as well as the previously identified sum1-1 mutation, and (5) are not new alleles of the known MAR/SIR loci. We designate these new regulatory loci SUM2 and SUM3 (suppressor of mar). Unlike the sum1-1 mutation, suppression by sum2-1 and sum3-1 is mar2-locus specific. Both sum2-1 and sum3-1 affect the expression of a information at the HM loci. Transcript analysis shows a significant reduction in HMLa and HMRa gene transcription in mar2-1 sum2-1 and mar2-1 sum3-1 cells. Furthermore, we have found genetic evidence to suggest that mar2-1 sum2-1 cells exhibit only partial expression of silent alpha information. We conclude that the SUM2 and SUM3 gene products are required for expression of the HM loci and act downstream of the MAR2 (SIR3) gene function. Possible mechanisms for the action of the SUM gene products are discussed.
Alleles↗
Effects of strophanthidin on the force-frequency relationship in dog ventricular working and conducting tissues.
Effects of strophanthidin on force-frequency relationship were studied in dog working ventricular myocardium (VM) and Purkinje fibers (PF). In VM, both strophanthidin (0.3-1 x 10(-6) M) and driving rate increase within physiological range of 1 to 2 Hz potentiated the force of contraction. In PF, the following different responses were observed. 1. The contractile force decreased as the driving rate increased within the same range (negative staircase). 2. The positive inotropic effect of strophanthidin first increased and then declined. During the rising phase of strophanthidin inotropy, the staircase was still negative. The staircase became positive as strophanthidin inotropy declined. 3. Strophanthidin also potentiated the contractile force of extrasystolic and post-extrasystolic beats as revealed by the Johnson's two-state experiments. 4. The inotropic effects of strophanthidin were mimicked by high [Ca2+] (8.1-12.1 mM) and reversed by Ca channel blockers. Effects of Ca2+ overloading are discussed and a quantitative difference in regulation of cytosolic Ca2+ between VM and PF is suggested.
Amiodarone↗
Pacemaker activity is modulated by tissue levels of cyclic adenosine 3',5'-monophosphate in human atrial fibers.
We studied the role of tissue cyclic AMP levels in the chronotropic effects of theophylline on automatic human atrial fibers obtained from the hearts of 17 patients undergoing corrective open-heart surgery. Atrial fibers were perfused with Tyrode solution and transmembrane action potentials were recorded with a conventional microelectrode technique. In normal Tyrode solution, theophylline (0.1-1 mM) often decreased the late diastolic slope and the spontaneous rate. In the presence of 0.3-1 microM epinephrine, however, theophylline dose-dependently increased the diastolic slope, the rate of spontaneous discharges and the force of contraction. The increase in tissue level of cyclic AMP (+288 +/- 69%) induced by 0.3 mM theophylline in the presence of epinephrine was much greater than the increase (+73 +/- 19%) in the absence of epinephrine. It is concluded that pacemaker activity in human atrial fibers is modulated by tissue levels of cyclic AMP and theophylline may induce atrial tachycardia through an increase in the diastolic slope and the rate of discharges of automatic atrial fibers.
Action Potentials↗
Role of acetylcholine in induction of repetitive activity in human atrial fibers.
The actions of acetylcholine and its interactions with epinephrine were studied in human atrial tissues by recording transmembrane potentials and contractile force. Acetylcholine (0.55-5.5 microM) reduced force, shortened the duration and shifted to more negative values the plateau of action potentials, abolished phase 4 depolarization, and suppressed the activity of spontaneous fibers. During the recovery, often there was a rebound increase in some parameters of the action potential and in force. Epinephrine (0.3-2.8 microM) induced oscillatory potentials and aftercontractions and acetylcholine abolished them. However, during the washout of acetylcholine in the presence of epinephrine, the oscillatory potentials and aftercontractions were larger than before acetylcholine, and repetitive activity was often induced. The inhibitory and excitatory effects of acetylcholine were mimicked by methacholine (5.1 microM) and abolished by atropine (1.5 microM). The postacetylcholine rebound was also potentiated by theophylline (0.6-2 mM) but was not blocked by propranolol (1-3.4 microM), prazosin (1 microM), and diltiazem (0.1 microM). It is concluded that in human atrial fibers acetylcholine has inhibitory as well as excitatory effects that are exaggerated in the presence of epinephrine and are mediated by the activation of the muscarinic receptor. The interaction between acetylcholine and epinephrine involves an antagonism at an intracellular level.
Acetylcholine↗
Electromechanical effects of protamine in isolated human atrial and canine ventricular tissues.
Effects of protamine sulfate (1-100 mg%) on the electrical and mechanical activities of isolated dog ventricular tissues and human atrial fibers were studied. In dog Purkinje fibers, 10 mg% protamine reduced markedly the maximum diastolic potential and the rate of phase 0 depolarization. Eventually, slow response action potential developed at a depolarized level and the twitch force declined abruptly. The depolarization and the negative inotropy were reversed by increasing [Ca])o or [K]o but not by tetrodotoxin. When Purkinje fibers were depolarized in 27 mM [K]o Tyrode solution plus 0.5 microM epinephrine, higher concentrations of protamine (30 mg% or above) were required to depress the slow response action potentials and twitch, in contrast to the action of verapamil and diltiazem (1-30 microM). Dog ventricular and human atrial muscle fibers were more resistant to the depressant effects of protamine. In human atrial fibers, however, 10 mg% protamine was able to depress significantly the oscillatory afterpotentials and aftercontractions induced by epinephrine and theophylline. The present findings suggest that the depolarization and decline in force of cardiac tissues induced by protamine, at a concentration about twice of the maximum clinically relevant dose, may be explained by the development of slow response action potentials as a result of decrease in membrane K+ and Na+ conductances.
Action Potentials↗
The electrophysiological and mechanical effects of atrial natriuretic peptide and acetylcholine on guinea pig ventricular papillary muscle.
The direct effects of atrial natriuretic factor (ANF) and acetylcholine (ACh) on isolated guinea pig ventricular papillary muscle were studied. ANF (3 x 10(-9) - 3 x 10(-7) M), a cardiogenic hormone, had no significant electrical or mechanical effects on guinea pig papillary muscle driven at a frequency of 60 beats/min in normal (4 mM) and high [K]0 (27 mM) Tyrode solutions. On the other hand, ACh (3 x 10(-8) - 3 x 10(-7) M) caused a significant shortening of action potential duration and the contractile force showed no change or a slight decrease. At high concentration (5 microM), ACh reduced action potential durations at 50% and 90% repolarization (APD50 and APD90) by 10.5 +/- 2.1% and 12.4 +/- 1.8%, respectively, but the contractile force was slightly increased by 9.8 +/- 1.2%. In eleven of twenty-six preparations, spontaneous activity occurred and intermingled with driven activity. The ectopic rhythms were suppressed by ACh (1-5 microM). The changes in electrical but not mechanic activity induced by ACh were suppressed in the presence of five micromolar atropine. These results reveal that, in guinea pig papillary muscle, ANF had no direct chronotropic or inotropic effect. ACh may reduce APD and spontaneous discharges through an activation of muscarinic receptors but enhance twitch tension through other mechanisms.
Acetylcholine↗
Depressant effects of isoflurane and halothane on isolated human atrial fibers.
The present experiments were designed to study the cellular mechanism responsible for the depressant effects of halothane and isoflurane on human atrial tissues obtained at cardiac surgery. The fibers were superfused in Tyrode's solution, and transmembrane potentials were recorded with a microelectrode technique. In atrial fibers showing fast response action potential (maximum velocity of depolarization [Vmax] greater than 100 V/s), halothane (0.75 vol%, 0.44 mM) and isoflurane (1.25 vol%, 0.53 mM) decreased slightly the upstroke velocity but depressed the plateau and twitch force significantly. In atrial fibers showing slow rate of phase-0 depolarization or when atrial fibers were depolarized in high [K]0, both halothane and isoflurane decreased the upstroke of slow response and the force. The depressant effects of anesthetics partially mimicked the actions of 1 microM tetrodotoxin and diltiazem and could be reversed by epinephrine or high [Ca]0. The delayed afterdepolarizations or aftercontractions and contracture induced by epinephrine or strophanthidin were also inhibited by both anesthetics. Halothane and isoflurane may depress normal electromechanical activity and arrhythmogenic triggered activity through a reduction of cation fluxes across the cell membrane.
Action Potentials↗
Suppressive effects of somatostatin in dog Purkinje fibres.
1. The effects of somatostatin (SS, 1 nM-3 microM) on the electrical and mechanical activities of isolated Purkinje fibres of the dog were studied. 2. In most Purkinje fibres driven electrically in normal [K]o Tyrode solution, SS decreased the force of contraction slightly and had very little effect on the fast response action potential. However, in sensitive fibres SS induced a moderate reduction of action potential duration and contractile force in normal [K]o and depressed the slow response action potentials in high [K]o. 3. In spontaneously beating Purkinje fibres, SS decreased the regular rhythms slightly but abolished bursts of fast rhythms at a concentration as low as 1 nM. 4. When the fibres were depolarized in the presence of 0.2 mM barium or in Na-free solution, SS suppressed the Ca-dependent slow response action potentials. 5. These findings suggest that SS may suppress abnormal automatic activity of dog Purkinje fibres through a reduction of transmembrane Ca influx or a modulation of intracellular calcium.
Action Potentials↗
Differential inotropic effects of halothane and isoflurane in dog ventricular tissues.
The differential effects of halothane (0.25-0.75%) and isoflurane (0.5-1.25%) on the electromechanical activity of canine ventricular tissues were compared in vitro. In Purkinje fibres, halothane but not isoflurane could induce an initial increase of contractile force which was not blocked by diltiazem or propranolol. In ventricular muscles, halothane decreased the resting state contraction more markedly than isoflurane. The results suggest that halothane induces a greater negative inotropy than isoflurane through a differential alteration of intracellular Ca2+ stores.
Action Potentials↗
Arrhythmogenic effects of theophylline in human atrial tissue.
We studied the effects of theophylline on the transmembrane action potential and the contractile force of human atrial fibers obtained from the hearts of 15 patients, undergoing corrective open-heart surgery. Atrial fibers were perfused with Tyrode solution and driven electrically at a constant rate of 60 beats per min. Theophylline (0.1-1 mM) steepened the diastolic depolarization, increased the amplitude of oscillatory potential during diastole and facilitated the development of spontaneous slow response action potentials. These arrhythmogenic effects of theophylline were suppressed after diltiazem (0.1-0.3 microM) pretreatment. The present findings provide the electrophysiologic evidence that abnormal atrial automaticity as a result of triggered activity may be the underlying cause for atrial ectopic activity and multifocal atrial tachycardia in patients taking theophylline.
Adult↗
Somatostatin effects in isolated human atrial fibres.
Effects of hypothalamic hormone somatostatin on the action potential and contractile force of 54 human atrial preparations obtained at cardiac surgery were studied with standard microelectrode techniques. In the atrial fibres responding to electrical stimuli with fast response action potentials in 4 mM [K]0 Tyrode solution (maximum rate of phase 0 depolarization greater than 50 V/s), somatostatin (10(-7) to 10(-6) M) reduced slightly the duration of action potential and decreased twitch force dose-dependently. In spontaneously active atrial fibres, somatostatin (10(-7) to 10(-6) M) abolished the action potentials in the preparations with low maximal diastolic potential (MDP, -48 +/- 2.8 mV), but induced only mild suppressive effect in the preparations with high MDP (-70 +/- 2.4 mV). When the fibres were depolarized in 27 mM [K]0 Tyrode solution, somatostatin decreased the maximum rate of depolarization and amplitude of the slow response action potentials induced by electrical stimuli. The delayed afterdepolarizations or triggered action potentials induced by high-frequency electrical drive in the presence of epinephrine were also suppressed by somatostatin. The above findings suggest that somatostatin may suppress the abnormal automaticity and the triggered activity in human atrial fibres through a reduction of cellular calcium.
Action Potentials↗
Electrophysiological effects of low pH in human atrial fibres.
In the studies of the electrophysiological properties of human atrial fibres obtained at cardiac surgery, it has often been reported that the diastolic potential, the maximum upstroke velocity of the phase 0 depolarization (Vmax) and the amplitude of action potential are relatively low. The same findings were also obtained in our previous study when the tissue preparations were perfused with a Tyrode solution which, as usually described in literatures on cardiac cell studies had a NaHCO3 concentration of 12 mM and was aerated with a gas mixture of 95% O2-5% CO2 at 37 degrees C. Recently we found that the relatively poor electrical activities of the human atrial fibres were related to the low pH value (around 7.06) of the perfusate used. Raising the pH value of the perfusate either by increasing the NaHCO3 concentration or by reducing the CO2 in the bubbling gas mixture significantly improved the electrical activities of the fibres. There is evidence that the suppressive effect of low pH on the electrical activities is due to the hindering action of H+ on the transportation of other cations across the plasma membrane.
Cardiac Surgical Procedures↗
Electromechanical effects of caffeine in isolated human atrial fibres.
Effects of caffeine on the action potential and contractile force of human atrial fibres obtained at cardiac surgery were studied with standard microelectrode technique. In 4 mmol . litre-1 [K]o, the only significant action produced by 0.3 to 3 mmol . litre-1 caffeine on the electro-mechanical activity of relatively normal atrial fibres was a slight shortening of the action potential duration at 50% repolarisation. When the fibres were depolarised in 27 mmol . litre-1 [K]o or in atrial fibres showing slow responses in 4 mmol . litre-1 [K]o, however, caffeine could increase the upstroke of slow response and the force. In 18% of atrial fibres showing slow responses in 4 mmol . litre-1 [K]o, caffeine induced spontaneous discharges and potentiated afterdepolarisations. The positive inotropic and the arrhythmogenic effects of caffeine could be diminished by pretreating the fibres with propranolol or Ca antagonists (diltiazem and verapamil). In fibres beating spontaneously in normal [K]o, caffeine accelerated spontaneous rhythms initially and then depressed them. Propranolol potentiated the later depression but did not block the initial acceleration. The results suggest that caffeine increases the transmembrane Ca influx and enhances the release of Ca from the intracellular stores in human atrial fibres. As a consequence, caffeine could induce arrhythmias in atria from certain individuals.
Action Potentials↗
Positive inotropic effect of acetylcholine in isolated human atrial fibers.
We studied the effects of acetylcholine on the transmembrane action potential and the contractile force of isolated human atrial fibers obtained at cardiac surgery. In 3 of 12 preparations, 10(-7)-10(-6) M acetylcholine induced a substantial increase in the contractile force following a brief initial decrease. Atropine diminished both the initial negative and the later positive inotropic effects induced by acetylcholine while propranolol abolished only the later effect.
Acetylcholine↗
The presence of the iron-sulfur protein (subunit V) of complex III in mitochondria of heme-deficient yeast cells lacking iron-sulfur clusters detectable by electron paramagnetic resonance.
The presence of subunit V, the iron-sulfur protein, of complex III has been demonstrated in mitochondria from a mutant of Saccharomyces cerevisiae which lacks 5-aminolevulinic acid synthase and, hence, is devoid of heme. The mature form (24 K Da) of the iron-sulfur protein was observed in equal amounts in the heme-deficient and heme-sufficient cells with antiserum against subunit V and either the sensitive immuno-transfer technique or immunoprecipitation from dodecylsulfate-solubilized mitochondria. In addition, a slight shoulder with a molecular mass 1.5 kDa larger than the mature form was present in mitochondria from the heme-deficient cells. Electron paramagnetic resonance spectroscopy revealed the absence of iron-sulfur signals due to clusters S-1, S-2 and S-3 of succinate dehydrogenase or to Rieske's iron-sulfur cluster of complex III in mitochondria from the heme-deficient cells. The lack of iron-sulfur centers in these cells may be a consequence of the absence of sulfite reductase in the cells without heme.
Electron Spin Resonance Spectroscopy↗
Attenuation of alcohol drinking in tetrahydroisoquinoline-treated rats by morphine and naltrexone.
In rats of either the Sprague-Dawley or Long-Evans strain, either tetrahydroisoquinoline (THP) was infused chronically ICV, or one of three protoberberine (PBN) compounds was administered subcutaneously at birth. When the animals were 120-180 days of age, a constant concentration of alcohol was offered simultaneously with water to those rats which demonstrated a clear-cut preference for alcohol. This concentration was selected on the basis of an alcohol preference screen. After alcohol intakes had stabilized, naltrexone was injected subcutaneously in a dose of either 1.0 or 5.0 mg/kg twice a day for three consecutive days. The higher dose (10.0 mg/kg total) of naltrexone suppressed the voluntary intake of alcohol by 26%, whereas the lower dose (2.0 mg/kg total) attenuated alcohol drinking by 14%. Both doses of naltrexone reduced food intake but did not appreciably affect water intake or body weight. When morphine was injected according to the same regimen in a dose of 10.0 or 2.5 mg/kg twice per day, a 49% reduction in alcohol intake was produced by the higher dose and a 32% decline followed the lower dose. Although morphine attenuated food intake, neither water intake nor body weight was affected. Saline control injections administered twice daily in the same way failed to alter any of the intake measures or body weight. These findings indicate that the long-lasting opiate antagonist naltrexone attenuates the voluntary consumption of alcohol in a manner similar to that produced by naloxone. The present results are discussed in terms of the evidence that an opiate agonist and antagonist may exert their actions by different mechanisms in the brain, possibly through separate subpopulations of opiate receptors.
Alcohol Drinking↗