Slower Restitution Research Articles

La tradizione religiosa degli Ainu e la rivitalizzazione di antichi rituali

The Ainu are a group of populations settled on the Kamchatka Peninsula, on the island of Sakhalin, in the Kurils and in Hokkaidō. I will examine the Ainu of the island of Hokkaidō. During the Tokugawa (1603-1868) and Meiji (1868-1912) periods, the Japanese imposed reforms and forced assimilation, depriving them of their cultural heritage. Initially labeled as "last", over time the Ainu have been invited to folklore along with a slow restitution of their cultural tradition, albeit with some compromise. In this way, tourist centers have most likely become the main gateways to a universe still pervaded by mystery. This article explores the changes in religious tradition, starting with the cosmogonic world, passing through ceremonies in their most traditional form, to examining how such ceremonials have been transformed for tourism purposes.

Electrical Restitution and Its Modifications by Antiarrhythmic Drugs in Undiseased Human Ventricular Muscle.

IntroductionRe-entry is a basic mechanism of ventricular fibrillation, which can be elicited by extrasystolic activity, but the timing of an extrasystole can be critical. The action potential duration (APD) of an extrasystole depends on the proximity of the preceding beat, and the relation between its timing and its APD is called electrical restitution. The aim of the present work was to study and compare the effect of several antiarrhythmic drugs on restitution in preparations from undiseased human ventricular muscle, and other mammalian species.MethodsAction potentials were recorded in preparations obtained from rat, guinea pig, rabbit, and dog hearts; and from undiseased human donor hearts using the conventional microelectrode technique. Preparations were stimulated with different basic cycle lengths (BCLs) ranging from 300 to 5,000 ms. To study restitution, single test pulses were applied at every 20th beat while the preparation was driven at 1,000 ms BCL.ResultsMarked differences were found between the animal and human preparations regarding restitution and steady-state frequency dependent curves. In human ventricular muscle, restitution kinetics were slower in preparations with large phase 1 repolarization with shorter APDs at 1000 ms BCL compared to preparations with small phase 1. Preparations having APD longer than 300 ms at 1000 ms BCL had slower restitution kinetics than those having APD shorter than 250 ms. The selective IKr inhibitors E-4031 and sotalol increased overall APD and slowed the restitution kinetics, while IKs inhibition did not influence APD and electrical restitution. Mexiletine and nisoldipine shortened APD, but only mexiletine slowed restitution kinetics.DiscussionFrequency dependent APD changes, including electrical restitution, were partly determined by the APD at the BCL. Small phase 1 associated with slower restitution suggests a role of Ito in restitution. APD prolonging drugs slowed restitution, while mexiletine, a known inhibitor of INa, shortened basic APD but also slowed restitution. These results indicate that although basic APD has an important role in restitution, other transmembrane currents, such as INa or Ito, can also affect restitution kinetics. This raises the possibility that ion channel modifier drugs slowing restitution kinetics may have antiarrhythmic properties by altering restitution.

Mechanisms Regulating the Organellar Ca 2+ Dynamics in Intact Hearts During Ischemia-Reperfusion

The accumulation of Ca2+ during ischemia, in both cytosol and sarcoplasmic reticulum (SR) of ventricular cardiomyocytes, contributes to the condition known as myocardial stunning. This not only disrupts normal Ca2+ dynamics in the contractile cells but also makes them more prone to apoptosis and/or necrosis. Therefore, the identification of the mechanisms underlying this phenomenon is important for understanding functional changes that occur during cardiac infarction. We examined the role of acidosis, inhibition of Na+/Ca2+ exchanger (NCX) and altered restitution of Ca2+ release as factors that can potentially be involved in the intracellular Ca2+ accumulation. Pulsed Local Field Fluorescence experiments on Langendorff-perfused mouse hearts reveal that a decrease in Tyrode solution's pH of from 7.4 to 6.2 diminished the amplitude of Ca2+ transients (52±3% of control) without elevation of diastolic Ca2+ level (measured with rhod-2 for cytosol and mag-fluo-4 for intra-SR). This suggests that acidosis alone cannot be responsible for accumulation of Ca2+ in myocytes. The combination of low pH (6.2) and partial (25%) replacement of Na+ with Li+ (to inhibit NCX) resulted in 1.4-fold increase in resting diastolic [Ca2+] in cytosol suggesting that the NCX activity might contribute to ischemia-induced changes in intracellular Ca2+ content. The restitution of Ca2+ release, measured with double-pulse protocols, slowed down during the ischemic period. Under these conditions, the decrease of Ca2+ release from SR might promote an accumulation of Ca2+ in this cellular compartment. Simultaneous measurements of intracellular action potentials (AP) and Ca2+ transients revealed that the restitution of AP is not the limiting step for Ca2+ release restitution during ischemia. Interestingly, the slow restitution persisted during reperfusion leading to an amplification of Ca2+ alternans. The study was supported by NIH R01-HL-084487 grant.

Na+ channel distribution and electrophysiological heterogeneities in guinea pig ventricular wall

We sought to explore the distribution pattern of Na(+) channels across ventricular wall, and to determine its functional correlates, in the guinea pig heart. Voltage-dependent Na(+) channel (Na(v)) protein expression levels were measured in transmural samples of ventricular tissue by Western blotting. Isolated, perfused heart preparations were used to record monophasic action potentials and volume-conducted ECG, and to measure effective refractory periods (ERPs) and pacing thresholds, in order to assess excitability, electrical restitution kinetics, and susceptibility to stimulation-evoked tachyarrhythmias at epicardial and endocardial stimulation sites. In both ventricular chambers, Na(v) protein expression was higher at endocardium than epicardium, with midmyocardial layers showing intermediate expression levels. Endocardial stimulation sites showed higher excitability, as evidenced by lower pacing thresholds during regular stimulation and downward displacement of the strength-interval curve reconstructed after extrasystolic stimulation compared with epicardium. ERP restitution assessed over a wide range of pacing rates showed greater maximal slope and faster kinetics at endocardial than epicardial stimulation sites. Flecainide, a Na(+) channel blocker, reduced the maximal ERP restitution slope, slowed restitution kinetics, and eliminated epicardial-to-endocardial difference in dynamics of electrical restitution. Greater excitability and steeper electrical restitution have been associated with greater arrhythmic susceptibility of endocardium than epicardium, as assessed by measuring ventricular fibrillation threshold, inducibility of tachyarrhythmias by rapid cardiac pacing, and the magnitude of stimulation-evoked repolarization alternans. In conclusion, higher Na(+) channel expression levels may contribute to greater excitability, steeper electrical restitution slopes and faster restitution kinetics, and greater susceptibility to stimulation-evoked tachyarrhythmias at endocardium than epicardium in the guinea pig heart.

Predictive value of electrical restitution in hypokalemia-induced ventricular arrhythmogenicity

The ventricular action potential (AP) shortens exponentially upon a progressive reduction of the preceding diastolic interval. Steep electrical restitution slopes have been shown to promote wavebreaks, thus contributing to electrical instability. The present study was designed to assess the predictive value of electrical restitution in hypokalemia-induced arrhythmogenicity. We recorded monophasic APs and measured effective refractory periods (ERP) at distinct ventricular epicardial and endocardial sites and monitored volume-conducted ECG at baseline and after hypokalemic perfusion (2.5 mM K(+) for 30 min) in isolated guinea pig heart preparations. The restitution of AP duration measured at 90% repolarization (APD(90)) was assessed after premature extrastimulus application at variable coupling stimulation intervals, and ERP restitution was assessed by measuring refractoriness over a wide range of pacing rates. Hypokalemia increased the amplitude of stimulation-evoked repolarization alternans and the inducibility of tachyarrhythmias and reduced ventricular fibrillation threshold. Nevertheless, these changes were associated with flattened rather than steepened APD(90) restitution slopes and slowed restitution kinetics. In contrast, ERP restitution slopes were significantly increased in hypokalemic hearts. Although epicardial APD(90) measured during steady-state pacing (S(1)-S(1) = 250 ms) was prolonged in hypokalemic hearts, the left ventricular ERP was shortened. Consistently, the epicardial ERP measured at the shortest diastolic interval achieved upon a progressive increase in pacing rate was reduced in the hypokalemic left ventricle. In conclusion, this study highlights the superiority of ERP restitution at predicting increased arrhythmogenicity in the hypokalemic myocardium. The lack of predictive value of APD(90) restitution is presumably related to different mode of changes in ventricular repolarization and refractoriness in a hypokalemic setting, whereby APD(90) prolongation may be associated with shortened ERP.

Characteristics of intracellular Ca2+ cycling in intact rat heart: a comparison of sex differences

Males and females show distinct differences in action potential waveform, ion channel expression patterns, and ECG characteristics. However, it is not known how sex-based differences in Ca2+ cycling might contribute to these differences in electrophysiological activity. The goal of this study was to investigate the differences in cellular Ca2+ transients in males and females and to examine how these might contribute to electrophysiological function. Ca2+ transients were measured in individual myocytes within microscopic regions of the fluo-4 AM-loaded left ventricular epicardium of intact rat heart of both sexes (3 to 5 mo old). Pacing protocols were used to measure transient characteristics at a basic cycle length of 500 ms and during 10-s trains of rapid pacing delivered to the left ventricular apex. Ca2+ transients were smaller in magnitude and longer in duration in females than in males. More importantly, the variability in Ca2+ transient characteristics between myocytes in a microscopic recording site (heterogeneity index) was greater for females than males for characteristics related to transient duration. The rate sensitivity of Ca2+ alternans development in individual myocytes was greater in females than in males, but there was also a greater heterogeneity in cellular responses to the rate dependence of alternans development in females. The longer Ca2+ transients in females were also associated with slower restitution, which was likely to be responsible for the development of Ca2+ and repolarization alternans at slower heart rates. These results demonstrate that there are distinct differences in cellular Ca2+ cycling in male and female rat hearts. Not only is there slower reuptake of Ca2+ in female rats, but there is greater local variability in Ca2+ cycling at the microscopic level. These sex-based differences in Ca2+ cycling could contribute to differences in ECG morphology and in arrhythmia sensitivity in males and females.

Oxidative stress changes in L-arginine-induced pancreatitis in rats.

The important role of oxygen radicals in acute experimental pancreatitis was demonstrated by study of the changes in the antioxidant system in the blood, liver, kidney, and pancreas of rats after the administration of a large quantity of L-arginine (L-Arg). The changes in lipid peroxidation and in reduced and oxidized glutathione were followed, as well as the activities of peroxide-decomposing enzymes (glutathione peroxidase and catalase) and H2O2-producing superoxide dismutases. The results demonstrated that "oxidative stress" develops and acute pancreatitis appears rapidly after L-Arg treatment. Oxidative stress symptoms are expressed 24 h after the final treatment. Slow restitution of the studied antioxidant system can be demonstrated as early as after 48 h.

Calcium Movements in Traumatic Brain Injury: The Role of Glutamate Receptor-Operated Ion Channels

Ion-selective microelectrodes were used to study acute effects of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy- 5-methyl-4-isoxazole (AMPA) receptor blockade on posttraumatic calcium disturbances. An autoradiographic technique with 45 Ca2+ was used to study calcium disturbances at 8, 24, and 72 h. Compression contusion trauma of the cerebral cortex was produced by a 21-g weight dropped from a height of 35 cm onto a piston that compressed the brain 2 mm. Pre- and posttrauma interstitial [Ca2+] ([Ca2+]e) concentrations were measured in the perimeter, i.e., the shear stress zone (SSZ) and in the central region (CR) of the trauma site. For the [Ca2+]e studies the animals were divided into controls and groups pretreated with dizocilipine maleate (MK-801) or with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[F]quinoxaline (NBQX). In all groups, [Ca2+]e decreased from pretrauma values of approximately 1 mM to posttraumatic values of 0.1 mM in both the CR and the SSZ. This was followed by a slow restitution toward pretraumatic levels during the 2-h observation period. There was no significant difference in recovery pattern between controls and pretreated animals. Accumulation of 45Ca2+ and serum proteins was seen in the entire SSZ, while neuronal necrosis was confined to a narrow band within the SSZ. The CR was unaffected apart from occasional eosinophilic neurons and showed no accumulation of 45Ca2+. Posttraumatic treatment with MK-801 or NBQX had no obvious effect on neuronal injury in the SSZ. We conclude that (a) acute [Ca2+]e disturbances in compression contusion brain trauma are not affected by blockade of NMDA or AMPA receptors, (b) 45Ca2+ accumulation in the SSZ reflects mainly protein accumulation due to blood-brain barrier breakdown rather than cell death, and (c) acute cellular Ca2+ over-load per se does not seem to be a major determinant of cell death after cerebral trauma in our model.

A contraction-related component of slow inward current in dog ventricular muscle and its relation to Na(+)-Ca2+ exchange.

1. The slow inward current component related to contraction (Isic) was studied in voltage clamp experiments on canine ventricular trabeculae at 30 degrees C with the aims of (a) estimating its relation to electrogenic Na(+)-Ca2+ exchange and (b) comparing it with similar currents as reported in cardiac myocytes. 2. Isic may be recorded under conditions of augmented contractility in response to depolarizing pulses below the threshold of the classic slow inward current (presumably mediated by L-type Ca2+ channels). In responses to identical depolarizing clamp pulses the peak value of Isic is directly related to the amplitude of contraction (Fmax). Isic peaks about 60 ms after the onset of depolarization and declines with a half-time of about 110 ms. 3. The voltage threshold of Isic activation is the same as the threshold of contraction. The positive inotropic clamp preconditions shift both thresholds to more negative values of membrane voltage, i.e. below the threshold of the classic slow inward current. 4. Isic may also be recorded as a slowly decaying inwardly directed current 'tail' after depolarizing pulses. In this representation the peak value of Isic changes with duration of the depolarizing pulses, again in parallel with Fmax. In response to pulses shorter than 100 ms both variables increase with depolarization time. If initial conditions remain constant, further prolongation of the pulse does not significantly influence either one (tail currents follow a common envelope). 5. Isic differs from classic slow inward current by: (a) its direct relation to contraction, (b) the slower decay of the current tail on repolarization, (c) slower restitution corresponding to the mechanical restitution, (d) its relative insensitivity to Ca(2+)-blocking agents (the decrease of Isic is secondary to the negative inotropic of Ca(2+)-blocking agents (the decrease of Isic is secondary to the negative inotropic effect) and (e) its disappearance after Sr2+ substitution for Ca2+. 6. The manifestations of Isic in multicellular preparations do not differ significantly from those reported in isolated myocytes (in contrast to calcium current). 7. The analysis of the correlation between Isic and Fmax transients during trains of identical test depolarizing pulses at variable extra- and intracellular ionic concentrations (changes of [Ca2+]o, 50% Li+ substitution for Na+, strophanthidin) indicate that the observed effects conform to the predictions based on a quantitative model of Na(+)-Ca2+ exchange. 8. It is concluded that Isic is activated by a transient increase of [Ca2+]i, in consequence of the release from the reticular stores.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of amiodarone on repolarization and refractoriness of cardiac fibers

The effects of superfusion (acute) and chronic amiodarone pretreatment on repolarization in dog Purkinje and guinea pig papillary muscle fibers were studied using standard microelectrode techniques. In dog Purkinje fibers superfusion with 5 and 50 μg/ml amiodarone shortened action potential duration, slowed restitution of premature action duration, and decreased the range of premature action potential durations. In Purkinje fibers from pretreated dogs action potential duration and range of premature action potential durations did not differ significantly from the corresponding control values but restitution was slowed. In guinea pig papillary muscle superfusion with 20 μg/ml amiodarone did not change action potential duration and restitution kinetics but in the muscle fibers from pretreated animals both the action potential duration and the range of premature action potential durations were increased. We concluded that the designation of ‘class III action’ applied to chronic amiodarone treatment in ventricular but not to chronic treatment in Purkinje fibers, and not to acute treatment in either fibers.

Post activity effects in mechanoreceptor afferents of the cockroach

1. Giant interneurons of the cockroachPeriplaneta americana show reduced responsiveness, for up to 800 ms, following activation by sound via their cereal inputs. The reduction in responsiveness is evident when tested either by a sound test stimulus, or by electrical stimulation of the cereal nerve. 2. Afferent axons of cereal filiform hair sensilla exhibit a reduced responsiveness during and immediately following activation by sound. 3. Use of oscillatory sound stimuli, rather than continuous deflections of the filiform hairs, circumvents the possibility that slow mechanical restitution of receptor elements after deflection is the cause of the post activity reduced responsiveness. 4. The magnitude of reduction in responsiveness of cereal afferents closely parallels their post activity afterpotential. 5. Amplitude and duration of the afterpotential were found to increase with stimulus intensity and to have the largest values at a stimulus frequency of 250 Hz and 300 ms duration. 6. The afterpotential curve was found to fit the equationV t= V(1-e −t/τ) τ=60 ms, at stimulus frequency of 100 Hz. 7. It is predicted that the reduced responsiveness of cereal afferents following activity will increase the threshold for escape immediately after a running bout.

Longitudinal studies of blood lymphocyte capacity in Hodgkin's disease.

Blood lymphocyte functional capacity and serum immunoglobulins were studied in 40 patients with Hodgkin's disease (HD) admitted to Radiumhemmet, Stockholm, before treatment and in complete remission 2-56 months following termination of radiotherapy (total nodal irradiation [TNI]; n = 29) or chemotherapy (MOPP; n = 11). Lymphocyte studies included determination of total lymphocyte and T-cell counts and evaluation of spontaneous DNA synthesis during the first day of culture and mitogen-(concanavalin A, pokeweed mitogen) and antigen (purified protein derivative, PPD)-induced activation on the third day. Blood lymphocyte and T-cell counts decreased dramatically following TNI. A slow restitution was seen, but pretreatment levels were not reached even four years following therapy. The responses to ConA and PPD but not PWM were significantly reduced shortly after TNI. The mitogen response did not increase with time as did the PPD response. Lymphocyte counts and lymphocyte stimulation, which were severely depressed before treatment of patients in the chemotherapy group, remained unchanged 2-36 months after termination of therapy. A significant reduction of IgM levels was observed regardless of the mode of treatment. Splenectomy prevented the profound reduction of blood lymphocyte and T-cell counts following therapy but did not influence the other immunologic variables under study.

On the Problem of Damage to the Organ of Corti in Manipulations on the Conductive Apparatus of the Ear

The authors studied the effect on microphone potentials of one-minute mechanical manipulation of the conductive apparatus without damage to the stapes and opening of the vestibulum in guinea pigs. A decrease in microphone potentials with a subsequent slow restitution to the initial values was observed. The results of the mechanical manipulation were compared with the effect of white noise, intensity 120 dB. After one-minute manipulation, the decrease in the amplitude of microphone potentials and their restitution simulate the course of changes in microphone potentials after 5-minute deafening with white noise.

Carbon monoxide dementia: A case report

A man, 32 years of age and of at least average native intelligence, consequent to a suicidal attempt suffered a carbon monoxide poisoning. After an initial phase characterized by unconsciousness and a neurological picture indicative of decerebrate rigidity and by the absence of gross pathology in the EEG, slow restitution set in which, 4 years after the accident, left the patient intellectually reduced to the level of imbecility. In addition, considerable losses in various functional areas resulted which led to the production of a global picture of an organic dementia. Some theoretical aspects have been discussed.