Biomedical subjects
Publications and source records attributed to P Schweitzer.
Pooled data from 32 studies were reviewed to assess the timing of thrombolic complications after cardioversion of atrial fibrillation or flutter. We found that 98% of embolic episodes occurred within 10 days of cardioversion.
Time domain analysis of heart period variability in patients without structural heart disease demonstrated increased parasympathetic modulation before paroxysmal atrial fibrillation (AF) occurring predominantly at night. However, diurnal differences in autonomic activity preceding AF episodes in a diverse patient population have not been assessed. Accordingly, we performed spectral analysis of heart period variability on Holter recordings during sinus rhythm preceding AF in 29 patients, 17 with night and 12 with day episodes. Samples taken 5, 10, and 20 minutes before AF onset were compared. Normalized high-frequency (HF) spectral power change was greater when comparing the interval 10 to 5 minutes with 20 to 10 minutes preceding AF in 26 of 29 patients (0.09 +/- 0.07 vs 0.03 +/- 0.02; p < 0.0001). HF spectral power increased before 3 of 12 AF episodes during the day compared with 15 of 17 AF episodes during the night (p = 0.001). Nocturnal AF episodes were preceded by increased HF spectral power in the 5- versus the 20-minute sample expressed as natural logarithm-transformed values (5.6 +/- 4.8 vs 4.2 +/- 4.0; p < 0.005) and normalized values (0.19 +/- 0.09 vs 0.10 +/- 0.07; p < 0.02), a decrease in low-frequency/HF ratio (1.05 +/- 0.61 vs 2.21 +/- 1.75; p < 0.05) and heart rate (60 +/- 13 vs 71 +/- 13 beats/min; p = 0.06). Structural heart disease was more common with daytime than nocturnal AF episodes (58% vs 18%, p < 0.05). In conclusion, HF spectral power change was increased preceding most AF episodes. However, diurnal differences were demonstrated. Contrary to daytime AF, increased parasympathetic activity preceded predominantly nocturnal AF, mostly in younger patients with structurally normal hearts.
We report on an 84-year-old patient with an ICD who received a shock after a spontaneously terminated nonsustained ventricular tachyarrhythmia. We discuss the possible mechanisms of cardioversion after conversion of ventricular tachycardia and interventions that may prevent this type of inappropriate shock.
Somatostatin (SST) is a neuropeptide involved in several central processes. In hippocampus, SST hyperpolarizes CA1 pyramidal neurons and augments the K+ M current (IM). However, the limited involvement of IM at resting potential in these cells suggests that the peptide also may modulate another channel to hyperpolarize hippocampal pyramidal neurons (HPNs). We studied the effect of SST on noninactivating conductances of rat CA1 HPNs in a slice preparation. Using MK886, a specific inhibitor of the enzymatic pathway that leads to the augmentation of IM by SST, we have uncovered and characterized a second conductance activated by the peptide. SST did not affect IM when applied with MK886 or the amplitudes of the slow Ca2+-dependent K+ afterhyperpolarization-current and the cationic Q current but still caused an outward current, indicating that SST acts upon another conductance. In the presence of MK886, SST elicited an outward current that reversed around -100 mV and that displayed a linear current-voltage relationship. Reversal potentials obtained in different external K+ concentrations are consistent with a conductance carried solely by K+ ions. The slope of the current-voltage relationship increased proportionately with the extracellular K+ concentration and remained linear. This suggests that SST opens a voltage-insensitive leak current (IK(L)) in HPNs not an inwardly rectifying K+ current as reported in other neuron types. A low concentration of extracellular Ba2+ (150 M) only slightly decreased the SST-induced effect in a voltage-independent manner, whereas a high concentration of Ba2+ (2 mM) completely blocked it. Extracellular Cs+ (2 mM) did not affect the outward SST current but inhibited the inward component. We conclude that SST inhibits HPNs by activating two different K+ conductances: the voltage-insensitive IK(L) and the voltage-dependent IM. The hyperpolarizing effect of SST at resting membrane potential appears to be mainly carried by IK(L), whereas IM dominates at slightly depolarized potentials.
Cannabinoid receptors are molecular targets for marijuana and hashish, the widespread drugs of abuse. These receptors are expressed in areas of the central nervous system that contribute in important ways to the control of memory, cognition, movement and pain perception. Indeed, such functions can be strongly influenced by cannabinoid drugs, with consequences that include euphoria, analgesia, sedation and memory impairment. Although the pharmacology of cannabinoid drugs is now beginning to be understood, we still lack essential information on the endogenous signalling system(s) by which cannabinoid receptors are normally engaged. An endogenous ligand for cannabinoid receptors, anandamide, has been described. Here we report that sn-2 arachidonylglycerol (2-AG), a cannabinoid ligand isolated from intestinal tissue, is present in brain in amounts 170 times greater than anandamide. 2-AG is produced in hippocampal slices by stimulation of the Schaffer collaterals, an excitatory fibre tract that projects from CA3 to CA1 neurons. Formation of 2-AG is calcium dependent and is mediated by the enzymes phospholipase C and diacylglycerol lipase. 2-AG activates neuronal cannabinoid receptors as a full agonist, and prevents the induction of long-term potentiation at CA3-CA1 synapses. Our results indicate that 2-AG is a second endogenous cannabinoid ligand in the central nervous system.
Acetylcholine (ACh) plays a key role in the transitions between the different phases of sleep: Slow-wave sleep requires low ACh concentrations in the brain, whereas rapid-eye-movement (REM) sleep is associated with high levels of ACh. Also, these phases of sleep are differentially sensitive to a number of endogenous neuropeptides and cytokines, including somatostatin, which has been shown to increase REM sleep without significantly affecting other phases. Here we report the cloning and initial characterization of cortistatin, a neuropeptide that exhibits strong structural similarity to somatostatin, although it is the product of a different gene. Administration of cortistatin depresses neuronal electrical activity but, unlike somatostatin, induces low-frequency waves in the cerebral cortex and antagonizes the effects of acetylcholine on hippocampal and cortical measures of excitability. This suggests a mechanism for cortical synchronization related to sleep.
Obstructive sleep apnea has been associated with various cardiac arrhythmias; however, supraventricular tachycardia has not been reported to occur in this disorder. This case report describes a patient who developed episodes of supraventricular tachycardia during periods of apnea and oxygen desaturation. With the initiation of nasal continuous positive airway pressure during sleep, the arrhythmia was abolished. The etiology and possible mechanisms responsible for the supraventricular tachycardia are discussed.
5-Lipoxygenase-activating protein (FLAP) is an 18-kDa integral membrane protein required, in peripheral cells, for the activation of 5-lipoxygenase (5-LO) and for the resulting synthesis of leukotrienes from arachidonic acid. In the brain, the leukotrienes have been implicated in several pathophysiological events and in the electrophysiological effect of somatostatin, yet the cellular origin and role of these messenger molecules are still poorly understood. In the present study, we used reverse transcriptase-polymerase chain reaction, in situ hybridization, and immunohistochemistry to demonstrate that 5-LO and FLAP are expressed in various regions of the rat brain, including hippocampus, cerebellum, primary olfactory cortex, superficial neocortex, thalamus, hypothalamus, and brainstem. Highest levels of expression were observed in cerebellum and hippocampus. In the latter we demonstrate the colocalization of 5-LO and FLAP in CA1 pyramidal neurons. Moreover, electrophysiological experiments show that selective inhibition of FLAP with the compound MK-886 (0.25-1 microM) prevents the somatostatin-induced augmentation of the hippocampal K+ M-current. Our results provide necessary evidence for the presence and signaling role of 5-LO and FLAP in central neurons and strongly support their proposed participation in somatostatin-receptor transmembrane signaling.
The taurinate analog acamprosate (calcium acetylhomotaurinate) has received considerable attention in Europe for its ability to prevent relapse in abstained alcoholics. To determine the mechanism of acamprosate actions in the CNS, we superfused acamprosate onto rat hippocampal CA1 pyramidal neurons using an in vitro slice preparation. In current-and voltage-clamp recordings, acamprosate (100 to 100 microM) superfusion had little effect on resting membrane potential or input slope resistance. Acamprosate had no effect on Ca(2+)-dependent action potentials when tetrodotoxin was used to block Na+ spikes. In whole-cell voltage-clamp recordings, and in the presence of tetraethylammonium and Cs+ to block K+ channels, acamprosate had little effect on a Cd(2+)-sensitive inward current likely to be a high voltage-activated Ca2+ current. However, in both current- and voltage-clamp recordings, acamprosate significantly increased the N-methyl-D-aspartate (NMDA) component of excitatory postsynaptic potentials evoked by stimulation of Schaffer collaterals in the stratum radiatum, in the presence of the selective non-NMDA (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid kainate) glutamate receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione and the GABAA receptor antagonist bicuculline. Acamprosate had inconsistent or no effects on the stratum radiatum-evoked non-NMDA component of the excitatory postsynaptic potentials, in the presence of bicuculline and the NMDA antagonist DL-2-amino-5-phosphonovalerate. Acamprosate, on average, had little effect on the late inhibitory postsynaptic potentials thought to be mediated by GABAB receptors. In the presence of tetrodotoxin to block synaptic transmission, acamprosate dramatically increased inward current responses in most CA1 neurons to exogenous NMDA applied by pressure or superfusion, with reversal on washout of acamprosate. These data suggest that acamprosate may act postsynaptically to increase the NMDA component of excitatory transmission to hippocampal CA1 pyramidal neurons. Considering the known interaction of ethanol with NMDA receptors, this acamprosate modulation of NMDA receptor-mediated neurotransmission could provide a mechanism of action underlying the clinical efficacy of acamprosate.
Previous studies from our laboratory showed that ethanol enhances muscarinic excitatory responses in rat hippocampal neurons in vivo and, like muscarinic agonists, reduces the M-current (IM) in these neurons in vitro. Therefore, we used extracellular and intracellular recording techniques in the hippocampal slice preparation to examine the mechanisms underlying this ethanol-muscarinic interaction. Surprisingly, superfusion or local application of low concentrations of acetylcholine (ACh), carbachol (CCh) or muscarine reduced the amplitudes of CA1 field potentials evoked by stratum radiatum (SR) stimulation. This effect was blocked by 1 microM atropine but was independent of the method of agonist application, the site of application or the SR stimulus paradigm. In intracellular and extracellular single unit recordings, cholinergic depressions of field potentials were correlated with: (1) depolarization of pyramidal neurons; (2) spike discharge increases; (3) reduction of amplitudes of postsynaptic potentials and (4) reduction of late afterhyperpolarizations (AHPs). Superfusion of low ethanol concentrations (11-22 mM) alone had little effect on SR-evoked field potentials but enhanced (by 10-90%) both the depressions of evoked field potentials and depolarizations elicited by the muscarinic agonists. Ethanol (22-44 mM) also enhanced both the amplitude and duration of the muscarinic slow excitatory postsynaptic potentials (sEPSPs) recorded intracellularly in CA1 and CA3 neurons. This effect was enhanced by eserine and blocked by atropine, verifying involvement of muscarinic receptors. These results suggest that: (1) caution be used in interpreting results of field potential studies regarding drug-induced excitability changes; and (2) ethanol in just-intoxicating concentrations enhances endogenous muscarinic synaptic transmission as well as responses to exogenous muscarinic agonists.
Radiation therapy is currently standard treatment for a number of malignancies, including Hodgkin's disease. With the advent of techniques (e.g., subcarnial blocks) that limit the dose of radiation to which the heart is exposed, the incidence of radiation-induced heart disease can be minimized. However, a small percentage of patients will eventually suffer iatrogenic effects. Most commonly seen is pericardial disease, but valvular, conduction system, and coronary artery disease are also seen. Further, because these patients are now surviving longer after therapy, those effects with a longer latent period may be seen with increasing frequency.
A case of complete atrioventricular block with ventricular asystole in a patient receiving intravenous phenytoin is presented. Although the potential for hypotension is generally recognized with the intravenous administration of phenytoin, conduction abnormalities are rarely reported. The differential diagnosis of atrioventricular block and the effects of phenytoin on cardiac conduction are discussed.
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Wide complex tachycardias may represent a rare proarrhythmic effect of some antiarrhythmic agents. The authors describe a patient who developed a wide complex tachycardia developing during stress testing while on therapy with flecainide, and the difficulty in interpreting the electrocardiogram. This article reviews potential proarrhythmic effects of flecainide in the treatment of atrial dysrhythmias and the difficulty in differentiating associated wide complex tachycardias.
Neonatal and adult respiratory-related functions of brain stem were compared using in vivo or in vitro approaches. The control of inspiratory off-switch by glutamate-like neurotransmitters was found active at birth. However, neurons from the nucleus tractus solitarius (NTS) are immature at birth because they present growth cones and the transient potassium current appears progressively during the first week of life in association with modification of the dendritic tree. These data support the hypothesis that the mechanisms of respiratory rhythmogenesis are different at birth and in the adult.
Opioid peptides, and especially the dynorphins, have been localized to several circuits in the CA3 hippocampal region, yet electrophysiological studies often find mixed effects of opiates on the excitability of CA3 neurons. Reasoning that these mixed effects might involve voltage-dependent actions, we tested the effect of several opiates on CA3 pyramidal neurons using single-electrode voltage-clamp recording in a slice preparation of rat hippocampus. In most CA3 neurons, the voltage-dependent K+ current known as the M-current (IM) was uniquely sensitive to the opioid peptides, with the direction of response dependent upon the opiate type and concentration. Thus, an opiate selective for kappa receptors, U-50,488H, significantly augmented IM. The kappa-selective agonists dynorphin A and dynorphin B, which exist in mossy fiber afferents to CA3 pyramidal neurons, also markedly augmented IM at low concentrations (20-100 nM). By contrast, dynorphin A at higher concentrations (1-1.5 microM) often reduced IM. Similarly, several opiates [e.g., D-Ala2,D-Leu5-enkephalin: (DADL), [D-Pen2,5]-enkephalin (DPDPE)] known to act on the delta receptor subtypes reduced the M-current, with partial reversal of this effect by naloxone. Neither the selective mu-receptor agonist [D-Ala2, NMe-Phe4, Gly-ol]-enkephalin (DAMGO) nor the nonopioid fragment of dynorphin, des-Tyr-dynorphin, consistently altered IM. These opiate effects on IM were accompanied by changes in conductance and holding current consistent with their respective effects on IM. Dynorphin A did not measurably affect the Q-current, a conductance known to contribute to inward rectification in hippocampal pyramidal neurons. The opiate effects on IM were not altered by pretreatment with Cs+ (which blocks IQ) or Ca2+ channel blockers. The opposing effects of the dynorphins (both A and B) and DADL on IM were antagonized by naloxone (1-3 microM), and the dynorphin-induced augmentations of IM were usually reversed by the kappa receptor antagonist norbinaltorphimine. These results suggest that the opiates can have opposing effects on the same voltage-dependent K+ channel type (the M channel) in the rat CA3 pyramidal neuron, with the direction of the response depending on which receptor subtype is activated. These data not only help explain the mixed effects of opiates seen in other studies, but also suggest a potential postsynaptic function for the endogenous opiates contained in the CA3 mossy fibers.
We have used electrophysiology and light microscopy of intracellularly labeled neurons in the nucleus of the tractus solitarius (nTS) in brainstem slices of the newborn rat (P0 to P6) to examine the functional and morphological correlation of their development. Three-dimensional reconstruction of neurons injected intracellularly with biocytin, following electrophysiological recording, revealed a close correspondence between morphological immaturity (appearing as polarization of the dendritic tree) and the absence of a ramp-like voltage trajectory at the offset of hyperpolarizing current injections-IA negativity (8 of the 8 cells examined showed this correlation). These morphologically polarized IA negative neurons showed preferential dendritic sprouting in two diametrically opposite poles of the perikaryon. The orientation of the polarity differed according to the rostrocaudal location of the neuron. The appearance of a polarized dendritic tree during the first (immature) phase was transient and closely coincident with IA negativity. Following the development of adult-like electrophysiological characteristics, i.e., IA positivity, nucleus of the tractus solitarius neurons showed remarkably different morphological features (9 of 10 cells). These included a wide-spread branching of the dendritic tree in all directions, giving it a bushy appearance (cell body to dendrite ratio of 1:40). Numerous dendritic spines, growth cones on both dendrites and axons, and axon collateralization were present during both phases and indicate that nTS neurons during the two phases of early development demonstrate dynamic features of growth and maturation. The development of adult-like electrophysiological characteristics, i.e., IA positivity, progressively increased in the postnatal period. During the later part of the first postnatal week, twice as many neurons showed IA positivity in days P3 to P6 as compared with days P0 to P2. These results reveal the dynamic nature of neurons in the nTS during early development and illustrate the close link between morphology and functional characteristics in this region. We suggest that the establishment of adult-like morphology can be modified by appropriate environmental clues provided to nTS neurons during the initial (immature) phase of early postnatal development.
We used electrophysiological methods in a slice preparation to study the mechanisms of somatostatin (SS) effects on hippocampal pyramidal neurons. SS hyperpolarizes hippocampal pyramidal neurons in part by augmenting the time- and voltage-dependent M-current (IM), which has been shown to be reduced by muscarinic agonists. The SS effects are abolished by the phospholipase A2 inhibitors 4-bromophenacyl bromide and quinacrine. Arachidonic acid (AA) mimics all the effects of SS on hippocampal pyramidal neurons. The effects of AA and SS on IM are blocked by the lipoxygenase inhibitor nordihydroguaiaretic acid but not by the cyclooxygenase inhibitor indomethacin. Prostaglandins E2, F2 alpha, and I2 do not increase IM. However, the specific 5-lipoxygenase inhibitors 5,6-methanoleukotriene A4 methylester and 5,6-dehydroarachidonic acid both blocked the IM-augmenting action of either SS or AA. Leukotriene C4 (but not leukotriene B4) increases IM to the same extent as AA. IM was not altered by the 12-lipoxygenase product 12-hydroperoxyeicosatetraenoic acid, and SS effects were not altered by the 12-lipoxygenase inhibitor baicalein. These data implicate 5-lipoxygenase metabolite(s) (probably leukotriene C4) as a mediator for the IM-augmenting effect of SS. In addition, when the IM effect is blocked by lipoxygenase inhibitors, both SS and AA elicit another outward current that is not blocked by either lipoxygenase or cyclooxygenase inhibitors, suggesting a direct role of AA itself distinct from the IM effect. SS did not alter significantly Ca(2+)-dependent action potentials or, in whole-cell recordings, inward currents likely to represent high-threshold Ca2+ currents. The combined results of these studies suggest that SS hyperpolarizes hippocampal neurons by two mechanisms, both mediated through the AA system. However, one mechanism (IM) involves a metabolite of AA and is most effective at slightly depolarized potentials, whereas the other may involve AA itself and be more effective at membrane potentials near rest.