Dual effects of dopamine on the adult heart of the isopod crustacean Ligia exotica

In the adult heart of the isopod crustacean Ligia exotica, the cardiac ganglion acts as the primary pacemaker with the myocardium having a latent pacemaker property. We show several lines of evidence that dopamine modulates the heartbeat of adult L. exotica affecting both pacemaker sites in the heart. Dopamine caused positive chronotropic (frequency increase) and inotropic (amplitude increase) effects on the heartbeat in a concentration dependent manner. The time courses of these effects were considerably different and the inotropic effect appeared later and lasted longer than the chronotropic effect. Dopamine rapidly increased the frequency of the bursting activity in the cardiac ganglion neurons and each impulse burst of the cardiac ganglion was always followed by a heartbeat. Moreover, dopamine slowly increased the amplitude and duration of the action potential plateau (plateau potential) of the myocardium. When the myocardial pacemaker activity was induced by application of tetrodotoxin, which suppresses cardiac ganglion activity, dopamine slowly increased the amplitude and duration of the myocardial plateau potential while decreasing its frequency. These results suggest that dopamine modulates the heartbeat in adult L. exotica producing a dual effect on the two pacemaker sites in the heart, the cardiac ganglion and myocardium.     

Electrophysiological characteristics of cardiac pacemaker cells of the frog Caudiverbera caudiverbera

1. The cardiac pacemaker cells of the frog Caudiverbera caudiverbera are centrally located in the sinus venosus. These cells are rounded, smaller than contractile fibres and have large nuclei. 2. Intracellular recording confirmed the existence of primary and transitional pacemaker cells. 3. Action potentials from primary cells were resistant to blockade by tetrodotoxin (TTX), but were abolished by verapamil suggesting that their bioelectric activity is dependent on a slow inward current. 4. Transitional cells appeared to have two different inward currents contributing to the upstroke: a fast TTX-sensitive and a slow verapamil-sensitive current.     

Pharmacological characterization of ionic currents that regulate the pacemaker rhythm in a weakly electric fish

Electric organ discharge (EOD) frequency in the brown ghost knifefish (Apteronotus leptorhynchus) is sexually dimorphic, steroid-regulated, and determined by the discharge rates of neurons in the medullary pacemaker nucleus (Pn). We pharmacologically characterized ionic currents that regulate the firing frequency of Pn neurons to determine which currents contribute to spontaneous oscillations of these neurons and to identify putative targets of steroid action in regulating sexually dimorphic EOD frequency. Tetrodotoxin (TTX) initially reduced spike frequency, and then reduced spike amplitude and stopped pacemaker activity. The sodium channel blocker muO-conotoxin MrVIA also reduced spike frequency, but did not affect spike amplitude or production. Two potassium channel blockers, 4-aminopyridine (4AP) and kappaA-conotoxin SIVA, increased pacemaker firing rates by approximately 20% and then stopped pacemaker firing. Other potassium channel blockers (tetraethylammonium, cesium, alpha-dendrotoxin, and agitoxin-2) did not affect the pacemaker rhythm. The nonspecific calcium channel blockers nickel and cadmium reduced pacemaker firing rates by approximately 15-20%. Specific blockers of L-, N-, P-, and Q-type calcium currents, however, were ineffective. These results indicate that at least three ionic currents-a TTX- and muO-conotoxin MrVIA-sensitive sodium current; a 4AP- and kappaA-conotoxin SIVA-sensitive potassium current; and a T- or R-type calcium current-contribute to the pacemaker rhythm. The pharmacological profiles of these currents are similar to those of currents that are known to regulate firing rates in other spontaneously oscillating neural circuits.     

Nitric oxide decreases pacemaker activity in lymphatic vessels of guinea pig mesentery

Intracellular microelectrode recordings were used to determine whether nitric oxide (NO), affects the pacemaker events that initiate vasomotion in lymphatic vessels of the guinea pig mesentery. This pacemaker activity is recorded as spontaneous transient depolarizations (STDs) and is likely to arise through synchronized Ca2+ release from intracellular stores. We show here that acetylcholine-induced endothelium-derived NO and exogenous NO released by sodium nitroprusside (SNP; 100 microM) and DEA-NONOate (500 microM) reduced the frequency and amplitude of STDs. This inhibition of STD frequency and amplitude was independent of the NO-induced hyperpolarization of the smooth muscle. The SNP-induced inhibition of STD frequency and amplitude was abolished during superfusion with the soluble guanylyl cyclase inhibitor ODQ (10 microM) and was diminished in the presence of cGMP and cAMP-dependent protein kinase inhibitors. The data are consistent with the hypothesis that NO inhibits vasomotion primarily by production of cGMP and activation of both cGMP- and cAMP-dependent protein kinases, which reduce the size and frequency of STDs, probably by acting on the underlying synchronized Ca2+ release from intracellular stores.     

Simulation of the hippocampal theta rhythm

Centre of Theoretical and Computational Neuroscience, University of Plymouth, UK Basing on the hypothesis about the mechanisms of the theta rhythm generation, the article presents mathematical and computational models of theta activity in the hippocampus. The problem of the theta rhythm modeling is nontrivial because the slow theta oscillations (about 5 Hz) should be generated by a neural system composed of frequently firing neural populations. We studied a model of neural pacemakers in the septum. In this model, the pacemaker follows the frequency of the external signal if this frequency does not deviate too far from the natural frequency of the pacemaker, otherwise the pacemaker returns to the frequency of its own oscillations. These results are in agreement with the experimental records of medial septum neurons. Our model of the septal pacemaker of the theta rhythm is based on the hypothesis that the hippocampal theta appears as a result of the influence of the assemblies of neurons in the medial septum which are under control of pacemaker neurons. Though the model of the pacemaker satisfies many experimental facts, the synchronization of activity in different neural assemblies of the model is not as strong as it should be. Another model of the theta generation is based on the anatomical data about the existence of the inhibitory GABAergic loop between the medial septum and the hippocampus. This model shows stable oscillations at the frequency of the theta rhythm in a broad range of parameter values. It also provides explanation to the experimental data about the variation of the frequency and the amplitude of the theta rhythm under different external stimulations of the system. The role of the theta rhythm for information processing in the hippocampus is discussed.     

Pacemaker potentials generated by interstitial cells of Cajal in the murine intestine

Pacemaker potentials were recorded in situ from myenteric interstitial cells of Cajal (ICC-MY) in the murine small intestine. The nature of the two components of pacemaker potentials (upstroke and plateau) were investigated and compared with slow waves recorded from circular muscle cells. Pacemaker potentials and slow waves were not blocked by nifedipine (3 µM). In the presence of nifedipine, mibefradil, a voltage-dependent Ca²⁺ channel blocker, reduced the amplitude, frequency, and rate of rise of upstroke depolarization (dV/dt_max) of pacemaker potentials and slow waves in a dose-dependent manner (1–30 µM). Mibefradil (30 µM) changed the pattern of pacemaker potentials from rapidly rising, high-frequency events to slowly depolarizing, low-frequency events with considerable membrane noise (unitary potentials) between pacemaker potentials. Caffeine (3 mM) abolished pacemaker potentials in the presence of mibefradil. Pinacidil (10 µM), an ATP-sensitive K⁺ channel opener, hyperpolarized ICC-MY and increased the amplitude and dV/dt_max without affecting frequency. Pinacidil hyperpolarized smooth muscle cells and attenuated the amplitude and dV/dt_max of slow waves without affecting frequency. The effects of pinacidil were blocked by glibenclamide (10 µM). These data suggest that slow waves are electrotonic potentials driven by pacemaker potentials. The upstroke component of pacemaker potentials is due to activation of dihydropyridine-resistant Ca²⁺ channels, and this depolarization entrains pacemaker activity to create the plateau potential. The plateau potential may be due to summation of unitary potentials generated by individual or small groups of pacemaker units in ICC-MY. Entrainment of unitary potentials appears to depend on Ca²⁺ entry during upstroke depolarization. pacemaker activity; slow waves; gastrointestinal motility; calcium channel     

Study of electrical activity in the area of the hypothalamic ventromedial nucleus and the lateral hypothalamus of rats fed on a high protein and high fat diet.

The authors studied bioelectric potentials in the area of the hypothalamic ventromedial nucleus and the lateral hypothalamus of rats fed on a standard, a high protein and a high fat diet. On the first 3--6 days after changing from the standard to the high fat and high protein diets, a decrease in the amplitude of electrical activity was recorded in both the areas in question. It was also found that the frequency of electrical activity in the hypothalamic ventromedial nucleus or the lateral hypothalamus rose, after 3 days administration of the high fat or the high protein diet, in correlation to the type of diet, and that, in the frequency spectrum, a change occurred in the proportion of basic frequency in relation to superimposed frequencies distorting it. It was further found that there was a permanent difference between the amplitude of electrical activity in the lateral hypothalamus and the hypothalamic ventromedial nucleus.     

Photoperiodism and changes in brain bioelectric activity in schoolchildren in the arctic zone

The dynamics of the main electroencephalographic patterns and their relationship with natural illumination periods have been described in this study. We have determined periods, which are the most favorable for brain functioning and development of cognitive function in northerner schoolchildren. We have found that adaptive changes in bioelectric activity of the brain take place during transitional seasons. An increase in the activity of all EEG rhythms in spring and predominance of the slow-wave Δ and θ activity in autumn have been found. The discovered dynamics of amplitude and spectral parameters of EEG are not dependent on age-related changes. The formation of bioelectric activity of the brain in northerner schoolchildren was mostly affected by the sex of a child and changes in the daytime duration.     

Adrenergic control of cardian pacemaker currents.

Pacemaker activity in atrial muscle and in Purkinje fibres is generated by a time-dependent decay of potassium current that allows the membrane to be depolarized to the threshold for action potential initiation. The kinetics of the pacemaker potassium currents in these two parts of the heart are sufficiently different to indicate that they correspond to different membrane structures. This conclusion is strengthened by the discovery that the mechanisms of acceleration produced by adrenaline are also quite different. In Purkinje fibres, the activation threshold for the potassium current is shifted in a depolarizing direction with no change in maximum amplitude. This voltage shift is adequate by itself to explain the acceleration. In atrial fibres the pacemaker potassium current is increased in amplitude with no shift in threshold. By itself, this action of adrenaline would slow pacemaker activity and the acceleration in this case is dependent on a large increase in the current attributable to calcium ions. The roles of cyclic 3',5'-AMP and of intracellular calcium ions in mediating the pacemaker actions of adrenaline will also be discussed.     

Effect of vitamin E (alpha-tocopherol) on the spontaneous activity of the cerebral cortex

In experiments on 55 Meriones tamariscinus and 49 white rats the influence of D, L, alpha-tocopherolacetate on background activity of the sensorimotor and visual zones of the cerebral cortex of intact and castrated rodents was studied. Species and sex differences were revealed in animals reaction to vitamin E in doses commensurable with therapeutic ones. It is shown that tocopherol elicits a reduction of frequency and increase of amplitude of ECoGs in Meriones males and female white rats. After animal castration tocopherol action basically changes. It is suggested that the inhibitory effect of vitamin E on bioelectric processes in the cerebral cortex results from a change in the level of free-radical oxidation of lipid components of cellular membranes of cortical neurones due to an intensification of activity of their antioxidant system.     

Spatial localization and properties of pacemaker potentials in the canine rectoanal region

The present study investigated the spatial organization of electrical activity in the canine rectoanal region and its relationship to motility patterns. Contraction and resting membrane potential (E(m)) were measured from strips of circular muscle isolated 0.5-8 cm from the anal verge. Rapid frequency [25 cycles/min (cpm)] E(m) oscillations (MPOs, 12 mV amplitude) were present across the thickness of the internal anal sphincter (IAS; 0.5 cm) and E(m) was constant (-52 mV). Between the IAS and the proximal rectum an 18 mV gradient in E(m) developed across the muscle thickness with the submucosal edge at -70 mV and MPOs were replaced with slow waves (20 mV amplitude, 6 cpm). Slow waves were of greatest amplitude at the submucosal edge. Nifedipine (1 micro M) abolished MPOs but not slow waves. Contractile frequency changes were commensurate with the changes in pacemaker frequency. Our results suggest that changing motility patterns in the rectoanal region are associated with differences in the characteristics of pacemaker potentials as well as differences in the sites from which these potentials emanate.     

Intracellular recording in the medullary pacemaker nucleus of the weakly electric fish,Apteronotus, during modulatory behaviors

1. The weakly electric gymnotiform fish, Apteronotus leptorhynchus, can be induced to perform a variety of modulations of its quasi-sinusoidal, electric organ discharge (EOD) in acute physiological preparations. These modulations, many of which are communicatory in function, include the jamming avoidance response (JAR). We have recorded intracellularly from neurons of the medullary pacemaker nucleus which is responsible for maintaining the ongoing EOD frequency during these modulatory behaviors. 2. We have used dye-filled microelectrodes to characterize single cell morphology of the two types of cells in the pacemaker nucleus (relay and pacemaker cells) and to localize anatomically the site of the differing responses we see during frequency modulations. We have also recorded with KCl-filled electrodes and attributed these data to cell type and location on the basis of characteristic behavior during these modulations. 3. Much of our data deals with chirps, brief accelerations of the EOD frequency lasting 10 to 14 ms. We see distinct patterns of activity in the pacemaker nucleus corresponding to different anatomical locations: the relay cell soma and axon, and the pacemaker cell soma and axon. Most of these loci show a marked rise in baseline voltage during the acceleration in spike frequency. The most unusual of these is the pacemaker cell axon which displays an often extreme decline in spike amplitude concurrent with the chirp (Fig. 7A). 4. 'Yodeling' (Dye 1987) appears to involve similar, characteristic changes in the pattern of firing as those seen during chirping. Similar quantitative analyses suggest that the JAR involves a different mechanism, however.     

The effect of microwaves on the bioelectric brain activity

The experiments on rats have shown that the effect of millimeter range electromagnetic radiation on the bioelectric brain activity is dependent on the initial functional state of central nervous system. Microwaves are able to cause a nonspecific electroencephalographic reaction of synchronization and probably the lower the bioelectric brain process dynamics of active rats. Enrichment of electrocorticograms with high-frequency rhythms and increase in degree of bioelectric brain dynamics can be observed in narcosis conditions. The appearance of biological resonance in the brain of narcotized rats preliminary injected aminazin by pulse-modulated microwaves is noted. This is expressed as epileptiform convulsive activity in electrocorticogram. It has been shown that the nonlinear dynamics method may provide a reliable characterization of changing bioelectric brain activity under of nonionized electromagnetic fields. It is possible to modulate the bioelectric brain activity by microwaves to change the functional state of central nervous system and probably of the whole organism.     

Actin Microfilament Involved in Regulation of Pacemaking Activity in Cultured Interstitial Cells of Cajal from Murine Intestine

The present study investigated the effect of actin microfilament structure on pacemaker currents and calcium oscillation in cultured murine intestinal interstitial cells of Cajal (ICCs) by whole-cell patch-clamp technique and calcium imaging technique. Cytochalasin B, a disruptor of actin microfilaments, decreased the amplitude and frequency of pacemaker currents from 491.32 ± 160.33 pA and 11.73 ± 0.79 cycles/min to 233.12 ± 92.00 pA and 10.29 ± 0.76 cycles/min. Cytochalasin B also decreased the amplitude and frequency of calcium oscillation from 0.32 ± 0.08 (ΔF/F0) and 2.75 ± 0.17 cycles/min to 0.02 ± 0.01 (ΔF/F0) and 1.20 ± 0.08 cycles/min. Phalloidin, a stabilizer of actin microfilaments, increased the amplitude and frequency of pacemaker currents from 751.79 ± 282.82 pA and 13.93 ± 1.00 cycles/min to 1234.34 ± 607.83 pA and 14.68 ± 1.00 cycles/min. Phalloidin also increased the amplitude and frequency of calcium oscillation from 0.26 ± 0.01 (ΔF/F0) and 2.27 ± 0.18 cycles/min to 0.43 ± 0.03 (ΔF/F0) and 2.87 ± 0.07 cycles/min. 2-Aminoethoxydiphenyl borane (2-APB), an IP₃ receptor blocker, suppressed both pacemaker currents and calcium oscillations. 2-APB also blocked the phalloidin-induced increase in pacemaker currents and calcium oscillation. Ryanodine, an inhibitor of calcium-induced calcium release, did not affect pacemaker current but suppressed calcium oscillations. Ryanodine had no effect on altering phalloidin-induced increases in pacemaker current and calcium oscillation. These results suggest that actin microfilaments regulate pacemaker activity via the IP₃-induced calcium release signaling pathway.     

Use of a microelectrode array to record extracellular pacemaker potentials from the gastrointestinal tracts of the ICR mouse and house musk shrew (Suncus murinus)

BackgroundThe rhythmic contraction and relaxation of smooth muscles in the gastrointestinal (GI) tract is governed by pacemaker electrical potentials, also termed slow waves, which are calcium currents generated by interstitial cells of Cajal (ICCs). Malfunction of pacemaker rhythms contributes to a number of clinically challenging gastrointestinal motility disorders.MethodA microelectrode array (MEA) was used to record slow waves in vitro from intact GI tissues freshly isolated from the ICR mouse and Suncus murinus. The effects of temperature, extracellular calcium and potassium concentrations on pacemaker potentials were quantified using spatiotemporal metrics.ResultsPacemaker frequency decreased from the duodenum to the ileum in the mouse, but this phenomenon was less significant in Suncus murinus. In both the mouse and Suncus murinus, the stomach had a much lower pacemaker frequency than the intestine. Propagation velocity and amplitude were highest in the proximal intestine. Temperature significantly increased pacemaker frequency in the intestinal tissues of both species. Removal of Ca²⁺ from the medium inhibited pacemaker potential and increasing the Ca²⁺ concentration increased pacemaker frequency in the mouse ileum. Increasing K⁺ concentration decreased pacemaker frequency in the absence of nifedipine.ConclusionsThe MEA allows efficient investigation of gut pacemaker frequency and propagation.     

Cyclopiazonic acid decreases spontaneous transient depolarizations in guinea pig mesenteric lymphatic vessels in endothelium-dependent and -independent manners

Guinea pig mesenteric lymphatic vessels exhibit vasomotion through a pacemaker mechanism that involves intracellular Ca(2+) release and resultant spontaneous transient depolarizations (STDs) of the smooth muscle membrane potential. This study presents a detailed characterization of the effects of cyclopiazonic acid (CPA) on this pacemaker activity. Microelectrode recordings from smooth muscle in vessel segments revealed that application of CPA (1-10 microM) caused a hyperpolarization accompanied by a decrease in the frequency and amplitude of STDs. The CPA-induced hyperpolarization was abolished after destruction of the endothelium and in the presence of N(G)-nitro-L-arginine (100 microM) or 1H-[1,2,4]oxadiazolol-[4,3-a]quinoxaline-1-one (10 microM), which suggests a contribution of endothelium-derived nitric oxide (EDNO) in this response. In the absence of EDNO-induced effects, CPA decreased the frequency and amplitude of STDs recorded before and in the presence of the thromboxane A(2) mimetic U-46619, norepinephrine, or thimerosal. CPA abolished U-46619-induced vasomotion as determined by measurement of constriction-associated intracellular Ca2+ concentration using the ratiometric Ca2+ indicator fura-2. The endothelial actions of CPA were compared with those of ACh, which is known to cause EDNO release in this preparation. Although CPA and ACh both increased endothelial intracellular Ca2+ concentration and depolarized the membrane potential, the kinetics of action for both parameters were markedly slower for CPA than ACh. These results suggest that CPA first hyperpolarizes the lymphatic smooth muscle and decreases STD frequency and amplitude through endothelial release of EDNO, and second, consistent with the action of CPA to inhibit sarcoplasmic reticulum Ca2+-ATPase and deplete Ca2+ stores, it further reduces STD activity. Inhibition of the lymphatic smooth muscle pacemaker mechanism is thought to abolish agonist-induced vasomotion.     

Blood supply as a factor regulating pacemaker activity of the rat uterine horn

The effect of ischemia of the uterine artery supplying blood to the main rhythmogenic ovarian zone of the uterine horn in non-pregnant rats was investigated. Parameters of pacemaker activity of the given locus and all the subsequent pacemaker areas up to the cervix were studied under the influence of ischemia. The greatest changes of the amplitude, frequency and burst duration time of spike activities were recorded in the ovarian end of horn. The uterine corpus and cervical end of horn were less affected by ischemia. However, amplitude of the slow-wave oscillations increased by more than one and a half in these conditions. Data obtained allow us to state about presence of certain connection between the ovarian end of horn and uterine cervix. Morphological studies revealed strong vascularization of the upper part of uterine horn.     

A biophysically based mathematical model of unitary potential activity in interstitial cells of Cajal

Unitary potential (UP) depolarizations are the basic intracellular events responsible for pacemaker activity in interstitial cells of Cajal (ICCs), and are generated at intracellular sites termed “pacemaker units”. In this study, we present a mathematical model of the transmembrane ion flows and intracellular Ca²⁺ dynamics from a single ICC pacemaker unit acting at near-resting membrane potential. This model quantitatively formalizes the framework of a novel ICC pacemaking mechanism that has recently been proposed. Model simulations produce spontaneously rhythmic UP depolarizations with an amplitude of ∼3 mV at a frequency of 0.05 Hz. The model predicts that the main inward currents, carried by a Ca²⁺-inhibited nonselective cation conductance, are activated by depletion of sub-plasma-membrane [Ca²⁺] caused by sarcoendoplasmic reticulum calcium ATPase Ca²⁺ sequestration. Furthermore, pacemaker activity predicted by our model persists under simulated voltage clamp and is independent of [IP₃] oscillations. The model presented here provides a basis to quantitatively analyze UP depolarizations and the biophysical mechanisms underlying their production.     

Biophysically Based Mathematical Modeling of Interstitial Cells of Cajal Slow Wave Activity Generated from a Discrete Unitary Potential Basis

Spontaneously rhythmic pacemaker activity produced by interstitial cells of Cajal (ICC) is the result of the entrainment of unitary potential depolarizations generated at intracellular sites termed pacemaker units. In this study, we present a mathematical modeling framework that quantitatively represents the transmembrane ion flows and intracellular Ca²⁺ dynamics from a single ICC operating over the physiological membrane potential range. The mathematical model presented here extends our recently developed biophysically based pacemaker unit modeling framework by including mechanisms necessary for coordinating unitary potential events, such as a T-Type Ca²⁺ current, V_m-dependent K⁺ currents, and global Ca²⁺ diffusion. Model simulations produce spontaneously rhythmic slow wave depolarizations with an amplitude of 65 mV at a frequency of 17.4 cpm. Our model predicts that activity at the spatial scale of the pacemaker unit is fundamental for ICC slow wave generation, and Ca²⁺ influx from activation of the T-Type Ca²⁺ current is required for unitary potential entrainment. These results suggest that intracellular Ca²⁺ levels, particularly in the region local to the mitochondria and endoplasmic reticulum, significantly influence pacing frequency and synchronization of pacemaker unit discharge. Moreover, numerical investigations show that our ICC model is capable of qualitatively replicating a wide range of experimental observations.