Na+ Current in Human Ventricle: Implications for Sodium Loading and Homeostasis

The Na current (I_Na) in human ventricle is carried through a specific isoform of the voltage gated Na channel in heart. The pore forming α-subunit is encoded by the gene SCN5A . Up to four β-subunits may be associated, and the larger macromolecular complex may include attachments to cytoskeleton and scaffolding proteins, all of which may affect the gating kinetics of the current. I_Na underlies initiation and propagation of action potentials in the heart and plays a prominent role in cardiac electrophysiology and arrhythmia. In addition, I_Na also loads the ventricular cell with Na⁺ ions and plays an important role in intracellular Na homeostasis. This review considers the structure and function of the human cardiac Na channel that carries I_Na with a particular consideration of the implications of alterations in I_Na in acquired cardiac diseases such as hypertrophy, failure, and ischemia, which affect Na loading.     

Human Neutrophil Functions Are Inhibited In Vitro by Clinically Relevant Ethanol Concentrations

Neutrophils [polymorphonuclear neutrophils (PMNs)] play a pivotal role in host defense in man. These defenses may be compromised, however, in alcohol users and abusers. We therefore evaluated the effect of ethanol levels (12.5 to 500 mg/dl), on key functions of human PMNs—chemotaxis and production of reactive oxygen species—and on changes in cytosolic-free calcium ([Ca²⁺]_i), a pivotal intracellular mechanism of PMN activation. Ethanol significantly inhibited chemotaxis as evaluated by formyl-methionyl-leucyl-phenylalanine (fMLP)-induced upregulation of surface adhesion molecules (CD11b), fMLP-induced PMN elongation was only inhibited by a very high ethanol concentration of 500 mg/dl. Production of reactive oxygen species by normal PMNs was assessed by either chemiluminescence (CL) for hypochlorous acid or ferricytochrome c reduction (FCR) for superoxide anions. For PMN stimulated by fMLP, ethanol inhibited CL but not FCR. For PMNs activated by phorbol myristate acetate, ethanol inhibited both CL and FCR. Ethanol did not alter baseline [Ca²⁺]_i, as assessed by videomicroscopy using the Ca²⁺-sensing fluorescent dye Fura-2-AM, but did significantly potentiate the increase in peak [Ca²⁺]_i, levels that occurs in response to stimulation by fMLP. Calcium channel blockers attenuated ethanol's inhibition of CL. Thus, acute in vitro ethanol, at clinically relevant concentrations, can inhibit several critical aspects of PMN functions. But, in PMNs, unlike neural cells, these inhibitory effects do not seem to be mediated by decreases in Ca²⁺ influx or in [Ca²⁺]_i.     

A requirement for calcium in the caspase-independent killing of Burkitt lymphoma cell lines by Rituximab

The therapeutic monoclonal antibody rituximab has previously been shown to kill B cells in a caspase-independent manner. The signalling pathways underpinning this novel death pathway are unknown. The present study showed that rituximab treatment of Burkitt lymphoma cell lines induced a slow rise in intracellular calcium ([Ca²⁺]_i). This rise was only witnessed in cell lines that were killed by antibody, suggesting a critical role for Ca²⁺ in mediating rituximab-driven caspase-independent cell death. Inhibition of the two main intracellular store-located Ca²⁺ channels, i.e. the ryanodine and inositol-1,4,5-triphosphate receptor channels by dantrolene and xestospongen-c respectively did not prevent the rise in Ca²⁺ seen with rituximab or protect cells from subsequent death. In sharp contrast, inhibition of Ca²⁺ entry via plasma membrane channels with (2-aminoethoxy) diphenylborate or SKF-96365 or complete chelation of extracellular Ca²⁺ with ethyleneglycol bis (aminoethylether) tetra-acetate inhibited the rise in [Ca²⁺]_i and increased cell viability. Together, these data suggest that ligation of the CD20 receptor with rituximab allows a slow sustained influx of Ca²⁺ from the external environment that under certain conditions can lead to cell death.     

The Phosphodiesterase III Inhibitor Olprinone Decreases Sensitivity of Rat Kupffer Cells to Endotoxin

Background: Sensitivity of Kupffer cells to endotoxin [lipopolysaccharide (LPS)] and overproduction of tumor necrosis factor-α (TNF-α) are critical for progression of alcoholic liver injury. Therefore, suppression of TNF-α should prove useful for treatment of alcoholic liver injury. However, a transient increase of intracellular calcium ([Ca²⁺]_i) is required for LPS-induced TNF-α production by the macrophage cell line. The phosphodiesterase III inhibitor olprinone has been shown to suppress [Ca²⁺]_i level in vascular smooth muscle cells. Accordingly, the purpose of this study was to determine whether olprinone could prevent sensitization of Kupffer cells to endotoxin.
Methods: Kupffer cells were isolated by collagenase digestion and differential centrifugation. LPS was added to Kupffer cells 24 hr after incubation with or without olprinone (0.1 μmol/liter). After addition of LPS (10 μg/ml) to culture media, [Ca²⁺]_i was measured using a fluorescent indicator, fura-2.
Results: LPS increased [Ca²⁺]_i of Kupffer cells in control rats from basal levels (28 ± 4 nmol/liter) to 280 ± 14 nmol/liter. This increase was blunted by olprinone (91 ± 8 nmol/liter). Similarly, olprinone diminished the LPS (1 μg/ml)-induced TNF-α production by Kupffer cells by 30% (2220 ± 116 vs. 1386 ± 199 pg/ml; p < 0.05).
Conclusions: These results indicate that olprinone decreases sensitivity of Kupffer cells to endotoxin.     

pH-Regulated Na+ Influx into the Mammalian Ventricular Myocyte: The Relative Role of Na+-H+ Exchange and Na+-HCO3− Co-Transport

In the heart, intracellular Na⁺ concentration (Na⁺_i) is a controller of intracellular Ca²⁺ signaling, and hence of key aspects of cell contractility and rhythm. Na⁺_i will be influenced by variation in Na⁺ influx. In the present work, we consider one source of Na⁺ influx, sarcolemmal acid extrusion. Acid extrusion is accomplished by sarcolemmal H⁺ and HCO₃⁻ transporters that import Na⁺ ions while exporting H⁺ or importing HCO₃⁻. The capacity of this system to import Na⁺ is enormous, up to four times the maximum capacity of the Na⁺-K⁺ ATPase to extrude Na⁺ ions from the cell. In this review we consider the role of Na⁺-H⁺ exchange (NHE) and Na⁺-HCO₃⁻co-transport (NBC) in mediating Na⁺ influx into cardiac myocytes. We consider, in particular, the role of NBC, as so little is known about Na⁺ influx through this transporter. We show that both proteins mediate significant Na⁺ influx and that although, in the ventricular myocyte, NBC-mediated Na⁺ influx is less than through NHE, the proportions may be altered under a variety of conditions, including exposure to catecholamines, membrane depolarization, and interference with activity of the enzyme, carbonic anhydrase.     

Melatonin restores impaired contractility in aged guinea pig urinary bladder

Abstract:  Urinary bladder disturbances are frequent in the elderly population but the responsible mechanisms are poorly understood. This study evaluates the effects of aging on detrusor myogenic contractile responses and the impact of melatonin treatment. The contractility of bladder strips from adult, aged and melatonin-treated guinea pigs was evaluated by isometric tension recordings. Cytoplasmatic calcium concentration ([Ca²⁺]_i) was estimated by epifluorescence microscopy of fura-2-loaded isolated detrusor smooth muscle cells, and the levels of protein expression and phosphorylation were quantitated by Western blotting. Aging impairs the contractile response of detrusor strips to cholinergic and purinergic agonists and to membrane depolarization. The impaired contractility correlates with increased [Ca²⁺]_i in response to the stimuli, suggesting a reduced Ca²⁺sensitivity. Indeed, the agonist-induced contractions in adult strips were sensitive to blockade with Y27362, an inhibitor of Rho kinase (ROCK) and GF109203X, an inhibitor of protein kinase C (PKC), but these inhibitors had negligible effects in aged strips. The reduced Ca²⁺ sensitivity in aged tissues correlated with lower levels of RhoA, ROCK, PKC and the two effectors CPI-17 and MYPT1, and with the absence of CPI-17 and MYPT1 phosphorylation in response to agonists. Interestingly, melatonin treatment restored impaired contractility via normalization of Ca²⁺ handling and Ca²⁺ sensitizations pathways. Moreover, the indoleamine restored age-induced changes in oxidative stress and mitochondrial polarity. These results suggest that melatonin might be a novel therapeutic tool to palliate aging-related urinary bladder contractile impairment.     

In vivo and in vitro effects of the pineal gland and melatonin on [Ca2++ Mg2+]-dependent ATPase in cardiac sarcolemma

Abstract: The possible diurnal variation in cardiac [Ca²⁺+ Mg²⁺]-dependent ATPase (Ca²⁺ pump) activity and the influence of pinealectomy and melatonin on this enzyme in rat heart have been studied. Lowest levels of cardiac sarcolemma] membrane [Ca²⁺+ Mg²⁺]-dependent ATPase activity were measured in late afternoon in rats kept under a 14:10 light:dark cycle. Late in the dark phase the enzyme activity began to increase with the rise continuing until 0900, 3 hr after light onset. These time-dependent changes in [Ca²⁺+ Mg²⁺]-dependent ATPase activity did not occur in either pinealectomized or light-exposed rats suggesting that melatonin, secreted from the pineal gland during the night, induces the change in [Ca²⁺+ Mg²⁺]-dependent ATPase activity. In vitro studies in which cardiac tissue was incubated in the presence of melatonin over a wide range of doses showed that this indole stimulated the Ca²⁺ pump. The half-maximal effect of melatonin was observed at a melatonin concentration of 28 ng/ml. These findings suggest that the daily change in [Ca²⁺+ Mg²⁺]-dependent ATPase activity in the sarcolemma of heart tissue is a result of the circadian rhythm in pineal melatonin production and secretion. These findings may be applicable to normal cardiac physiology.     

Protective effect of melatonin on Ca2+ homeostasis and contractility in acute cholecystitis

Abstract:  Impaired Ca²⁺ homeostasis and smooth muscle contractility co-exist in acute cholecystitis (AC) leading to gallbladder dysfunction. There is no pharmacological treatment for this pathological condition. Our aim was to evaluate the effects of melatonin treatment on Ca²⁺ signaling pathways and contractility altered by cholecystitis. [Ca²⁺]_i was determined by epifluorescence microscopy in fura-2 loaded isolated gallbladder smooth muscle cells, and isometric tension was recorded from gallbladder muscle strips. Malondialdehyde (MDA) and reduced glutathione (GSH) contents were determined by spectrophotometry and cycloxygenase-2 (COX-2) expression was quantified by western blot. Melatonin was tested in two experimental groups, one of which underwent common bile duct ligation for 2 days and another that was later de-ligated for 2 days. Inflammation-induced impairment of Ca²⁺ responses to cholecystokinin and caffeine were recovered by melatonin treatment (30 mg/kg). This treatment also ameliorated the detrimental effects of AC on Ca²⁺ influx through both L-type and capacitative Ca²⁺ channels, and it was effective in preserving the pharmacological phenotype of these channels. Despite its effects on Ca²⁺ homeostasis, melatonin did not improve contractility. After de-ligation, Ca²⁺ influx and contractility were still impaired, but both were recovered by melatonin. These effects of melatonin were associated to a reduction of MDA levels, an increase in GSH content and a decrease in COX-2 expression. These findings indicate that melatonin restores Ca²⁺ homeostasis during AC and resolves inflammation. In addition, this indoleamine helps in the subsequent recovery of functionality.     

Comparison of the Effects of Regional Ischemia and Hyperkalemia on the Membrane Action Potentials of the In Situ Pig Heart

APD During Ischemia. Introduction: This study was designed to determine the role of increased extracellular potassium [K⁺]_e on action potential duration (APD) in the in situ porcine heart during acute regional no-flow ischemia.
Methods and Results: In open chest, anesthetized swine, an arterial shunt from the carotid artery to the mid-left anterior descending coronary artery was created through which a solution of KCl was infused to raise [K⁺]_e, Myocardial [K⁺]_e, was determined by potassium-sensitive electrodes, and transmembrane action potential was recorded by floating glass microelectrode. During the first 2 minutes of ischemia, APD at 90% repolarization (APD₉₀) lengthened by 31.2 ± 1.1 msec (P < 0.05). The comparable increase in [K⁺]_e alone shortened APD₉₀, During the next 6 minutes of ischemia. [K⁺]_e, rose to 11.3 ± 0.3 mM and APD₉₀, showed a decrease. However, the comparable increase in |K⁺]_e, by infusion of KCl caused further shortening of APD₉₀, at similar levels of [K⁺]_e.
Conclusions: Acutely ischemic myocardium showed a brief increase in APD₉₀, during the first 2 minutes of ischemia, followed by a fall in APD₉₀, after 2 minutes of ischemia, but the shortening is less than anticipated by the rise in [K⁺]_e. Thus, we hypothesize that other component(s) of ischemia may inhibit action potential repolarization.     

Platelet activation induced by an antiplatelet autoantibody against CD9 antigen and its inhibition by another autoantibody in immune thrombocytopenic purpura

Summary. In a patient with immune thrombocytopenic purpura (ITP), we found a novel platelet-activating IgG (act-IgG) and an inhibitory IgG (inhi-IgG) that prevented activation induced by both CD9 monoclonal antibody (mAb) and the act-IgG. Purified IgG from the patient plasma caused a rise in [Ca²⁺]_i and the aggregation of normal platelets, and bound to a 24 kD membrane protein. This aggregation was inhibited by aspirin, staurosporine, an inhibitor of protein kinase C, and F(ab')₂ fragments of MALL13, a CD9 mAb. When the platelet count of this patient rose to normal range, the act-IgG disappeared. About 2 weeks later, the relapse of thrombocytopenia was observed. The purified IgG obtained in this period did not activate platelets but inhibited both the rise in [Ca²⁺]_i and platelet aggregation stimulated by NNKY 1–19, a CD9 mAb, as well as the act-IgG, and bound to a 40 kD membrane protein. The inhi-IgG prevented the binding of IV-3, a mAb against Fcγ receptor II (FcγRII), but did not prevent the binding of NNKY 1–19 to its antigen. We suggest that the activating autoantibody recognized CD9 antigen and activated both the thromboxane- and phospholipase C-dependent pathways, while the inhibitory autoantibody recognized the FcγRII and inhibited CD9 antibody-induced platelet activation mediated via this receptor.     

Shortcomings of current models of glucose-induced insulin secretion

Glucose-induced insulin secretion by pancreatic β-cells is generally schematized by a 'consensus model' that involves the following sequence of events: acceleration of glucose metabolism, closure of ATP-sensitive potassium channels (K_ATP channels) in the plasma membrane, depolarization, influx of Ca²⁺ through voltage-dependent calcium channels and a rise in cytosolic-free Ca²⁺ concentration that induces exocytosis of insulin-containing granules. This model adequately depicts the essential triggering pathway but is incomplete. In this article, we first make a case for a model of dual regulation in which a metabolic amplifying pathway is also activated by glucose and augments the secretory response to the triggering Ca²⁺ signal under physiological conditions. We next discuss experimental evidence, largely but not exclusively obtained from β-cells lacking K_ATP channels, which indicates that these channels are not the only possible transducers of glucose effects on the triggering Ca²⁺signal. We finally address the identity of the widely neglected background inward current (Cl⁻ efflux vs. Na⁺ or Ca²⁺ influx through voltage-independent channels) that is necessary to cause β-cell depolarization when glucose closes K_ATP channels. More attention should be paid to the possibility that some components of this background current are influenced by glucose metabolism and have their place in a model of glucose-induced insulin secretion.     

Na+/Ca2+ Exchanger Expression and Function in a Rabbit Model of Myocardial Infarction

Introduction: In general, sarcolemmal Na⁺/Ca²⁺ exchanger (NCX) protein and activity is increased in hearts with ventricular dysfunction. However, in a subset of studies, reduced activity of NCX has been reported. Left ventricular dysfunction (LVD) was induced in the rabbit eight weeks after an apical myocardial infarction.
Methods: Using single microelectrode voltage clamp to assess the NCX activity in isolated ventricular cells, a decrease in NCX activity by ∼30% was observed. Immunoblot analysis indicated increased NCX protein levels by ∼20% in the LVD group. The cause of this paradox is unknown. Overexpression of the protein sorcin increased the activity of NCX without affecting NCX protein levels.
Results: Sorcin protein (dimer) levels were significantly lower in the LVD group (0.67 ± 0.05 n = 15, P < 0.05) compared to sham (1.0 ± 0.16, n = 15). Sorcin monomer levels were not significantly different (sham: 1.0 ± 0.26, LVD: 0.83 ± 0.13). Mathematical modeling of NCX suggests that a reduction of NCX activity during diastole to that in LVD could be achieved by holding the diastolic membrane potential at −60 mV instead of −80 mV. Holding E_m at −60 mV decreased NCX-mediated Ca²⁺ efflux rates to values comparable to those seen in LVD and increased SR Ca²⁺ content and peak systolic [Ca²⁺] in sham and LVD cardiomyocytes.
Conclusions: In conclusion, reduced sorcin expression may be linked to the lower NCX activity in the rabbit model of LVD. Reduced NCX activity during diastole increases SR Ca²⁺ content and Ca²⁺ transient amplitude.     

Role of L-Type Calcium Channel Window Current in Generating Current-Induced Early Afterdepolarizations

Ionic Mechanism of EADs. Introduction: Early afterdepolarizations (EADs) can give rise to triggered activity and thereby produce cardiac arrhythmias. We used the whole-cell patch clamp technique to examine the relationship between L-type Ca²⁺ channel window current and the generation of EADs in single ventricular myocytes isolated from guinea pig hearts.
Methods and Results: With a high concentration of EGTA in the internal solution and Na⁺-containing physiologic external solution, EADs were induced in unclamped cells by injecting intracellular depolarizing current pulses. During voltage clamp protocols designed to simulate action potentials interrupted by EADs, we recorded an inward shift in total current up to 0.7 pA/pF over 400 msec at test steps in the range of the take-off potential for EADs. Cd^2t (0.2 mM) blocked most of the inward shift of current during the test steps and abolished EADs. When the same voltage clamp protocol was used following perfusion with an Na⁺-free, K⁺-free external solution, the Cd²⁺-sensitive inward currents recorded during the test steps were similar to those obtained in physiologic external solution. The overlapping range of potentials for partial activation of the d and f variables of L-type Ca²⁺ current ("window" region) measured in Na⁺-free, K⁺-free external solution was virtually the same as the voltage range of the Cd²⁺–sensitive inward currents.
Conclusion: Our experiments suggest that: (1) EADs can arise under conditions of high EGTA buffering of intraccllular [Ca²⁺]; and (2) under these conditions, L-type Ca²⁺ channel window current plays a major role in the initiation of EADs.     

Intervention of pyrrolidine dithiocarbamate and tetrandrine on cellular calcium overload of pancreatic acinar cells induced by serum and ascitic fluid from rats with acute pancreatitis

Background and Aim:  To investigate the effects of serum and ascitic fluid from rats with acute pancreatitis (AP) on cellular free calcium concentration ([Ca²⁺]i) of isolated rat pancreatic acinar cells, and the intervention of pyrrolidine dithiocarbamate (PDTC) and tetrandrine (Tet) to cellular calcium overload in AP.
Methods:  AP was induced in Sprague–Dawley rats with a retrograde pancreatic duct injection of 3% sodium deoxycholate, and confirmed by histopathological examination and amylase activity assay. The rat serum and ascitic fluid were collected at 1, 5 and 10 h after AP induction, and used as irritants on isolated rat pancreatic acinar cells. The effects on intracellular [Ca²⁺]i, and cell viability were examined. Then, the antagonistic effects of different concentrations of PDTC and Tet were assessed.
Results:  The irritation with AP serum and ascitic fluid reduced the survival rate of the isolated rat pancreatic acinar cells and increased the cellular [Ca²⁺]i significantly ( P  < 0.05). As AP induction course prolonged, the stimulation effect of the AP serum and ascitic fluid intensified. In the pretreated acinar cells with PDTC or Tet, the decreased cell vitality reverted. The elevation of [Ca²⁺]i in the acinar cells significantly ameliorated (significant, P  < 0.05; very significant, P  < 0.01).
Conclusion:  The serum and ascitic fluid from AP rats drastically elevate the [Ca²⁺]i in isolated pancreatic acinar cells and decrease cell vitality, while the pretreatment of cells with PDTC and Tet offsets the calcium overload irritated by the AP serum and ascitic fluid and protects these isolated acinar cells.     

Effects of Chronic Ethanol on the Mobilization of Arachidonate and Docosahexaenoate Stimulated by the Type 2A Serotonin Receptor Agonist (±)-2,5-Dimethoxy-4-iodoamphetamine Hydrochloride in C6 Glioma Cells

We studied the effects of chronic ethanol exposure on the mobilization of polyunsaturated fatty acids stimulated by activation of the type 2A serotonin receptor in C6 glioma cells. In our in vitro model, we prelabeled cells with [³H]arachidonate and [¹⁴C]docosahexaenoate and subsequently stimulated with the type 2A serotonin receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride. In as early as 10 days of exposure to 20 or 50 mM ethanol, the (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride-stimulated mobilization of [³H]arachidonic acid ([³H]AA) and [¹⁴C]docosahexaenoic acid ([¹⁴C]DHA) was significantly inhibited, and this inhibition was accompanied by decreased mobilization of intracellular [Ca²⁺]_i. Exposure to ethanol did not alter significantly the release of [³H]AA and [¹⁴C]DHA stimulated by the calcium ionophore A23187 nor the incorporation of [³H]AA and [¹⁴C]DHA into cellular lipids. Decreased mobilization of polyunsaturated fatty acids and calcium in astroglia may contribute to neurotoxicity caused by chronic ethanol exposure.     

Potentiating Effect of Acetylcholine on Stimulation by Isoproterenol of L-Type Ca2+ Current and Arrhythmogenic Triggered Activity in Guinea Pig Ventricular Myocytes

ACh Facilitation of Triggered Activity. Introduction : The objective of this study was to determine whether the effect of isoproterenol (Iso) to increase L-type Ca²⁺ current [I_ca(L)] and action potential duration (APD) was potentiated in ventricular myocytes following termination of an exposure of these cells to acetylcholine (ACh), and whether this potentiating effect of Ach could he arrhythmogenic.
Methods and Results : Transmembrane currents and potentials of guinea pig Isolated ventricular myocytes were measured using the whole cell, patch clamp technique. Stimulation of I_ca(L) and prolongation of APD caused by Iso (10 nmol/L) were attenuated in the presence of Ach (10 μ mol/L), but were transiently enhanced by 111%± 20% and 214%± 44%, respectively, following termination of a 2- to 4-minute exposure of myocytes to ACh. No changes were observed in the absence of Iso. Both the amplitude and incidence of isoinduced transient inward current, afterdepolarizations, and sustained triggered activity were greater immediately after termination of exposure to ACh than before application of ACh.
Conclusion : Stimulation by Iso of I_ca(L) is transiently enhanced in guinea pig ventricular myocytes following termination of exposure of these cells to ACh. The rebound increase of Iso-stimulated I_ca(L) is associated with an increase of APD and induction of arrhythmogenic triggered activity.     

The L-type Ca2+ channel is involved in microvesicle-mediated glutamate exocytosis from rat pinealocytes

Abstract: Pinealocytes, parenchymal cells of the pineal gland, secrete glutamate through microvesicle-mediated exocytosis upon depolarization by KC1 in the presence of Ca²⁺, which is involved in a novel paracrine-like intercellular signal transduction mechanism in neuroendocrine organs. In the present study, we investigated whether or not the L-type Ca²⁺ channel is involved in the microvesicle-mediated glutamate secretion from cultured rat pinealocytes. Nifedipine, a specific antagonist of the L-type Ca²⁺ channel, inhibited the Ca²⁺-dependent glutamate exocytosis by 48% at 20 uM. Other L-type Ca²⁺ channel antagonists, such as nitrendipine, showed similar effects. 1,4-Dihydro-2,6-dimethyl-5-nitro-4[2-(trifluoromethyl)-phenyl]-3-pyridinecarboxylic acid methyl ester (BAY K8644), an agonist of the L-type Ca²⁺ channel, at 1 uM, on the other hand, stimulated the glutamate exocytosis about 1.6-fold. Consistently, these Ca²⁺ channel antagonists inhibited about 50% of the Ca²⁺ uptake, whereas BAY K8644 increased the uptake 5.3-fold. An antibody against the carboxyl-terminal region of the rabbit L-type Ca²⁺ channel recognized polypeptides of pinealocytes with apparent molecular masses of 250 and 270 kDa, respectively, and immunostained the plasma membrane region of the pinealocytes. These results strongly suggested that the entry of Ca²⁺ through L-type Ca²⁺ channel(s), at least in part, triggers microvesicle-mediated glutamate exocytosis in pinealocytes.     

Quantitative Reconstruction of Cardiac Electromechanics in Human Myocardium:

Introduction: Myocytes from normal and failing myocardium show significant differences in electromechanical behavior. Mathematical modeling of the behavior provides insights into the underlying physiologic and pathophysiologic mechanisms. Electromechanical models of cardiomyocytes exist for various species, but models of human myocytes are lacking.
Methods and Results: A mathematical model of electromechanics in normal and failing cardiac myocytes in humans was created by assembly and adaptation of parameters of an electrophysiologic model at the level of single cells and a force development model at the level of the sarcomere. The adaptation was performed using data from recent studies of ventricular myocytes and myocardium. The model was applied to quantitatively reconstruct measurement data from different experimental studies of normal and failing myocardium. Several simulations were performed to quantify the transmembrane voltage V_m , intracellular concentration of calcium[ Ca²⁺ ] _i , the [ Ca²⁺ ] _i –force relationship, and force transients. Furthermore, frequency dependencies and restitution of action voltage duration to 90% recovery APD₉₀, peak [ Ca²⁺ ] _i , duration to 50% force recovery FD₅₀, and peak force were determined.
Conclusion: The presented mathematical model was capable of quantitatively reconstructing data obtained from different studies of electrophysiology and force development in normal and failing myocardium of humans. In future work, the model can serve as a component for studying macroscopic mechanisms of excitation propagation, metabolism, and electromechanics in human myocardium. (J Cardiovasc Electrophysiol, Vol. 14, pp. S210-S218, October 2003, Suppl.)