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J N Weiss

Publications and source records attributed to J N Weiss.

At least 55 records · Page 3Linked to original sources
PubMed1999

Cardiac electrical restitution properties and stability of reentrant spiral waves: a simulation study.

Spiral wave breakup is a proposed mechanism underlying the transition from ventricular tachycardia to fibrillation. We examined the importance of the restitution of action potential duration (APD) and of conduction velocity (CV) to the stability of spiral wave reentry in a two-dimensional sheet of simulated cardiac tissue. The Luo-Rudy ventricular action potential model was modified to eliminate its restitution properties, which are caused by deactivation or recovery from inactivation of K+, Ca2+, and Na+ currents (IK, ICa, and INa, respectively). In this model, we find that 1) restitution of ICa and INa are the main determinants of the steepness of APD restitution; 2) for promoting spiral breakup, the range of diastolic intervals over which the APD restitution slope is steep is more important than the maximum steepness; 3) CV restitution promotes spiral wave breakup independently of APD restitution; and 4) "defibrillation" of multiple spiral wave reentry is most effectively achieved by combining an antifibrillatory intervention based on altering restitution with an antitachycardia intervention. These findings suggest a novel paradigm for developing effective antiarrhythmic drugs.

Action Potentials↗
PubMed1999

Induction of monocyte binding to endothelial cells by MM-LDL: role of lipoxygenase metabolites.

Treatment of human aortic endothelial cells (EC) with minimally oxidized LDL (or minimally modified LDL, MM-LDL) produces a specific pattern of endothelial cell activation distinct from that produced by LPS, tumor necrosis factor-alpha, and interleukin-1, but similar to other agents that elevate cAMP. The current studies focus on the signal transduction pathways by which MM-LDL activates EC to bind monocytes. We now demonstrate that, in addition to an elevation of cAMP, lipoxygenase products are necessary for the MM-LDL response. Treatment of EC with inhibitors of the lipoxygenase pathway, 5,8,11, 14-eicosatetraynoic acid (ETYA) or cinnamyl-3, 4-dihydroxy-alpha-cyanocinnamate (CDC), blocked monocyte binding in MM-LDL-treated EC (MM-LDL=118+/-13%; MM-LDL+ETYA=33+/-4%; MM-LDL+CDC=23+/-4% increase in monocyte binding) without reducing cAMP levels. To further investigate the role of the lipoxygenase pathway, cellular phospholipids were labeled with arachidonic acid. Treatment of cells for 4 hours with 50 to 100 microg/mL MM-LDL, but not native LDL, caused a 60% increase in arachidonate release into the medium and increased the intracellular formation of 12(S)-HETE (approximately 100% increase). There was little 15(S)-HETE present, and no increase in its levels was observed. We demonstrated that 12(S)-HETE reversed the inhibitory effect of CDC. We also observed a 70% increase in the formation of 11,12-epoxyeicosatrienoic acid (11, 12-EET) in cells treated with MM-LDL. To determine the mechanism of arachidonate release induced by MM-LDL, we examined the effects of MM-LDL on intracellular calcium levels. Treatment of EC with both native LDL and MM-LDL caused a rapid release of intracellular calcium from internal stores. However, several pieces of evidence suggest that calcium release alone does not explain the increased arachidonate release in MM-LDL-treated cells. The present studies suggest that products of 12-lipoxygenase play an important role in MM-LDL action on the induction of monocyte binding to EC.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1998

Role of pectinate muscle bundles in the generation and maintenance of intra-atrial reentry: potential implications for the mechanism of conversion between atrial fibrillation and atrial flutter.

To determine the role of pectinate muscle (PM) bundles in the formation of intra-atrial reentry, 10 isolated canine right atrial tissues were perfused with Tyrode's solution containing 1 to 2.5 micromol/L acetylcholine (ACh). The endocardium was mapped using 477 bipolar electrodes with 1.6-mm resolution. Reentry was induced by a premature stimulus (S2). Computer simulation studies were used to investigate the importance of regional myocardial thickness in reentry formation. A total of 40 episodes of reentry were induced; 28 episodes were stationary, and the remaining 12 were nonstationary. The stationary reentry was induced either immediately after the S2 stimuli (n=9) or after an initial period of irregular activations that lasted 1460+/-1077 ms (n= 19). Of 28 episodes, 20 were initiated by conduction block along large PM ridges, leading to wave break and the initiation of reentry. The reentrant wave fronts remained stationary and rotated around these ridges as anchoring sites. During the transition from the initial irregular activations to stationary reentry, the electrogram morphology converted from "fibrillation-like" to "flutter-like" activity. In 8 episodes, initially stationary reentry converted to irregular activations because of interference with outside wave fronts (n=5) or spontaneous separation of waves from the ridges (n=3). Compared with stationary reentry, nonstationary reentry always occurred over an area without large PMs, and the mean life span was much shorter (102+/-151 versus 3.8+/-1.1 rotations, P<0.001). Computer simulation studies showed that a critical ridge thickness is needed for reentry to anchor, thereby converting fibrillation to flutter. We conclude that PM ridge forms an area where wave break occurs, allowing the initiation of reentry. It also provides a natural anchor to the reentrant wave front, lengthening the life span of reentry. The attachment and detachment of the reentrant wave front to and from the ridge determine "flutter-like" or "fibrillation-like" activity.

Animals↗
PubMed1998

The sulphonylurea receptor SUR1 regulates ATP-sensitive mouse Kir6.2 K+ channels linked to the green fluorescent protein in human embryonic kidney cells (HEK 293).

1. Using a chimeric protein comprising the green fluorescent protein (GFP) linked to the C-terminus of the K+ channel protein mouse Kir6.2 (Kir6.2-C-GFP), the interactions between the sulphonylurea receptor SUR1 and Kir6.2 were investigated in transfected human embryonic kidney cells (HEK 293) by combined imaging and patch clamp techniques. 2. HEK 293 cells transfected with mouse Kir6.2-C-GFP and wild-type Kir6.2 exhibited functional K+ channels independently of SUR1. These channels were inhibited by ATP (IC50 = 150 microM), but were not responsive to stimulation by ADP or inhibition by sulphonylureas. Typically 15 +/- 7 active channels were found in an excised patch. 3. The distribution of Kir6.2-C-GFP protein was investigated by imaging of GFP fluorescence. There was a lamellar pattern of fluorescence labelling inside the cytoplasm (presumably associated with the endoplasmic reticulum and the Golgi apparatus) and intense punctate labelling near the cell membrane, but little fluorescence was associated with the plasma membrane. 4. In contrast, cells co-transfected with Kir6.2-C-GFP and SUR1 exhibited intense uniform plasma membrane labelling, and the lamellar and punctate labelling seen without SUR1 was no longer prominent. 5. In cells co-transfected with Kir6.2-C-GFP and SUR1, strong membrane labelling was associated with very high channel activity, with 484 +/- 311 active channels per excised patch. These K+ channels were sensitive to inhibition by ATP (IC50 = 17 microM), stimulated by ADP and inhibited by sulphonylureas. 6. We conclude that co-expression of SUR1 and Kir6.2 generates channels with the properties of native KATP channels. In addition, SUR1 promotes uniform insertion of Kir6.2-C-GFP into the plasma membrane and a 35-fold increase in channel activity, suggesting that SUR1 facilitates protein trafficking of Kir6.2 into the plasma membrane.

Adenosine Triphosphate↗
PubMed1998

Mechanosensitivity of the cardiac muscarinic potassium channel. A novel property conferred by Kir3.4 subunit.

Muscarinic potassium channels are heterotetramers of Kir3.1 and other Kir3 channel subunits and play major roles in regulating membrane excitability in cardiac atrial, neuronal, and neuroendocrine tissues. We report here that rabbit atrial muscarinic potassium channels are rapidly and reversibly inhibited by membrane stretch, possibly serving as a mechanoelectrical feedback pathway. To probe the molecular basis for this phenomenon, we heterologously expressed heteromeric Kir3.1/Kir3.4 channels in Xenopus oocytes and found that they possess similar mechanosensitivity in response to hypo-osmolar stress. This could be attributed in part, if not exclusively, to the Kir3.4 subunit, which reproduced the mechanosensitivity of the heteromeric channel when expressed as a homomeric channel in oocytes. Kir3.4 is the first stretch-inactivated potassium channel to be identified molecularly. Physiologically, this feature may be important in atrial volume-sensing and other responses to stretch.

Animals↗
PubMed1998

Topology of a functionally important region of the cardiac Na+/Ca2+ exchanger.

The cardiac Na+/Ca2+ exchanger, NCX1, has been modeled to consist of 11 transmembrane segments and a large cytoplasmic loop (loop f). Cysteine mutagenesis and sulfhydryl modification experiments demonstrate that the loop connecting transmembrane segments 1 and 2 (loop b) is located on the cytoplasmic side of the membrane, as previously modeled. A mutation in loop b, asparagine 101 to cysteine (N101C), renders the exchanger insensitive to regulation by cytoplasmic Na+ and Ca2+. Nearby mutations at residue threonine 103 (T103C or T103V) increase the apparent affinity of the exchanger for cytoplasmic Na+ and also produce a significant Li+ transport capacity. The evidence suggests that the region at the interface of cytoplasmic loop b and transmembrane segment 2 is important in Na+ transport and also in secondary regulation. Thus, this region may form part of the link between the ion translocation pathway formed by the transmembrane segments and regulatory sites that have previously been localized to loop f.

Animals↗
PubMed1998

Treatment of central retinal vein occlusion by injection of tissue plasminogen activator into a retinal vein.

PURPOSE: To report the injection of tissue plasminogen activator into a retinal vein to treat central retinal vein occlusion. METHODS: An 81-year-old woman with visual loss of the right eye secondary to central retinal vein occlusion developed central retinal vein occlusion and visual loss in her left eye. Treatment of her left eye with topical ocular hypotensive medications, pentoxifylline, and laser chorioretinal anastomosis was without benefit. Thereafter, she underwent vitreoretinal surgery, including tissue plasminogen activator injection into a branch retinal vein of her left eye. RESULTS: The patient reported subjective improvement in the vision of her left eye. Ophthalmoscopic and fluorescein angiographic improvement were also noted. CONCLUSION: The feasibility of cannulating a retinal vein for treatment has been demonstrated.

Aged↗
PubMed1998

Surfing-related ocular injuries.

PURPOSE: This report evaluates the clinical characteristics of surfing-related ocular trauma to learn the nature of such injuries and propose possible preventive measures. METHODS: The authors reviewed 11 cases of surfing-related eye injuries caused by direct trauma from the surfboard, studying their mechanism of injury, the associated ocular complications, and the anatomic and visual outcomes of surgical repair. RESULTS: Surfing-related ocular injuries occurred exclusively in young males (mean age, 24.8 years; range, 14-37 years). The mechanism of injury most frequently responsible was impact with the sharp nose of the surfboard following a fall. Serious posterior segment complications were observed in all 11 patients, with nine patients suffering ruptured globes. Despite immediate medical attention, five patients did not recover ambulatory levels of visual acuity (>5/200). CONCLUSIONS: Surfing-related ocular trauma presenting to the retinal specialist typically leaves the patient with a permanent visual disability. Important factors contributing to these high-velocity injuries include the sharply pointed nose of the surfboard and the leash keeping the surfer in close proximity to the board following a fall. A simple modification in surfboard design such as blunting the sharp nose of the surfboard, or appropriate protective guards fitted over the surfboard nose, should lessen the severity of such injuries.

Adolescent↗
PubMed1998

Localization and functional effects of adenosine A1 receptors on cardiac vagal afferents in adult rats.

There is evidence to suggest that during ischemia adenosine acts on cardiac vagal afferent neurons to activate systemic reflexes and to modulate cardiac nociception. The purpose of this study was to determine whether adenosine receptors are present and have direct cellular electrophysiological actions on cardiac vagal afferent neurons. In radioreceptor assays of nodose ganglion tissue from rats, binding was detectable for A1 (39.6 +/- 1.2 fmol/mg protein) but not A2a adenosine receptors. These findings were confirmed using the complementary approach of receptor-labeling autoradiography. Using in situ hybridization, we saw specific labeling over approximately 50% of neurons in the nodose ganglia, but not over nonneuronal cells. In colabeling studies, cardiac vagal afferent neurons were identified by retroneuronal labeling with fluororuby. Of cardiac vagal afferents approximately one-half were strongly positive for A1 adenosine receptors (immunocytochemistry). In patch-clamping experiments, adenosine inhibited peak inward calcium current in 7 of 11 cells by 48 +/- 13%. In conclusion, adenosine A1 receptors reside on a subset of vagal afferent neurons, including cardiac vagal afferents, and have electrophysiological effects that modulate neuroexcitability in cultured nodose ganglion neurons.

Afferent Pathways↗
PubMed1997

Spatiotemporal complexity of ventricular fibrillation revealed by tissue mass reduction in isolated swine right ventricle. Further evidence for the quasiperiodic route to chaos hypothesis.

We have presented evidence that ventricular fibrillation is deterministic chaos arising from quasiperiodicity. The purpose of this study was to determine whether the transition from chaos (ventricular fibrillation, VF) to periodicity (ventricular tachycardia) through quasiperiodicity could be produced by the progressive reduction of tissue mass. In isolated and perfused swine right ventricular free wall, recording of single cell transmembrane potentials and simultaneous mapping (477 bipolar electrodes, 1.6 mm resolution) were performed. The tissue mass was then progressively reduced by sequential cutting. All isolated tissues fibrillated spontaneously. The critical mass to sustain VF was 19.9 +/- 4.2 g. As tissue mass was decreased, the number of wave fronts decreased, the life-span of reentrant wave fronts increased, and the cycle length, the diastolic interval, and the duration of action potential lengthened. There was a parallel decrease in the dynamical complexity of VF as measured by Kolmogorov entropy and Poincaré plots. A period of quasiperiodicity became more evident before the conversion from VF (chaos) to a more regular arrhythmia (periodicity). In conclusion, a decrease in the number of wave fronts in ventricular fibrillation by tissue mass reduction causes a transition from chaotic to periodic dynamics via the quasiperiodic route.

Action Potentials↗
PubMed1997

Mechanism of hypoxic K loss in rabbit ventricle.

Although a critical factor causing lethal ischemic ventricular arrhythmias, net cellular K loss during myocardial ischemia and hypoxia is poorly understood. We investigated whether selective activation of ATP-sensitive K (KATP) channels causes net cellular K loss by examining the effects of the KATP channel agonist cromakalim on unidirectional K efflux, total tissue K content, and action potential duration (APD) in isolated arterially perfused rabbit interventricular septa. Despite increasing unidirectional K efflux and shortening APD to a comparable degree as hypoxia, cromakalim failed to induce net tissue K loss, ruling out activation of KATP channels as the primary cause of hypoxic K loss. Next, we evaluated a novel hypothesis about the mechanism of hypoxic K loss, namely that net K loss is a passive reflection of intracellular Na gain during hypoxia or ischemia. When the major pathways promoting Na influx were inhibited, net K loss during hypoxia was almost completely eliminated. These findings show that altered Na fluxes are the primary cause of net K loss during hypoxia, and presumably also in ischemia. Given its previously defined role during hypoxia and ischemia in promoting intracellular Ca overload and reperfusion injury, this newly defined role of intracellular Na accumulation as a primary cause of cellular K loss identifies it as a central pathogenetic factor in these settings.

Action Potentials↗
PubMed1997

Importance of location and timing of electrical stimuli in terminating sustained functional reentry in isolated swine ventricular tissues: evidence in support of a small reentrant circuit.

BACKGROUND: In excitable chemical media, a spiral wave is formed by reentrant excitation around a core and normal propagation away from the core. Whether or not this applies to cardiac muscle is unknown. METHODS AND RESULTS: In six isolated swine ventricular slices, we induced sustained episodes of functional reentry with a stationary core. A train of stimuli applied away from the core (7- to 8-mm distance) and near the core (within 1.6 mm) terminated 5 of 24 and 14 of 17 episodes of reentry, respectively (P<.001). When the stimulus was applied away from the core, successful terminations occurred when the line connecting the stimulus and the core was along the myocardial fiber orientation and when the coupling interval was 54+/-11% of the reentrant cycle length. Stimulation near the core terminated reentry primarily by propagation of the stimulus-induced wave fronts that closed up the excitable gap. However, in two episodes, the application of a stimulus near the core changed the electrogram morphology in only four bipolar pairs. This was sufficient to cause abrupt termination of reentry. CONCLUSIONS: (1) A thin layer of activation near the core is responsible for the maintenance of functional reentry. (2) Access to the tissue near the core is essential for the termination of functional reentry by a point stimulus. (3) To terminate reentry with a stimulus away from the core, the stimulus must occur at certain critical coupling intervals, and the line connecting the stimulus and the core must be roughly parallel to the fiber orientation.

Animals↗
PubMed1997

Quasiperiodicity and chaos in cardiac fibrillation.

In cardiac fibrillation, disorganized waves of electrical activity meander through the heart, and coherent contractile function is lost. We studied fibrillation in three stationary forms: in human chronic atrial fibrillation, in a stabilized form of canine ventricular fibrillation, and in fibrillation-like activity in thin sheets of canine and human ventricular tissue in vitro. We also created a computer model of fibrillation. In all four studies, evidence indicated that fibrillation arose through a quasiperiodic stage of period and amplitude modulation, thus exemplifying the "quasiperiodic transition to chaos" first suggested by Ruelle and Takens. This suggests that fibrillation is a form of spatio-temporal chaos, a finding that implies new therapeutic approaches.

Action Potentials↗
PubMed1997

Spirals, chaos, and new mechanisms of wave propagation.

The chaos theory is based on the idea that phenomena that appear disordered and random may actually be produced by relatively simple deterministic mechanisms. The disordered (aperiodic) activation that characterizes a chaotic motion is reached through one of a few well-defined paths that are characteristic of nonlinear dynamical systems. Our group has been studying VF using computerized mapping techniques. We found that in electrically induced VF, reentrant wavefronts (spiral waves) are present both in the initial tachysystolic stage (resembling VT) and the later tremulous incoordination stage (true VF). The electrophysiological characteristics associated with the transition from VT to VF is compatible with the quasiperiodic route to chaos as described in the Ruelle-Takens theorem. We propose that specific restitution of action potential duration (APD) and conduction velocity properties can cause a spiral wave (the primary oscillator) to develop additional oscillatory modes that lead to spiral meander and breakup. When spiral waves begin to meander and are modulated by other oscillatory processes, the periodic activity is replaced by unstable quasiperiodic oscillation, which then undergoes transition to chaos, signaling the onset of VF. We conclude that VF is a form of deterministic chaos. The development of VF is compatible with quasiperiodic transition to chaos. These results indicate that both the prediction and the control of fibrillation are possible based on the chaos theory and with the advent of chaos control algorithms.

Animals↗
PubMed1997

The Hill equation revisited: uses and misuses.

The Hill coefficient is commonly used to estimate the number of ligand molecules that are required to bind to a receptor to produce a functional effect. However, for a receptor with more than one ligand binding site, the Hill equation does not reflect a physically possible reaction scheme; only under the very specific condition of marked positive cooperativity does the Hill coefficient accurately estimate the number of binding sites. The Hill coefficient is best thought of as an "interaction" coefficient, reflecting the extent of cooperativity among multiple ligand binding sites. Several relatively simple, physically plausible reaction schemes are shown here to produce a variety of ligand dose-response curve phenotypes more appropriately suited to modeling ligand-receptor interactions, especially if independent information about the stochiometry of the ligand-receptor interaction is available.

Animals↗
PubMed1996

Inward rectification of the IRK1 channel expressed in Xenopus oocytes: effects of intracellular pH reveal an intrinsic gating mechanism.

1. The effects of intracellular pH (pHi) were investigated in inside-out giant patches from Xenopus oocytes expressing the inward rectifier K+ channel IRK1. 2. After excising patches into Mg2(+)- and polyamine-free solution, a residual time-dependent inactivation of outward current during depolarizing voltage-clamp pulses persisted, reaching an apparent steady-state by 5 min. Raising pHi from 7.2 to 9.0 increased the inactivation rate of the outward current. 3. In the presence of intracellular Mg2+ or polyamines, however, pHi 9.0 either decreased or did not change the inactivation rate of outward current. 4. These results suggest that the inactivation of outward current remaining after > 5 min in Mg2(+)- and polyamine-free solution is not due to slow washout of these substances, but represents a third and probably intrinsic gating mechanism contributing to the inward rectifying property of IRK1. 5. The voltage dependence and kinetics of this gating mechanism were well described by a sequential two open- and one closed-state model in which the rate constants for transitions between the open states were voltage dependent, and those between the open and closed state were pH dependent. 6. In the absence of intracellular Mg2+ and polyamines, reduced pHi blocked inward and outward current through IRK1 channels in a voltage-independent manner without appreciably altering the kinetics. Half-maximal block occurred at pH 6.2-6.4 (Hill coefficient, 1.6). Block of IRK1 by intracellular protons may contribute to membrane depolarization in ischaemic tissue.

Animals↗
PubMed1996

Endothelium-dependent vasodilators do not cause propagated intercellular Ca2+ waves in vascular endothelial monolayers.

Local application of a number of vasoactive agents affects vasomotor tone not only downstream to the point of application but also upstream. The mechanism(s) of upstream propagation is unknown. In endothelial cell monolayers, mechanical stimulation of one cell leads to intercellular propagation of increases in endothelial cell (EC) [Ca2+]i. In this study, we tested whether increases in EC [Ca2+]i induced by the local application of the endothelium-dependent vasodilators ATP, bradykinin and acetylcholine could spread across the monolayer. We demonstrate that unlike the response seen to a mechanical stimulus, there was no significant propagation of increases in EC [Ca2+]i levels in response to localized application of these agents. These findings suggest that upstream vasodilation in response to endothelium-dependent vasodilators is not mediated by propagation of EC [Ca2+]i waves and suggest that other electrical or chemical signals are responsible.

Acetylcholine↗