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Biomedical subjects

D Noble

Publications and source records attributed to D Noble.

At least 19 recordsLinked to original sources
PubMed1999

Stretch-induced changes in heart rate and rhythm: clinical observations, experiments and mathematical models.

Clinical and research data indicate that active and passive changes in the mechanical environment of the heart are capable of influencing both the initiation and the spread of cardiac excitation via pathways that are intrinsic to the heart. This direction of the cross-talk between cardiac electrical and mechanical activity is referred to as mechano-electric feedback (MEF). MEF is thought to be involved in the adjustment of heart rate to changes in mechanical load and would help to explain the precise beat-to-beat regulation of cardiac performance as it occurs even in the recently transplanted (and, thus, denervated) heart. Furthermore, there is clinical evidence that MEF may be involved in mechanical initiation of arrhythmias and fibrillation, as well as in the re-setting of disturbed heart rhythm by 'mechanical' first aid procedures. This review will outline the clinical relevance of cardiac MEF, describe cellular correlates to the responses observed in situ, and discuss the role that quantitative mathematical models may play in identifying the involvement of cardiac MEF in the regulation of heart rate and rhythm.

Animals↗
PubMed1999

Biological simulations in drug discovery.

Simulation of biological processes, systems and organs is a necessary complement to genetic and molecular sequencing. Using the heart as an example, the authors describe the way in which such modelling can be used in drug discovery, development and assessment. The technology is readily applicable to other organs and systems as well; models of neurones and neuronal systems, the pancreas and the lungs have already been developed. Ultimately, a virtual corpus is feasible. Genes can only specify the properties of the proteins they code for, and any integrative properties of the system must be 'computed' by their interactions-Sydney Brenner

Journal Article↗
PubMed1999

Effect of isoprenaline, carbachol, and Cs+ on Na+ activity and pacemaker potential in rabbit SA node cells.

Effects of isoprenaline, carbachol, and Cs+ on intracellular Na+ activity (a(i)Na) and spontaneous action potentials were studied in multicellular and single cell preparations isolated from rabbit sinoatrial (SA) nodes. a(i)Na was measured with double-barreled Na+-selective microelectrodes and the fluorescent Na+-indicator sodium-binding benzofuran isophthalate (SBFI). In spontaneously beating cells, aiNa measured with Na+-selective microelectrodes and SBFI were 4.5 +/- 1.2 mM (means +/- SD, n = 21) in multicellular preparations and 4.0 +/- 1.1 mM (n = 16) in single cells, respectively. Measurements of a(i)Na with microelectrodes showed that isoprenaline increased a(i)Na from 4.7 +/- 1.2 to 5.5 +/- 1.6 mM (n = 16, P < 0.01) and shortened the action potential cycle length (ACL) from 338 +/- 46 to 269 +/- 35 ms (n = 16, P < 0.01). However, increasing the action potential rate by pacing produced a much smaller increase in a(i)Na. Changes in a(i)Na and ACL produced by isoprenaline were blocked by Cs+. The selective hyperpolarization-activated inward current (If) blocker ZD-7288 decreased a(i)Na from 5.2 +/- 1.0 to 4.6 +/- 1.3 mM (n = 4, P < 0.01) and prolonged ACL from 394 +/- 20 to 553 +/- 68 ms (n = 4, P < 0.01). The If blocker substantially inhibited the increase in a(i)Na produced by isoprenaline. Carbachol and Cs+ decreased aiNa from 4.6 +/- 1.4 to 3.9 +/- 1.2 mM (n = 15, P < 0.01) and from 4.9 +/- 1.0 to 3.9 +/- 1.3 mM (n = 18, P < 0.01), respectively. In addition, carbachol and Cs+ prolonged ACL from 345 +/- 44 to 587 +/- 100 ms (n = 15, P < 0.01) and from 353 +/- 30 to 464 +/- 87 ms (n = 18, P < 0.01), respectively. However, carbachol and Cs+ almost did not change a(i)Na when SA node cells became quiescent in a 25.4 mM extracellular K+ concentration. The results suggest that isoprenaline, ZD-7288, carbachol, or Cs+ might have changed a(i)Na and action potential rate by possibly stimulating or inhibiting If carried by Na+. Measurements of a(i)Na with SBFI showed that isoprenaline, carbachol, and Cs+ produced a(i)Na changes that were similar to those measured with the microelectrodes.

Action Potentials↗
PubMed1998

Reduction and integration in understanding the heart.

The heart provides an excellent example of the limits of the reductive approach. Cardiac cells function through the interaction of a very large number of ion transporters, and the processes that link these to metabolic states and to contraction. Yet, the great majority of the advances made recently have been at the cellular and molecular levels. The pressing problem now is to begin to understand the highly complex interactions that create physiological function at a cellular level and, in turn, to understand the way in which large numbers of cells interact to produce the activity of the whole heart. Many kinds of arrhythmia, for example, can only be understood at the whole organ level. Successful interventions using drugs designed to treat cardiac disease depend on an integrative understanding, which at present we do not have. This is one of the reasons why clinical trials of drugs treating cardiac arrhythmias have been spectacularly disappointing. This paper illustrates some of these problems by analysing normal and abnormal heart rhythms, and by focusing on one particular transporter, the sodium-calcium exchanger, that is deeply involved both in normal calcium balance in the heart and in the generation of pathological states, including life-threatening arrhythmias. It will be shown that some surprising counterintuitive results appear when computations are done at an integrative level.

Animals↗
PubMed1998

Modelling myocardial ischaemia and reperfusion.

Substrate depletion and increased intracellular acidity are believed to underlie clinically important manifestations of myocardial ischaemia. Recent advances in measuring ion concentrations and metabolite changes have provided a wealth of detail on the processes involved. Coupled with the rapid increase in computing power, this has allowed the development of a mathematical model of cardiac metabolism in normal and ischaemic conditions. Pre-existing models of cardiac cells such as Oxsoft HEART contain highly developed dynamic descriptions of cardiac electrical activity. While biophysically detailed, these models do not yet incorporate biochemical changes. Modelling of bioenergetic changes was based and verified against whole heart NMR spectroscopy. In the model, ATP hydrolysis and generation are calculated simultaneously as a function of [Pi]i. Simulation of pH regulation was based on the pHi dependency of acid efflux, examined in time-course studies of pHi recovery (measured in myocytes with the fluorophore carboxy-SNARF-1) from imposed acid and alkali loads. The force-[Ca2+]i relationship of myofibrils was used as the basis of modelling H+ competition with Ca2+, and thus of pH effects on contraction. This complex description of biochemically important changes in myocardial ischaemia was integrated into the OXSOFT models. The model is sufficiently complete to simulate calcium-overload arrhythmias during ischaemia and reperfusion-induced arrhythmias. The timecourse of both metabolite and pH changes correlates well with clinical and experimental studies. The model possesses predictive power, as it aided the identification of electrophysiological effects of therapeutic interventions such as Na(+)-H+ block. It also suggests a strategy for the control of cardiac arrhythmias during calcium overload by regulating sodium-calcium exchange. In summary, we have developed a biochemically and biophysically detailed model that provides a novel approach to studying myocardial ischaemia and reperfusion.

Adenine Nucleotides↗
PubMed1998

Isolation of translactone-containing triterpenes with thrombin inhibitory activities from the leaves of Lantana camara.

Methanolic extracts prepared from the leaves of Lantana camara have been found to inhibit human thrombin. An assay, in which thrombin activity is measured as a function of clot formation from fibrinogen, was used to guide the fractionation and purification of five principal active constituents (1-5), which were all characterized as 5,5-trans-fused cyclic lactone-containing euphane triterpenes.

Carbohydrate Sequence↗
PubMed1998

The effects of sodium substitution on currents determining the resting potential in guinea-pig ventricular cells.

It has recently been shown that a sodium background current, ib,Na, exists in cardiac muscle cells whose effect is to depolarize the membrane so that the resting potential, Vm, is positive to the potassium equilibrium potential, EK. In ventricular cells, where ib,Na is smallest, Vm is about 10 mV positive to EK (EK = -87 mV at 37 degrees C). Yet, replacement of Na+ ions by large impermeant cations does not cause the expected hyperpolarization. We have studied this problem in guinea-pig myocytes using a single microelectrode recording technique in combination with a rapid external solution switch. Cells depolarized < or = 0.5 mV from potentials between -80 and -73 mV and hyperpolarized up to 5 mV from potentials between -73 and -64 mV when 70 mM choline chloride or N-methyl-D-glucamine chloride were used to replace 70 mM Na+ in the bathing solution. Replacement by 70 mM lithium chloride, however, only caused hyperpolarization in very depolarized cells when the voltage change was much smaller. The changes were complete almost as soon as the solution change, i.e. within 250 ms, indicating that the actions are attributable to the external solution change rather than to secondary changes in intracellular concentrations. Patch clamp recording was used to investigate the mechanism involved. These experiments showed that the presence or absence of the inward rectifier current iK1 determines in which direction Na+ removal acts. In the absence of iK1 the changes are attributable to removal of ib,Na, whereas in the presence of iK1 the changes resemble the i(V) relation for iK1, implying that Na+ regulates iK1 in a way that can mask the changes in ib,Na. These results explain why removal of Na+ does not lead to hyperpolarization in ventricular cells as would be expected if changes in ib,Na were solely responsible. Computer reconstruction shows that the effects may be attributed to actions of sodium removal on the conductance and gating of iK1.

Animals↗
PubMed1998

Modelling of sodium-overload arrhythmias and their suppression.

Models of the electrophysiological properties of cardiac cells are now capable of accounting not only for normal activity, but also for some of the mechanisms of arrhythmia. A good example is the reconstruction of the inotropic and arrhythmogenic effects of sodium pump inhibition leading to the generation of ectopic beats. The models can also be used to investigate the possible mechanisms of suppression of arrhythmias. The authors show how the antiarrhythmic actions of lidocaine may be reproduced. The results account for the large difference between therapeutic levels (approximately 30 microM) in whole tissue and the concentration (approximately 500 microM) required to suppress excitation in isolated cells.

Animals↗
PubMed1998

Cellular mechanisms of cardiac mechano-electric feedback in a mathematical model.

BACKGROUND: Cardiac mechanical and electrical activity are closely interrelated. While excitation-contraction coupling is rather well characterized, less is known about cellular mechanisms that promote mechanically induced changes in cardiac electrical activity--mechano-electric feedback. OBJECTIVE: To integrate experimental findings on stretch activation of ion channels and length-dependent changes in intracellular calcium handling into a mathematical description of cardiac cellular activity. METHODS: Simulations are based on the cellular OXSOFT HEART v4.8 models of electrical activity of single cardiac cells of different populations and species. Sarcolemmal stretch-activated channels, mechanically induced changes in the affinity of troponin C to calcium, and length-dependent modulation of calcium handling by the sarcoplasmic reticulum were introduced into the models and linked to a description of sarcomere length or isometric tension. RESULTS: Transient or sustained stretch of cardiomyocytes was simulated during electrical systole and diastole. The electrophysiological response observed in the model depended on timing and severity of mechanical stimulation and on the main subcellular target of the intervention. Responses ranged from triggering of premature action potentials, over changes in action potential shape and duration, to length-dependent variations in contractile behaviour. Modelling findings could be related to experimental observations and may help to explain some of the contradictory data in the literature. The model is sufficiently complete to reproduce experimental findings and to help identify causally linked events.

Animals↗
PubMed1998

Improved guinea-pig ventricular cell model incorporating a diadic space, IKr and IKs, and length- and tension-dependent processes.

The guinea-pig ventricular cell model, originally developed by Noble et al in 1991, has been greatly extended to include accumulation and depletion of calcium in a diadic space between the sarcolemma and the sarcoplasmic reticulum where, according to contempory understanding, the majority of calcium-induced calcium release is triggered. The calcium in this space is also assumed to play the major role in calcium-induced inactivation of the calcium current. Delayed potassium current equations have been developed to include the rapid (IKr) and slow (IKs) components of the delayed rectifier current based on the data of of Heath and Terrar, along with data from Sanguinetti and Jurkiewicz. Length- and tension-dependent changes in mechanical and electrophysiological processes have been incorporated as described recently by Kohl et al. Drug receptor interactions have started to be developed, using the sodium channel as the first target. The new model has been tested against experimental data on action potential clamp, and on force-interval and duration-interval relations; it has been found to reliably reproduce experimental observations.

Animals↗
PubMed1998

Anaesthetic management of the morbidly obese patient.

Morbidly obese patients are prone to many clinical conditions that can effect anaesthesia. Of major concern to the anaesthetist are difficulties with airway management and abnormalities of cardiorespiratory function. Safe anaesthesia requires an appreciation of potential problems and a thorough understanding of the pathophysiological changes that accompany morbid obesity.

Anesthesia↗
PubMed1997

Modeling of internal pH, ion concentration, and bioenergetic changes during myocardial ischemia.

Arrhythmias are caused by the interdependent processes of change in energy metabolism and alterations in sarcolemmal ion gradients that occur during ischemia. Depletion of energy metabolites and increased proton concentrations in ischemic heart may underlie the observed phenomena of reduced contractile force and also of malignant ventricular arrhythmias that can lead to tachycardia and ventricular fibrillation. Recent advances in measuring changes in ion concentrations and metabolites during cardiac ischemia have provided a wealth of detail on the processes involved. Some of the experimental data have been used to construct a computer model that integrates cardiac energetics with electrophysiological changes. This is a novel approach to studying myocardial ischemia, and the resulting model would aid in the prediction of the effects of therapeutic interventions.

Adenine Nucleotides↗
PubMed1997

An efficient process for production of N-acetylneuraminic acid using N-acetylneuraminic acid aldolase.

N-acetyl-D-neuraminic acid (Neu5Ac) aldolase (EC 4.1.3.3) has bee reported for synthesis of Neu5Ac,1-5 but there are no reports of processes which do not have significant drawbacks for large-scale operation. Here, Neu5Ac aldolase from an overexpressing recombinant strain of Escherichia coli has been used to develop an immobilized enzyme process for production of Neu5Ac. The enzyme was immobilized onto Eupergit-C and could be reused many times in the reaction. Base-catalyzed epimerization of N-acetyl-D-glucosamine (GlcNAc) yielded GlcNAc/N-acetyl-D-mannosamine (ManNAc) mixtures (c 4:1) which could be used directly in the aldolase reaction; however, inhibition of the enzyme by GlcNAc limited the concentration of ManNAc which could be used in the reaction by this approach. This necessitated the addition of a large molar excess of pyruvate (five- to seven-fold) to drive the equilibrium over to Neu5Ac; nevertheless, a method has been developed to remove the excess pyruvate effectively by complexation with bisulfite, thus allowing Neu5Ac to be recovered by absorption onto an anion-exchange resin. In a second approach, a method has been developed to enrich GlcNAc/ManNAc mixtures for ManNAc. ManNAc can be used at high concentrations in the reaction, thus obviating the need to use a large molar excess of pyruvate. Neu5Ac can be isolated from such reaction mixtures by a simple crystallization. This work shows the importance of integrated process solutions for the effective scale-up of biotransformation reactions.

1-Propanol↗
PubMed1996

Voltage- and time-dependent block of delayed rectifier K+ current in rabbit sino-atrial node cells by external Ca2+ and Mg2+.

1. The properties of the delayed rectifier K+ current (IK) of rabbit isolated sino-atrial node cells were investigated in high (140 mM) [K+]o using the whole-cell-clamp technique. 2. Hyperpolarizing clamp pulses from 0 mV induced an instantaneous current jump (I-V relation linear) followed by a time-dependent increase in inward current to a peak, whereas depolarizing clamp pulses induced little outward current. The peak I-V relation showed a strong inward rectification. The inwardly rectifying current was blocked by E-4031. 3. The inward K+ current induced by hyperpolarizing clamp pulses from 0 mV relaxed after reaching its peak. The rate of the relaxation increased as the membrane potential became more negative and concentrations of external Ca2+ or Mg2+ were increased. The steady-state current was smaller as the relaxation of the current accelerated on increasing [Ca2+]o or [Mg2+]o. 4. Depolarizing clamp pulses from -80 mV induced an increase in inward current, reaching a steady state. The amplitude of the steady-state current became smaller and the rate of current increase became slower as [Ca2+]o or [Mg2+]o was increased. 5. The effects of Ca2+ and Mg2+ are well explained by a time- and voltage-dependent blockade of the K+ channel by these ions. The fractional electrical distance of the binding site calculated from the voltage dependence of the blocking rate constant is 0.69 for Ca2+ and 0.88 for Mg2+. The blocking rate constant at 0 mV for Ca2+ is about 15 times faster than that for Mg2+, indicating stronger effects of Ca2+. 6. A re-interpretation of IK in sino-atrial node cells is proposed: there are two independent gates (an activation gate which opens on hyperpolarization and an inactivation gate which closes on hyperpolarization) and a binding site for Ca2+ and Mg2+ inside the channel. Binding of these ions, which is facilitated by hyperpolarization, causes channel blockade, resulting in the observed voltage dependence of IK in physiological concentrations of Ca2+ and Mg2+.

Animals↗
PubMed1996

Induction of phenazine biosynthesis in cultures of Pseudomonas aeruginosa by L-N-(3-oxohexanoyl)homoserine lactone.

A range of Pseudomonas spp. and other Gram-negative bacteria were screened for induction of antimicrobial activity in response to the autoregulatory factor L-N-(3-oxohexanoyl)homoserine lactone. In one of these, P. aeruginosa ATCC 10145, the production of phenazine metabolites was shown to be inducible in a dose-dependent manner. The production of phenazine-1-carboxamide increased over 50-fold compared to control cultures when supplemented with 200 micrograms/ml of the autoregulator. In addition, the production of an unidentified polar antibacterial substance by this strain increased with autoregulator concentration.

4-Butyrolactone↗