A model study of the regulation of gastric acid secretion.

A computer simulation model is presented of the gastric phase regulation of gastric acid secretion in humans. The model is based on experimental data from the literature and includes terms representing gastric pH and gastric volume-dependent gastrin secretion, gastrin-dependent acid secretion, food storage in the stomach, and gastric emptying. We have explored the predictive value of the model in assessing the relative importance of gastric pH-dependent and gastric volume-dependent acid secretion mechanisms under various conditions. Similarly we have studied the role of gastric acid deregulation in achlorhydria, the Zollinger-Ellison syndrome, and duodenal ulcer, and the influence of the antacid drugs cimetidine and ranitidine under duodenal ulcer conditions. Model analysis of normal gastric acid regulation suggests that gastric volume-controlled acid secretion is of major importance during eating and predicts that pH-dependent gastrin secretion is of major importance in preventing excessively low pH levels between meals and during the night.

Phagocytosis by human macrophages is accompanied by changes in ionic channel currents.

The present study has shown that changes in ionic channel currents accompany the phagocytosis of particles by mononuclear phagocytes. The patch-clamp technique in the cell-attached configuration was applied to human monocyte-derived macrophages to measure the activity of single transmembrane ionic channels in intact cells. During such measurements, IgG-opsonized and non-opsonized latex particles were offered for phagocytosis under continuous video-microscopical observation. Single particles were presented to the phagocytes at a membrane location some distance from that of the patch electrode. After a lag period following particle attachment, enhanced inward and outward time-variant single channel currents coinciding with particle engulfment were observed. On the basis of current-voltage characteristics and membrane potential measurements, the outward-directed channels were identified as K+ channels. Phagocytosis was also accompanied by slow transient changes in background membrane currents, probably due to changes in the membrane potential of the phagocytosing cell. Phagocytosis of IgG-coated latex particles differed from phagocytosis of uncoated or albumin-coated particles by a shorter lag time between particle attachment and the onset of enhanced ionic channel activity.

Force-interval relationship in heart muscle of mammals. A calcium compartment model.

A mathematical model was derived that describes peak force of contraction as a function of stimulus interval and stimulus number in terms of Ca2+ transport between three hypothetical Ca2+ compartments. It includes the conventional uptake and release compartments and recirculation of a fraction r of the activator Ca2+. Peak force is assumed to be proportional to the amount of activator Ca2+ released from the release compartment into the sarcoplasm. A new extension is a slow exchange of Ca2+ with the extracellular space via an exchange compartment. Six independent parameters were necessary to reproduce the different effects of postextrasystolic potentiation, frequency potentiation, and post-rest potentiation in isolated heart muscle from the rat. The normalized steady state peak force (F/Fmax) under standard conditions varied by a factor of ten between preparations from rat heart. Analysis with the model indicated that most of this variation was caused by two variables: the Ca2+ influx per excitation and the recirculating fraction of activator Ca2+. The influence of the Ca2+ antagonist nifedipine of the force-interval relationship was reproduced by the model. It is concluded that the model may serve to analyze the variability of contractile force and the mode of actions of drugs in heart muscle.

Intracellular microelectrode measurements in small cells evaluated with the patch clamp technique.

Microelectrode penetration of small cells leads to a sustained depolarization of the resting membrane potential due to a transmembrane shunt resistance (Rs) introduced by the microelectrode. This has led to underestimation of the resting membrane potential of various cell types. However, measurement of the fast potential transient occurring within the first few milliseconds after microelectrode penetration can provide information about pre-impalement membrane electrophysiological properties. We have analyzed an equivalent circuit of a microelectrode measurement to establish the conditions under which the peak of the impalement transients (Ep) approaches the pre-impalement resting membrane potential (Em) of small cells most closely. The simulation studies showed that this is the case when the capacitance of the microelectrode is low and the membrane capacitance of the cell high. In experiments performed to assess the reliability of Ep as a measure of Em, whole-cell patch clamp measurements were performed in the current clamp mode to monitor, free from the effects of Rs, Em in cultured human monocytes. Microelectrode impalement of such patch clamped cells and measurement of Ep made it possible to detect correlation between Ep and Em and showed that for small cells such as human monocytes Ep is on average 6 mV less negative than the resting membrane potential.

Estimation of the membrane potential of cultured macrophages from the fast potential transient upon microelectrode entry.

Analysis of membrane potential recordings upon microelectrode impalement of four types of macrophages (cell lines P388D1 and PU5-1.8, cultured mouse peritoneal macrophages, and cultured human monocytes) reveals that these cells have membrane potentials at least two times more negative than sustained potential values (E(s)) frequently reported. Upon microelectrode entry into the cell (P388D1), the recorded potential drops to a peak value (E(p)) (mean -37 mV for 50 cells, range -15 to -70 mV) within 2 ms, after which it decays to a depolarized potential (E(n)) (mean -12 mV) in about 20 ms. Thereafter, the membrane develops one or a series of slow hyperpolarizations before a final sustained membrane potential (E(s)) (mean -14 mV, range -5 to -40) is established. The mean value of the peak of the first hyperpolarization (E(h)) is -30 mV (range -10 to -55 mV). The initial fast peak transient, measured upon microelectrode entry, was first described and analyzed by Lassen et al. (Lassen, U.V., A.M. T. Nielson, L. Pape, and L. O. Simonsen, 1971, J. Membr. Biol. 6:269-288 for other change in the membrane potential from its real value before impalement to a sustained depolarized value. This was shown to be true for macrophages by two-electrode impalements of single cells. Values of E(p), E(n), E(h), E(s), and membrane resistance (R(m)) measured for the other macrophages were similar to those of P388D1. From these results we conclude that E(p) is a better estimate of the true membrane potential of macrophages than E(s), and that the slow hyperpolarizations upon impalement should be regarded as transient repolarizations back to the original membrane potentials. Thus, analysis of the initial fast impalement transient can be a valuable aid in the estimation of the membrane potential of various sorts of small isolated cells by microelectrodes.

Theory of diseases of steady-state proportional control systems.

In many diseases of a semi-stationary nature (chronical diseases) the level of the regulated variable of the diseased system either is too high (a hyper-state disease) or too low (a hypo-state disease). In this paper the steady-state behavior of proportional control systems is, hence, analysed with regard to a longterm pathological change of each single variable or parameter. Each pathological change has its own pattern of changes of the system variables, which also depends upon the system class (left- or right-regulating). Both the block diagram and the regulation characteristic, when used together, allow one to easily derive the pathological behaviour of the system in the steady-state.

Silent endocrine tumors. A steady-state analysis of the effects of changes in cell number for biological feedback systems.

Some tumors of hormonal organs are clinically active, while others are not. The "silent" tumors may be discovered by accident or because of effects due to their increase in size. From a simple steady state analysis of hormonal feedback systems follows that hormonal cell multiplication does not significantly influence the systems steady state behaviour (hence the clinical silence).--Exceptions to this rule occur in three situations: when the gain of the system is low; when the growth concerns cells with isolated sensor or reference functions; or because of the growth of autonomous cells. In many biological systems the dangerous situation of clamping to low levels upon sensor cell multiplication has been prevented by lumping, such as the combination of sensor and comparator functions into sensor-comparator cells.

Conductance fluctuations in Ranvier nodes.

Voltage fluctuations associated with the sodium system were measured upon elimination of the potassium current in the nodal membrane by internal application of cesium-ions. The intensity of this noise reaches a maximal value at a membrane potential in the vicinity of --40 mV. Here the power spectrum consists of two additive components: a 1/f component and a Lorentzian. The Lorentzian is associated with h-gate kinetics and is consistent with the binary state conduction model. On the basis of this model the sodium-channel conductance is calculated to be 2 to 5-10(-12) S. The analysis is complicated by the existence of an incomplete slow sodium inactivation process.

Fluctuations of resting neural membrane potential.

The menmbrane potential of myelinated axons in the resting state shows fluctuations for which the power per cycle of bandwidth is inversely proportional to frequency between I and 10,000 radians per second. Reduction of potassiulm ion flux leads to a decrease in noise power.