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D C Mikulecky

Publications and source records attributed to D C Mikulecky.

At least 37 records · Page 2Linked to original sources
PubMed1983

A network thermodynamic approach to the Hill-King and Altman approach to kinetics: computer simulation.

The network simulation of kinetic systems is a rather painless way to produce dynamic analogs of these models without becoming involved in needless mathematical difficulty. The methods of King and Altman, Hill, Mason, and others fall into a universal paradigm applicable in both the kinetic and thermodynamic coordinate systems. (It is a small extra step to turn the state concentrations into chemical potentials and affinities using diode subcircuits during any simulation. This will be spelled out in detail in future work. Thus the simulation can be carried out using the exact kinetic rate laws, but the results are readily put into a form which allows the energetics to be analyzed as well). Another virtue of network modeling and simulation is the hierarchical nature of the networks and its correspondence to that of the living system. It is now possible to simulate complicated multicellular epithelial membranes with channels and/or carriers in certain selected cell membranes. The only limitation to progress in this area is the lack of experimental information to feed into the models. On the other hand, the network models are rapidly becoming an indispensable aid in experimental design for precisely this reason. Living systems have always been characterized by their morphology to a great extent. There is no reason why that morphology can be ignored as their function is analyzed. In the past, it often had to be simplified due to the weakness of the analytical tools available. Now, by utilizing the same methods that have caused an explosion of progress in electronics, it is possible to hope to understand the structure-function relationship of living systems with equal facility. The challenge remaining is to develop experimental techniques which will keep up with the demand for information generated by the models.

Animals↗
PubMed1982

The simple model of adipocyte hexose transport. Kinetic features, effect of insulin, and network thermodynamic computer simulations.

Kinetic studies of the rat adipocyte hexose transport system were performed using the integrated rate approach and these compared to the simple carrier model of transport. Equilibrium exchange 3-O-methylglucose entry and exit studies showed directional symmetry with Km = overall dissociation constants = 8-10 mM. Comparison of zero-trans and equilibrium exchange entry also revealed similar Km and Vmax values. Insulin pretreatment increased the maximal rate of transport at 20 mM 3-O-methylglucose about 5- to 6-fold with each procedure. Studies of glucose-induced steady state 3-O-methylglucose countertransport provided evidence that carrier permeability and not carrier-substrate dissociation was rate limiting for overall transport. These data, therefore, indicate equal mobility of the loaded and unloaded carriers. Network thermodynamic computer simulations of the simple carrier model using kinetic parameters derived from zero-trans experiments provided good fits of actual data. The effect of insulin was best represented by an increase in total number of carrier units. It is concluded that the adipocyte hexose carrier displays bidirectional symmetry, limitation of transport by carrier movement rather than substrate-carrier interaction, equal rates of movement of loaded and unloaded carriers, and adherence to a simple carrier model in which insulin increases the total number of carrier units.

3-O-Methylglucose↗
PubMed1982

Dynamic simulation of pharmacokinetic systems using the electrical circuit analysis program SPICE2.

The electrical circuit simulation program SPICE2 is used to perform computer simulations of linear and non-linear pharmacokinetic systems. This is achieved by applying novel network thermodynamic principles which make use of the analogy between the conservation laws of chemical reactions and mass transport and Kirchoff's laws of current and voltage balance for electrical circuits. A simple description of program input for general pharmacokinetic simulation as well as simulation of complex pharmacokinetic and physiologic phenomena such as single and multiple divided daily dosing, Michaelis--Menten kinetics, gastric emptying cycle, drug resorption and linear and non-linear drug protein binding is provided. Drug concentrations or amounts in different compartments are graphically obtained or tabulated as time functions. The economy of time and effort afforded by this program is illustrated by simulating the metabolism and accumulation kinetics of salicylic acid on single and repeated divided dosing. The advantages of SPICE2 over other available simulation packages and its educational value as a teaching and research tool are discussed.

Computers↗
PubMed1981

A network thermodynamic model of glomerular dynamics: application in the rat.

A model of glomerular dynamics has been developed by using network thermodynamics and the SPICE 2 computer program to further explore the determinants of glomerular filtration. The model is designed to be holistic and self-adjusting, taking cognizance of and permitting quantitation of the secondary alterations in individual effective glomerular resistances, glomerular blood and plasma flow, capillary oncotic pressure and glomerular capillary pressure, which inevitably result when any parameter affecting glomerular dynamics changes. Such automatic adjustment adds to the precision of computation and is unique to the present model. Few assumptions are introduced, independent variables (arterial pressure, individual resistances, hydraulic conductivity, hematocrit, and serum protein concentration) being entered whereas values for the dependent variables are determined by the computer. In rats, filtration pressure equilibrium is seen not to obtain either under physiologic conditions or with reasonably large changes in any of the independent variables. Capillary pressure is shown to be affected by any maneuver that modulates single nephron GFR (SNGFR) and flow across the efferent arteriole (for example, tubule pressure, serum protein concentration) even when arteriolar caliber is held constant. The axial rise in colloid oncotic pressure and serum protein concentration along the capillary is found to be neither linear nor semilogarithmic, a characteristic that reflects on equations used to determine capillary hydraulic conductivity. Isolated change in afferent arteriolar resistance is shown by the model to produce a linear relationship between glomerular plasma flow and capillary pressure, and thus between the former parameter and filtration. Large solitary increases in efferent arteriolar resistance raise SNGFR and a 60% fall in resistance virtually abolishes filtration while exerting little change in blood flow. Concomitant and equal alterations of afferent and efferent arteriolar resistances cause filtration to rise linearly with blood flow but to produce minor change in glomerular capillary pressure, an example of true plasma flow dependence. Plasma flow dependence is, however, found to be unique to this particular circumstance under physiologic conditions. Adding an optional element that automatically adjusts effective efferent arteriolar resistance as a function of Hct2 has but modest effects on glomerular dynamics except when systemic hematocrit is substantially altered. The data and conclusions derived in this study are based on typical values for resistances, hydraulic conductivity, systemic protein concentration, hematocrit, and arterial and tubular pressures reported for normal hydropenic rats. They will not necessarily hold in other species in which these values may be distinctly different.

Animals↗
PubMed1979

Network thermodynamic approach compartmental analysis. Na+ transients in frog skin.

We introduce a general network thermodynamic method for compartmental analysis which uses a compartmental model of sodium flows through frog skin as an illustrative example (Huf and Howell, 1974a). We use network thermodynamics (Mikulecky et al., 1977b) to formulate the problem, and a circuit simulation program (ASTEC 2, SPICE2, or PCAP) for computation. In this way, the compartment concentrations and net fluxes between compartments are readily obtained for a set of experimental conditions involving a square-wave pulse of labeled sodium at the outer surface of the skin. Qualitative features of the influx at the outer surface correlate very well with those observed for the short circuit current under another similar set of conditions by Morel and LeBlanc (1975). In related work, the compartmental model is used as a basis for simulation of the short circuit current and sodium flows simultaneously using a two-port network (Mikulecky et al., 1977a, and Mikulecky et al., A network thermodynamic model for short circuit current transients in frog skin. Manuscript in preparation; Gary-Bobo et al., 1978). The network approach lends itself to computation of classic compartmental problems in a simple manner using circuit simulation programs (Chua and Lin, 1975), and it further extends the compartmental models to more complicated situations involving coupled flows and non-linearities such as concentration dependencies, chemical reaction kinetics, etc.

Animals↗
PubMed1979

A network thermodynamic two-port element to represent the coupled flow of salt and current. Improved alternative for the equivalent circuit.

A two-port for coupled salt and current flow is created by using the network thermodynamic approach in the same manner as that for coupled solute and volume flow (Mikulecky et al., 1977b; Mikulecky, 1977). This electrochemical two-port has distinct advantages over the equivalent circuit representation and overcomes difficulties pointed out by Finkelstein and Mauro (1963). The electrochemical two-port is used to produce a schematic diagram of the coupled flows through a tissue. The network is superimposable on the tissue morphology and preserves the physical qualities of the flows and forces in each part of an organized structure (e.g., an epithelium). The topological properties are manipulated independently from the constitutive (flow-force) relations. The constitutive relations are chosen from a number of alternatives depending on the detail and rigor desired. With the topology and constitutive parameters specified, the steady-state behavior is simulated with a network simulation program. By using capacitance to represent the filling and depletion of compartments, as well as the traditional electrical capacitances, time-dependent behavior is also simulated. Nonlinear effects arising from the integration of equations describing local behavior (e.g., the Nernst-Planck equations) are dealt with explicitly. The network thermodynamic approach provides a simple, straightforward method for representing a system diagrammatically and then simulating the system's behavior from the diagram with a minimum of mathematical manipulation.

Animals↗
PubMed1978

A network thermodynamic model of salt and water flow across the kidney proximal tubule.

This network thermodynamic model of kidney proximal tubule epithelium treats coupled salt and water flow across each component membrane of the epithelium. We investigate the effects of various relative internal parameter values on the concentration of transepithelial flow, the concentrations in the cell and interspace, and the distribution of flows between cellular and paracellular routes. Best fit is obtaine if the apical and basolateral membrane reflection coefficients (or) are equal. The measured transepithelial filtration coefficient, Lp, is a function not only of the component Lps but also of the internal concentrations, or's, and permeabilities. For the given system topology (i.e., connectedness), parameters of component membranes must be within a narrow range to be consistent with experimental results. The dependence of the concentration of transported fluid on the balance between the solute pump rate and the transepithelial volume flow driving force is shown. This has implications for the effects of peritubular or lumen oncotic pressure on salt and water flow. With Appendix B of this paper and a user's guide for a circuit-simulation package (e.g., SPICE or PCAP) the reader can perform similar network analyses of transport models himself.

Biological Transport↗
PubMed1973

Dilute solution approximation and generalization of the reflection coefficient method of describing volume and solute flows.

Kedem and Katchalsky introduced an approximation for dilute solutions which requires that the quantity (Deltapi/Deltapi(i))ø(i) be much less than one. Zelman attempted to generalize the reflection coefficient concept to apply to solutions of multiple solutes, both penetrable and impenetrable, of concentrations sufficiently high for the approximation not to work. By simple algebraic manipulation, Zelman introduced a pair of new reflection coefficients, and a third new parameter gamma which he misleadingly calls the "deviation from the dilute solution approximation." It is shown here that the original Kedem-Katchalsky form for the flow equations can be preserved in such a way that no new coefficients need be introduced and an explicit statement of the effect of the dilute solution approximation can be made. There is an option of using a new set of conjugate driving forces for the solute flows or, alternatively, incorporating the nondilute solution correction in the coefficients in a clear way.

Biological Transport↗