Modeling of diffusion with partitioning in stratum corneum using a finite element model.

Partitioning and diffusion of chemicals in skin is of interest to researchers in areas such as transdermal penetration and drug disposition, either for risk assessment or transdermal delivery. In this study a finite element method is used to model diffusion in the skin's outermost layer, the stratum corneum (SC). The SC is considered to be a finite two-dimensional composite having different diffusivity values in each medium as well as a partition coefficient at the interfaces between media. A commercial finite element package with thermal analysis capabilities is selected due to the flexibility of this software to handle irregular geometries. Partitioning is accommodated through a change of variables technique. This technique is validated by comparison of model results with analytical solutions of steady-state flux, transient concentration profiles, and time lag for diffusion in laminates. Two applications are presented. Diffusion is solved in a two-dimensional "brick and mortar" geometry that is a simplification of human stratum corneum, with a partition coefficient between corneocyte and lipid. Results are compared to the diffusion in multiple laminates to examine effects of the partition coefficient. The second application is the modeling of diffusion with partitioning through an irregular geometry which is obtained from a micrograph of hairless mouse stratum corneum.

Random sampling or 'random' model in skin flux measurements? [Commentary on "Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships"].

Transdermal therapy receives increasing attention as an attractive alternative to traditional drug delivery. Unfortunately the exact algorithm of transdermal permeation that could guide medicinal chemists towards delivery optimization at an early stage of the drug design process still remains to be decoded. This paper discusses some major hurdles on the way to full understanding of Quantitative Structure-Activity Relationships (QSAR) of skin permeation. From the statistical perspective, a recently published combined data set is found to be inappropriate with respect to the distribution of major molecular descriptors, and therefore should be approached cautiously as a source for QSAR model training and in modelling of occupational and environmental skin exposures.

Sequential V(A)/Q distributions in the normal rabbit by micropore membrane inlet mass spectrometry.

We developed micropore membrane inlet mass spectrometer (MMIMS) probes to rapidly measure inert-gas partial pressures in small blood samples. The mass spectrometer output was linearly related to inert-gas partial pressure (r(2) of 0.996-1.000) and was nearly independent of large variations in inert-gas solubility in liquid samples. We infused six inert gases into five pentobarbital-anesthetized New Zealand rabbits and used the MMIMS system to measure inert-gas partial pressures in systemic and pulmonary arterial blood and in mixed expired gas samples. The retention and excretion data were transformed into distributions of ventilation-to-perfusion ratios (V(A)/Q) with the use of linear regression techniques. Distributions of V(A)/Q were unimodal and broad, consistent with prior reports in the normal rabbit. Total blood sample volume for each VA/Q distribution was 4 ml, and analysis time was 8 min. MMIMS provides a convenient method to perform the multiple inert-gas elimination technique rapidly and with small blood sample volumes.

Endothelin-1 is elevated in monocrotaline pulmonary hypertension.

These studies document striking pulmonary vasoconstrictor response to nitric oxide synthase (NOS) inhibition in monocrotaline (MCT) pulmonary hypertension in rats. This constriction is caused by elevated endothelin (ET)-1 production acting on ETA receptors. Isolated, red blood cell plus buffer-perfused lungs from rats were studied 3 wk after MCT (60 mg/kg) or saline injection. MCT-injected rats developed pulmonary hypertension, right ventricular hypertrophy, and heightened pulmonary vasoconstriction to ANG II and the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA). In MCT-injected lungs, the magnitude of the pulmonary pressor response to NOS inhibition correlated strongly with the extent of pulmonary hypertension. Pretreatment of isolated MCT-injected lungs with combined ETA (BQ-123) plus ETB (BQ-788) antagonists or ETA antagonist alone prevented the L-NMMA-induced constriction. Addition of ETA antagonist reversed established L-NMMA-induced constriction; ETB antagonist did not. ET-1 concentrations were elevated in MCT-injected lung perfusate compared with sham-injected lung perfusate, but ET-1 levels did not differ before and after NOS inhibition. NOS inhibition enhanced hypoxic pulmonary vasoconstriction in both sham- and MCT-injected lungs, but the enhancement was greater in MCT-injected lungs. Results suggest that in MCT pulmonary hypertension, elevated endogenous ET-1 production acting through ETA receptors causes pulmonary vasoconstriction that is normally masked by endogenous NO production.

Improved oxygenation with prostaglandin F2alpha with and without inhaled nitric oxide in dogs.

Dogs of mixed breed (n = 7) were anesthetized, right lung atelectasis was established, and the cyclooxygenase pathway was blocked with ibuprofen. Measurements of pulmonary gas exchange were performed (fractional concentration of inspired O2 = 0.95) after infusions of prostaglandin F2alpha (PGF2alpha; 2 microg . kg-1 . min-1), ventilation with nitric oxide (NO; 40 ppm), or both (PGF2alpha + NO) in random order. The arterial PO2 (PaO2) under control conditions was 117 +/- 16 Torr (shunt = 33 +/- 2.5%), was unchanged with NO alone (PaO2 = 114 +/- 17 Torr; shunt = 35.7 +/- 3. 1%), but was significantly improved with PGF2alpha alone (PaO2 = 180 +/- 28 Torr; shunt = 23.2 +/- 2.8%) and with the combination of PGF2alpha + NO (PaO2 = 202 +/- 30 Torr; shunt = 20.9 +/- 2.5%). The addition of NO did not significantly enhance the effectiveness of the PGF2alpha on PaO2. Simulation of these data in a computer model, combining pulmonary gas exchange and pulmonary blood flow, reproduced the results on the basis that vasoconstriction with PGF2alpha was maximal under hypoxia in the atelectatic lung and reduced by hyperoxia in the ventilated lung, consistent with the hypothesis of O2 dependence of PGF2alpha vasoconstriction.

Two-port analysis of microcirculation: an extension of windkessel.

We examined the suitability of the three-element windkessel as a reduced model of pulsatile pressure-flow relations at arteriolar and venular ends of a microcirculatory bed. Frequency domain (two-port) analysis of a distributed model of an idealized (single input, single output) microvascular network in skeletal muscle, consisting of 391 discrete vessel segments from a 20-microns-diameter arteriole to a 28-microns-diameter venule, demonstrated that the three-element windkessel is a good representation of arterial input impedance when pressure pulsations are absent at the venous end. The same model with different parameter values accounts well for venous pressure-flow relations if no pulsations occur at the arterial end. We showed that a five-element model (2 compliances, 3 resistors) provided a superior representation of pulsatile pressure-flow relations at both arterial and venous ends. Relating parameter values to known properties of the network revealed the physiological significance of the five elements. This model may prove a useful component in circulatory models incorporating both arteries and veins. While parameter values obtained herein were strictly valid for the particular microvascular network described, guidelines are provided based on physiological properties so that values may be estimated for different microvascular beds.

Causes of hypercarbia with oxygen therapy in patients with chronic obstructive pulmonary disease.

OBJECTIVES: To compare data derived from a computer model of the pulmonary circulation with data from a case series of patients with chronic obstructive pulmonary disease (COPD). To evaluate the specific factors contributing to CO2 retention due to oxygen therapy in patients with acute exacerbations of COPD. DESIGN: Data from a computer model of the pulmonary circulation were compared with a previous case series. PATIENTS: Patient data were derived from previous case series. INTERVENTIONS: Simulated application of oxygen therapy. MEASUREMENTS AND MAIN RESULTS: The computer model of the pulmonary circulation generates data comparable with those data from a series of patients with COPD treated with supplemental oxygen and permits identification of the causes for hypercarbia. Therapy with supplemental oxygen alters hypoxic pulmonary vasoconstriction and modulates the Haldane effect, resulting in changes in physiologic deadspace. CONCLUSION: Changes in physiologic deadspace are sufficient to account for the hypercarbia developed by patients with acute exacerbations of COPD when treated with supplemental oxygen.

Effects of venous pressure on coronary circulation and intramyocardial fluid mechanics.

This investigation examined the interaction between right heart pressure (RHP), coronary perfusion pressure (CPP), intramyocardial tissue pressure (IMP), and coronary flow mechanics, including partitioning of coronary effluent in the isolated Krebs-Henseleit perfused rabbit heart. The major new finding was a parallel shift in the IMP-inflow relationship to a higher tissue pressure level in response to an increase in RHP. Accompanying the rise in RHP from 0 to 15 and 25 mmHg, IMP at zero coronary inflow in the beating (and arrested) heart increased from 5.8 +/- 1.0 (7.7 +/- 1.2) to 16.3 +/- 1.2 (17.9 +/- 1.3) and 28.6 +/- 1.7 (26.4 +/- 2.0) mmHg, respectively. A concomitant parallel shift in the CPP-inflow relation to higher pressures was consistently observed. The fraction of total coronary flow drained by the right heart was not constant. A higher partition of coronary outflow to the left heart (7.8 +/- 3.8, 34.3 +/- 3.0, and 47.9 +/- 4.3%, respectively) accompanied the increase in RHP. Intramyocardial partitioning of coronary outflow pathways mediates the effects of venous pressure modulation on coronary circulation. The interaction between coronary venous pressure and the extravascular environment modifies the effective back pressure to arterial inflow.

Wave transmission and input impedance of a model of skeletal muscle microvasculature.

We analyzed wave transmission properties and input impedance of a microvascular network model. The model, derived from rat spinotrapezius muscle and previously described and validated by other investigators for steady pressure-flow relations, was expanded to include pulsatile phenomena. Microvessels are considered purely elastic, with compliances a function of vessel type; viscous dissipation follows Poiseuille's law. Linear and nonlinear results are presented. In the nonlinear case, shear rate-dependent viscosity of blood and transmural pressure-dependent vascular diameters were calculated and small signal perturbations were imposed around several working points. We investigated effects on input impedance of physiological variability of network parameters and structure: distribution of capillary diameters, capillary segment length, and presence or absence of cross-connecting capillaries. Results show that although wave transmission properties are complex, input impedance is simple. Apparent wave speeds differ substantially from phase velocities and change markedly from branch to branch; pressure and flow waves appear to travel at different speeds. These features result from the mesh-like structure of the network and the prominence of reflection at branchpoints. Input impedance displays a similar form under all conditions: Magnitude is a monotonically decreasing function of frequency, and phase decreases from 0 to approximately -45 degrees. Consideration of the characteristic impedance of a microvessel leads to modification of the three-element Windkessel as a reduced model of the observed input impedance.

Pulse reflection sites and effective length of the arterial system.

The concept of effective length (L) of the arterial system implies that it may be represented by a single viscoelastic tube terminated by an impedance, creating a single reflection site. Although the concept is straightforward, investigators for years have been unable to agree on the value of L. Proposed values range from a few millimeters to a few meters, confounding the identification of arterial reflection sites. This report shows analytically and illustrates with experimental data that the determination of the effective length leaves room for an infinite number of exact solutions for L and the corresponding terminal impedance if the input impedance of the tube is to match the measured input impedance of an arterial system. None of the possible values of L needs to bear any relationship to actual reflection sites.