Branching exponent heterogeneity and wall shear stress distribution in vascular trees.

A bifurcating arterial system with Poiseuille flow can function at minimum cost and with uniform wall shear stress if the branching exponent (z) = 3 [where z is defined by (D(1))(z) = (D(2))(z) + (D(3))(z); D(1) is the parent vessel diameter and D(2) and D(3) are the two daughter vessel diameters at a bifurcation]. Because wall shear stress is a physiologically transducible force, shear stress-dependent control over vessel diameter would appear to provide a means for preserving this optimal structure through maintenance of uniform shear stress. A mean z of 3 has been considered confirmation of such a control mechanism. The objective of the present study was to evaluate the consequences of a heterogeneous distribution of z values about the mean with regard to this uniform shear stress hypothesis. Simulations were carried out on model structures otherwise conforming to the criteria consistent with uniform shear stress when z = 3 but with varying distributions of z. The result was that when there was significant heterogeneity in z approaching that found in a real arterial tree, the coefficient of variation in shear stress was comparable to the coefficient of variation in z and nearly independent of the mean value of z. A systematic increase in mean shear stress with decreasing vessel diameter was one component of the variation in shear stress even when the mean z = 3. The conclusion is that the influence of shear stress in determining vessel diameters is not, per se, manifested in a mean value of z. In a vascular tree having a heterogeneous distribution in z values, a particular mean value of z (e.g., z = 3) apparently has little bearing on the uniform shear stress hypothesis.

Detection of changes in lung tissue properties with multiple-indicator dilution.

We evaluated the potential utility of a group of indicators, each of which targets a particular tissue property, as indicators in the multiple-indicator dilution method to detect and to identify abnormalities in lung tissue properties resulting from lung injury models. We measured the pulmonary venous outflow concentration vs. time curves of [14C]diazepam, 3HOH, [14C]phenylethylamine, and a vascular reference indicator following their bolus injection into the pulmonary artery of isolated perfused rabbit lungs under different experimental conditions, resulting in changes in the lung tissue composition. The conditions included granulomatous inflammation, induced by the intravenous injection of complete Freund's adjuvant (CFA), and intratracheal fluid instillation, each of which resulted in similar increases in lung wet weight. Each of these conditions resulted in a unique pattern among the concentration vs. time outflow curves of the indicators studied. The patterns were quantified by using mathematical models describing the pulmonary disposition of each of the indicators studied. A unique model parameter vector was obtained for each condition, demonstrating the ability to detect and to identify changes in lung tissue properties by using the appropriate group of indicators in the multiple-indicator dilution method. One change that was particularly interesting was a CFA-induced change in the disposition of diazepam, suggestive of a substantial increase in peripheral-type benzodiazepine receptors in the inflamed lungs.

Structure-function relationships in the pulmonary arterial tree.

Knowledge of the relationship between structure and function of the normal pulmonary arterial tree is necessary for understanding normal pulmonary hemodynamics and the functional consequences of the vascular remodeling that accompanies pulmonary vascular diseases. In an effort to provide a means for relating the measurable vascular geometry and vessel mechanics data to the mean pressure-flow relationship and longitudinal pressure profile, we present a mathematical model of the pulmonary arterial tree. The model is based on the observation that the normal pulmonary arterial tree is a bifurcating tree in which the parent-to-daughter diameter ratios at a bifurcation and vessel distensibility are independent of vessel diameter, and although the actual arterial tree is quite heterogeneous, the diameter of each route, through which the blood flows, tapers from the arterial inlet to essentially the same terminal arteriolar diameter. In the model the average route is represented as a tapered tube through which the blood flow decreases with distance from the inlet because of the diversion of flow at the many bifurcations along the route. The taper and flow diversion are expressed in terms of morphometric parameters obtained using various methods for summarizing morphometric data. To help put the model parameter values in perspective, we applied one such method to morphometric data obtained from perfused dog lungs. Model simulations demonstrate the sensitivity of model pressure-flow relationships to variations in the morphometric parameters. Comparisons of simulations with experimental data also raise questions as to the "hemodynamically" appropriate ways to summarize morphometric data.

A murine model of latex allergy-induced airway hyperreactivity.

Sensitization to latex proteins can cause immediate IgE mast cell-mediated reactions. Health care workers have been found to be particularly at risk because of high exposure. Latex allergy can be produced in mice as demonstrated by IgE and eosinophil responses. Thus the mouse is a potential animal model for studying this disease, but the airway response to latex sensitization in mice has not been evaluated previously. In the present study, we immunized BALB/c mice intranasally with nonammoniated latex proteins. Animals were anesthetized, and lung mechanics were evaluated plethysmographically. Changes in pulmonary conductance (GL) and compliance (Cdyn) were measured in response to a nonspecific challenge with methacholine or to a direct challenge with intravenous latex antigen. Latex sensitization resulted in elevated levels of IgE and latex-specific IgG1 as well as interstitial infiltrates consistent with an allergic response. The methacholine dose-response ED50 for GL was 116.4 microg for the control mice and fell significantly to 20.9 microg for latex-sensitized mice. The ED50 calculated for Cdyn was also significantly lower after latex sensitization. The GL in latex-sensitized mice challenged with latex antigen fell significantly from a prechallenge value of 1.87 +/- 0.41 (S.E.) to 0. 198 +/- 0.03 ml x s-1 x cmH2O after latex antigen challenge. The results indicate that latex-sensitized mice did exhibit increased airway reactivity in the methacholine challenge test. The latex allergic response in mice is unique in that direct challenge with latex antigen itself also resulted in a significant airway response.

Accounting for the heterogeneity of capillary transit times in modeling multiple indicator dilution data.

To mathematically model multiple indicator dilution (MID) data for the purpose of estimating parameters descriptive of indicator-tissue interactions, it is necessary to account for the effects of the distribution of capillary transit times, h(c)(t). In this paper, we present an efficient approach for incorporating h(c)(t) in the mathematical modeling of MID data. In this method, the solution of the model partial differential equations obtained at different locations along the model capillary having the longest transit time provides the outflow concentrations for all capillaries. When weighted by h(c)(t), these capillary outflow concentrations provide the outflow concentration versus time curve for the capillary bed. The method is appropriate whether the available data on capillary dispersion are in terms of capillary transit time or relative flow distributions, and whether the dispersion results from convection time differences among heterogeneous parallel pathways or axial diffusion along individual pathways. Finally, we show that the knowledge of a relationship among the moments of h(c)(t), rather than h(c)(t) per se, is sufficient information to account for the effect of h(c)(t) in the mathematical modeling interpretation of MID data. This relationship can be determined by including a flow-limited indicator in the injected bolus, thus providing an efficient means for obtaining the experimental data sufficient to account for capillary flow and transit time heterogeneity in MID modeling.

Pulmonary disposition of lipophilic amine compounds in the isolated perfused rabbit lung.

We measured the pulmonary venous concentration vs. time curves for [3H]alfentanil, [14C]lidocaine, and [3H]codeine after the bolus injection of each of these lipophilic amine compounds (LAC) and a vascular-reference indicator (fluorescein isothiocyanate-dextran) into the pulmonary artery of isolated perfused rabbit lungs. A range of flows and perfusate albumin concentrations was studied. To evaluate the information content of the data, we developed a kinetic model describing the pulmonary disposition of these LAC that was based on indicator dilution theory, and we sought a robust approach for interpreting the estimated model parameters. We found that the distribution of the kinetic model rate constants of the lipophilic amine-tissue interactions can be described by alpha, H, and psi, where alpha is a measure of the capacity of the rapidly equilibrating interactions between the lipophilic amine and the tissue; H is a measure of the equilibrium capacity of the slowly equilibrating interactions between the lipophilic amine and the tissue; and psi is the mean sojourn time. The values of alpha, H, and psi were 0.8 +/- 0.1 (SE), 0.6 +/- 0.1, and 1.6 +/- 0.5 s; 1.9 +/- 0.1, 5.3 +/- 0.4, and 5.6 +/- 0.5 s; and 1.1 +/- 0.1, 9.8 +/- 0.4, and 4.7 +/- 0.2 s for alfentanil, lidocaine, and codeine, respectively. These values for alpha, H, and psi reveal the relative dominance of the slowly equilibrating interactions for lidocaine and codeine in comparison with alfentanil. This approach to data analysis may have utility for the potential use of LAC to reveal and to quantify changes in lung tissue composition associated with lung disease.

An interpretation of 14C-urea and 14C-primidone extraction in isolated rabbit lungs.

We measured the venous concentration versus time curves of 14C-urea and 14C-primidone after rapid bolus injections of a vascular reference indicator, fluorescein isothiocyanate dextran, and one of the two 14C-labeled indicators in isolated rabbit lungs perfused with Krebs-Ringer bicarbonate solution containing 4.5% bovine serum albumin at flow rates (F) of 6.67, 3.33, 1.67, and 0.83 ml/sec and with nearly constant microvascular pressure and total lung vascular volume. When we calculated the permeability-surface area product, PS, from the 14C-urea and 14C-primidone outflow curves using the Crone model, the estimates of the PS product were directly proportional to F. However, the fractional change in the PS with flow was different for the two indicators. We also estimated the PS from the same 14C-urea and 14C-primidone data using an alternative model that includes perfusion heterogeneity, estimated in a previous study, and flow-limited and barrier-limited extravascular volumes accessible to both urea and primidone. This model was able to fit the outflow curves of either 14C-urea or 14C-primidone at all four flows studied with one flow-independent PS for each indicator. The ability of the new model to explain the 14C-urea and 14C-primidone data with no flow-dependent change in PS suggests that a change in PS with F estimated using other models such as the Crone model is not sufficient for capillary surface area recruitment.

Estimation of the pulmonary capillary transport function in isolated rabbit lungs.

Recently, we presented a method for estimating the pulmonary capillary volume and transport function based on the use of a reference indicator and two or more indicators that rapidly equilibrate (radially) with the tissue (i.e., the concentrations in the vascular and extravascular spaces at a given axial location are in equilibrium) during transit through the capillaries in a bolus-injection indicator dilution method (S. H. Audi, G. S. Krenz, J. H. Linehan, D. A. Rickaby, and C. A. Dawson. J. Appl. Physiol. 77:332-351, 1994). The objectives of the present study were 1) to determine whether [14C]diazepam and [3H]alfentanil equilibrate sufficiently rapidly between the vascular space and tissue and with sufficiently different pulmonary extra-vascular mean residence times to be used in a single bolus to estimate the pulmonary capillary volume and transport function using this method and 2) to estimate the pulmonary capillary volume and transit time distribution in isolated perfused rabbit lungs. Both [14C]diazepam and [3H]alfentanil were found to be rapidly equilibrating indicators by the criteria that, over a wide range of flow rates, their respective venous effluent concentration curves were nearly congruent on a time scale normalized to the lung mean transit time for the reference indicator (fluorescein isothiocyanate dextran). In addition, at a given plasma albumin concentration, [14C]diazepam had a significantly longer extravascular mean residence time than [3H]alfentanil, e.g., at 6% plasma albumin concentration, the extravascular mean residence time of [14C]diazepam was more than twice that of [3H]alfentanil. On average, the estimated pulmonary capillary volume for a 2.7-kg was approximately 4.2 ml or approximately 44% of the total pulmonary vascular volume (9.5 ml). The relative dispersion of the pulmonary capillary transport function of the rabbit was approximately 90%.

Reduction and accumulation of methylene blue by the lung.

We studied the disposition of methylene blue added to the perfusate passing through isolated perfused rabbit lungs. Experiments were carried out in a recirculating or single-pass mode, the latter with either a steady infusion or bolus injection of the dye in its blue oxidized form (MB+) or in its colorless reduced leukomethylene blue form (MBH). The recirculation experiments revealed that the dye was taken up by the lungs and that a substantial fraction (approximately 16%) of the MB+ entering the pulmonary artery was reduced before it emerged from the pulmonary veins. Sequestration of the dye by the lungs was a relatively slow process, and the blue color of the lungs at a time when there was little dye left in the perfusate suggests that much of the sequestered dye was in the oxidized form. The results from the single-pass bolus and steady infusion experiments suggest that MBH diffuses rapidly between perfusate and tissue and that it is more soluble in the tissue than in the perfusates used in the study. In this context, the concept of "solubility" includes the impact of the rapidly equilibrating associations of the dye with the perfusate albumin and tissue components. The observed characteristics of the disposition of the methylene blue within the lungs and the rapid rate of its reduction on passage through the lungs suggest that it may be useful to evaluate the possibility that changes in reduction, uptake, and/or sequestration rates may reflect alterations in the metabolic function of the lungs.

Impact of parallel heterogeneity on a continuum model of the pulmonary arterial tree.

Model arterial trees were constructed following rules consistent with morphometric data, Nj = (Dj/Da)-beta 1 and Lj = La(Dj/Da)beta 2, where Nj, Dj, and Lj are number, diameter, and length, respectively, of vessels in the jth level; Da and La are diameter and length, respectively, of the inlet artery, and -beta 1 and beta 2 are power law slopes relating vessel number and length, respectively, to vessel diameter. Simulated heterogeneous trees approximating these rules were constructed by assigning vessel diameters Dm = Da[2/(m + 1)]1/beta 1, such that m-1 vessels were larger than Dm (vessel length proportional to diameter). Vessels were connected, forming random bifurcating trees. Longitudinal intravascular pressure [P(Qcum)] with respect to cumulative vascular volume [Qcum] was computed for Poiseuille flow. Strahler-ordered tree morphometry yielded estimates of La, Da, beta 1, beta 2, and mean number ratio (B); B is defined by Nk + 1 = Bk, where k is total number of Strahler orders minus Strahler order number. The parameters were used in P(Qcum) = Pa [formula: see text] and the resulting P(Qcum) relationship was compared with that of the simulated tree, where Pa is total arterial pressure drop, Q is flow rate, Ra = (128 microLa)/(pi D4a (where mu is blood viscosity), and Qa (volume of inlet artery) = 1/4D2a pi La. Results indicate that the equation, originally developed for homogeneous trees (J. Appl. Physiol. 72: 2225-2237, 1992), provides a good approximation to the heterogeneous tree P(Qcum).

Pulmonary capillary transport function from flow-limited indicators.

The objective of this study was to examine the use of rapidly diffusing (flow-limited) indicators for estimating the pulmonary capillary blood volume (i.e., fraction of the lung blood volume wherein the diffusible indicators equilibrate with the tissue) and the capillary transit time distribution. Supporting theory and an application to experimental data are presented. The theory leads to the following equations, which relate the mean transit time (t), the variance (sigma 2), and the third central moment (m3) of the capillary transport function, hc(t), to the moments of the venous concentration-time curves for a vascular reference indicator, CR(t), and a flow-limited diffusible indicator, CD(t), after a bolus injection of the indicators upstream from an organ: sigma 2D - sigma 2R = ([1 + (te/tc)]2-1)sigma 2c and m3D-m3R = ([1 + (te/tc)]3-1)m3c, where te = tD - tR and tc is capillary t. The moments of hc(t) can be estimated if the injected bolus includes, along with the vascular reference indicator, at least two flow-limited diffusible indicators, each with a different te. A least-squares optimization procedure can then be used to specify the moments of hc(t). This approach was applied to isolated dog lung lobes with [14C]-diazepam as the diffusible indicator. The tissue-to-perfusate partition coefficient for [14C]diazepam could be adjusted to any desired value by altering the perfusate albumin concentration. Thus, by making a number of injections, each at a different perfusate albumin concentration, data were obtained in a manner equivalent to making one injection with a number of flow-limited diffusible indicators, each with a different te. On average, the estimated capillary volume and mean transit time were approximately 48% of the total lobar volume and mean transit time, and the relative dispersion of the hc(t) was approximately 75%.

Influence of hypoxia and serotonin on small pulmonary vessels.

X-ray angiograms obtained from isolated perfused dog lungs were used to measure changes in the internal diameter of small intraparenchymal pulmonary arteries (150-1,600 microns) and veins (200-1,000 microns) in response to hypoxia or intra-arterial serotonin [5-hydroxytryptamine (5-HT)] infusion. The diameter changes in response to the two stimuli were measured over a range of stimulus-induced increases (delta Pa) in the total arteriovenous pressure drop. When the resulting delta Pa was small, all arteries in the diameter range studied constricted in response to either stimuli. The maximum decrease in diameter was approximately 25% with hypoxia and 36% with 5-HT. However, when delta Pa was large, arteries with a control diameter larger than approximately 800 microns distended with hypoxia. On the other hand, 5-HT constricted all the arteries in the size range studied regardless of the resulting magnitude of delta Pa. Hypoxia caused a small (approximately 9%) constriction in all veins in the diameter range studied independent of diameter or the magnitude of delta Pa, whereas in the concentration range studied 5-HT had no significant influence on these veins. An analysis of the potential impact of these vessels on total pulmonary vascular resistance suggested that although vessels in the size range studied contributed significantly to the total response to these two stimuli, vessels smaller than those studied also made a major contribution to the total response.

A distensible vessel model applied to hypoxic pulmonary vasoconstriction in the neonatal pig.

Recently, we presented a simple two-parameter distensible vessel model as a potential tool for characterizing pulmonary vascular pressure vs. flow curves under zone 3 conditions (Linehan et al. J. Appl. Physiol. 73: 987-994, 1992). One parameter, alpha, represents the distensibility of the resistance vessels as the fractional change in vessel diameter per Torr change in pressure, and the other parameter, R0, represents the vascular resistance that would exist if the resistance vessels were at their respective diameters obtained if the vascular pressure were zero. The objective of the present study was to determine whether this distensible vessel model was capable of describing the pressure vs. flow data obtained during hypoxia vasoconstriction and under control conditions in isolated lungs from neonatal pigs. The piglet lungs were perfused with autologous blood, and the pulmonary arterial pressure was measured over a range of flow rates from 15 to 250 ml.min-1 x kg-1 at constant left atrial (3 Torr) pressure. The model provided a reasonable fit to the data under both conditions. Hypoxia resulted in a significant increase in R0, from 0.39 +/- 0.10 Torr.ml-1 x min.kg during control conditions to 1.41 +/- 0.46 Torr.ml-1 x min.kg during hypoxia. alpha was 2.4 +/- 0.4%/Torr under control conditions and 2.0 +/- 0.4%/Torr during hypoxia, but this difference was not statistically significant. The results suggest that the distensible vessel model may be useful for interpreting pressure-flow data in terms of changes in geometry and distensibility of the resistance vessels in response to a vasoconstrictor stimulus such as hypoxia.

Model-free numerical deconvolution of recirculating indicator concentration curves.

This paper investigates two model-free methods for numerical deconvolution of recirculating indicator concentration curves. The two methods, damped least squares and discrete orthogonal polynomial deconvolution, are applied to simulated data to verify the reliability of the algorithms. Both deconvolution methods provide damping that results in estimated transport functions that are smooth and reasonable estimates of the actual simulated transport function. On convolution with the simulated input curve, the estimated transport functions provide good fits to the simulated output curve. In addition, methods for identifying an optimal solution and for truncating the artifactually long oscillatory tails of the estimated transport functions are proposed, which appear to allow for reasonably accurate estimation of the mean transit times and variances of the transport functions as well. When either method was applied to indicator dilution data obtained from the pulmonary artery and left atrium, it was computationally stable while producing transport functions that when convolved with the input concentration curves provided good fits to the output concentration curves. The combined simulation and experimental results suggest that the proposed methods should be useful for estimating circulation transport functions from indicator dilution data.

A simple distensible vessel model for interpreting pulmonary vascular pressure-flow curves.

A simple distensible vessel model was developed for the purpose of interpreting the vascular pressure-flow curve in the zone 3 lung. The model-governing equation has two parameters: R0, representing the hemodynamic resistance of the undistended pulmonary vascular bed, and alpha, representing the distensibility of the resistance vessels. To evaluate the model, the governing equation was used in a nonlinear regression analysis of the pressure-flow data from isolated dog lung lobes. The dependency of the estimates of the model parameters in response to changes in perfusate viscosity (hematocrit) was determined. The distensible vessel model provided reasonable fits to the data, and, as predicted, R0, but not alpha, was hematocrit dependent. On the other hand, the traditional linear ohmic-Starling resistor model fit to the same pressure-flow data generally provided fits approaching those of the distensibility model only if the pressure intercept (the mean "critical closing pressure") was allowed to increase with hematocrit. Because the ohmic-Starling resistor concept does not predict a hematocrit dependence of the critical closing pressure, this latter observation is evidence that the distensible vessel model offers an alternative conceptualization of the pulmonary circulation worthy of additional study with respect to the interpretation of experimental pressure-flow data.

A fractal continuum model of the pulmonary arterial tree.

The extant morphometric data from the intrapulmonary arteries of dog, human, and cat lungs produce graphs of the log of the vessel number, (N) or length (l) in each level vs. the log of the mean diameter (D) in each level that are sufficiently linear to suggest that a scale-independent self-similar or fractal structure may underlie the observed relationships. These data can be correlated by the following formulas: Nj = a1Dj-beta 1, and lj = a2Dj beta 2, where j denotes the level (order or generation) number measured from the largest vessel at the entrance to the arterial tree to the smallest vessel at the entrance to the capillary bed. With the hemodynamic resistance (R) represented by Rj = 128 microliterj/(Nj pi Dj4) and the vascular volume (Q) by Qj = Nj pi Dj2lj/4, the continuous cumulative distribution of vascular resistance (Rcum) vs. cumulative vascular volume (Qcum) (where Rcum and Qcum represent the total resistance or volume, respectively, upstream from the jth level) can be calculated from [formula: see text] where r = Dj/Dj+1 is a constant independent of j. Analogous equations are developed for the inertance and compliance distributions, providing simple formulas to represent the hemodynamic consequences of the pulmonary arterial tree structure.

Use of diazepam for interpreting changes in extravascular lung water.

Estimates of extravascular lung water volume (Qew) by use of the multiple indicator-dilution method with a hydrophilic indicator such as tritiated water, along with a vascular reference indicator, depend not only on tissue hydration but also on tissue perfusion. Separation of these effects might be facilitated if both hydrophilic and lipophilic indicators were used, with the assumption that the extravascular volume accessible to the lipophilic indicator would be independent of hydration. We found that in isolated perfused dog lung lobes the extravascular volume accessible to the lipophilic amine [14C]diazepam (Qed) was inversely proportional to the albumin concentration of the perfusate. This suggested that while the bolus was in the lungs, only a small fraction of the diazepam was in the aqueous phase of either lung tissue or perfusate. Changing the flow rate over a fairly wide range had little influence on the pattern of the tritiated water or [14C]diazepam effluent concentration curves when time was normalized to the lobar mean transit time. This suggests that the association of the diazepam with both the plasma albumin and the lipoid fraction of the tissue was in very rapid equilibrium on the time scale of a single pass through the lung lobe and that there was little barrier to its diffusion to and from the tissue. When the extravascular water volume was increased by either raising the hydrostatic pressure or instilling saline into the airways, both Qew and Qew/Qed increased.(ABSTRACT TRUNCATED AT 250 WORDS)

An algorithm for angiographic estimation of blood vessel diameter.

This study was carried out in an attempt to develop an objective and robust method for measuring changes in the diameters of small blood vessels from X-ray angiographic images. Recognizing potential problems with edge detection methods applied to cylindrical vessels in which the contrast diminishes as the boundary is approached, we have attempted to utilize the X-ray absorbance data across the entire cross section of the vessel. Then, assuming a cylindrical geometry, the absorbance data are fit to the cylindrical absorbance function by use of nonlinear regression analysis. The method was tested and calibrated using glass tubes filled with various concentrations of contrast medium. The diameters of small pulmonary arteries were estimated by applying the method of angiograms obtained from an isolated dog lung lobe. The structure of the residuals obtained after the fitting procedure was analyzed to test the appropriateness of the model for use with images of vessels. The results suggest that this approach will have utility for systematically quantifying vessel dimensions.

Effect of vasoconstriction on longitudinal distribution of pulmonary vascular pressure and volume.

We used an improved version of the low-viscosity bolus method to evaluate longitudinal (arterial-to-venous) differences in the sensitivity of the dog lung lobe vasculature to selected vasoconstrictor stimuli, including hypoxia, and serotonin, histamine, and norepinephrine infusions. This method revealed a bimodal distribution of local vascular resistance vs. cumulative vascular volume under the zone 3 conditions studied. Our interpretation of the two modes of relatively high resistance is that they correspond to high resistance per unit volume segments of the arteries and veins upstream and downstream from the relatively low resistance per unit volume capillary bed. Thus an increase in the height of the upstream and downstream modes of the resistance distribution suggests constriction in small arteries and veins, respectively. Horizontal displacement of the modes along the cumulative volume axis suggests changes in the distribution of volume among the arteries, veins, and capillary bed. By use of these criteria, the results are consistent with the concept that each of the vasoconstrictor stimuli studied had a different longitudinal response pattern. Hypoxia constricted mainly small arteries, whereas serotonin constricted small and large arteries. Histamine constricted large and small veins, and norepinephrine constricted large and small veins and arteries.