Correction of inert gas washin or washout for gas solubility in blood

We show that when an inert gas is washed into the lungs its retention in the blood during any one breath is approximately proportional to its solubility. This relationship makes possible the correction of washin or washout data for blood uptake or release, provided that two gases of different solubility are used simultaneously. The method automatically allows for the characteristics of an individual washin or washout and for the occurrence of recirculation within a fairly short washin or washout period. It has been tested in models with nonuniform ventilation and perfusion and closely approximates the behavior of a truly insoluble gas. In the derived ventilation distribution, gas solubility appears as ventilation to units of low turnover. In the case of N2 this effect is small but causes appreciable overestimation of lung volume. The recovered dead space and main alveolar distribution are insignificantly affected.     

Oxygen consumption and blood flow distribution in perfused skeletal muscle of chinook salmon

An isolated, perfused salmon tail preparation showed oxyconformance at low oxygen delivery rates. Addition of pig red blood cells to the perfusing solution at a haematocrit of 5 or 10% allowed the tail tissues to oxyregulate. Below ca. 60 ml O₂ kg⁻¹ h⁻¹ of oxygen delivery (DO₂), VO₂ was delivery dependent. Above this value additional oxygen delivery did not increase VO₂ of resting muscle above ca. 35 ml O₂ kg⁻¹ h⁻¹. Following electrical stimulation, VO₂ increased to ca. 65 ml O₂ kg⁻¹ h⁻¹, with a critical DO₂ of ca. 150 ml O₂ kg⁻¹ h⁻¹. Dorsal aortic pressure fell to 69% of the pre-stimulation value after 5 min of stimulation and to 54% after 10 min. Microspheres were used to determine blood flow distribution (BFD) to red (RM) and white muscle (WM) within the perfused myotome. Mass specific BFD ratio at rest was found to be 4.03 ± 0.49 (RM:WM). After 5 min of electrical stimulation the ratio did not change. Perfusion with saline containing the tetrazolium salt 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) revealed significantly more mitochondrial activity in RM. Formazan production from MTT was directly proportional to time of perfusion in both red and WM. The mitochondrial activity ratio (RM:WM) did not change over 90 min of perfusion.     

A theory of blood flow in skeletal muscle

A theoretical analysis of blood flow in the microcirculation of skeletal muscle is provided. The flow in the microvessels of this organ is quasi steady and has a very low Reynolds number. The blood is non-Newtonian and the blood vessels are distensible with viscoelastic properties. A formulation of the problem is provided using a viscoelastic model for the vessel wall which was recently derived from measurements in the rat spinotrapezius muscle (Skalak and Schmid-Sch?nbein, 1986b). Closed form solutions are derived for several physiologically important cases, such as perfusion at steady state, transient and oscillatory flows. The results show that resting skeletal muscle has, over a wide range of perfusion pressures an almost linear pressure-flow curve. At low flow it exhibits nonlinearities. Vessel distensibility and the non-Newtonian properties of blood both have a strong influence on the shape of the pressure-flow curve. During oscillatory flow the muscle exhibits hysteresis. The theoretical results are in qualitative agreement with experimental observations.     

Influence of blood flow on cutaneous permeability to inert gas

A thermally regulated Plexiglas chamber was designed for investigation of transcutaneous diffusion of N2 and helium (He) in the human hand. Influence of cutaneous blood flow in this process was studied simultaneously with gas diffusion measurements. Changes in cutaneous blood flow (Q, in ml X min-1 X 100 ml tissue-1) were effected by altering ambient temperature (T) from 20 to 40 degrees C (Q = 0.08 X 100.07T). We found that the rate of inert gas diffusion through human skin, expressed as conductance (G, in ml STPD X h-1 X m-2 X atm-1), increases exponentially as a function of blood flow, and was indistinguishable between He and N2 (G = 21.19 X 100.0124Q). The permeability, diffusion coefficient per unit diffusion distance (D/h, in cm/h), also rose exponentially as a function of blood flow. But permeability for He (D/h = 0.1748 X 100.0203Q) was greater than that for N2 (D/h = 0.1678 X 100.0114Q). As cutaneous blood flow rises, because of increased temperature, the apparent diffusion distance falls linearly for both N2 and He. The change is more prominent for He than for N2 diffusion. Estimated replacement time for the body stores of N2 by transcutaneous diffusion alone was shortened from 26.8 h at 31 degrees C to 15.1 h at 37 degrees C. It is suggested from this study that beneficial results may be derived during decompression procedure 1) by maintaining an appropriate transcutaneous pressure gradient of inert gases, and 2) by elevating ambient temperature.     

Spatial heterogeneity in skeletal muscle microvascular blood flow distribution is increased in the metabolic syndrome

Previous studies have demonstrated that the metabolic syndrome is associated with impaired skeletal muscle arteriolar function, although integrating observations into a conceptual framework for impaired perfusion in peripheral vascular disease (PVD) has been limited. This study builds on previous work to evaluate in situ arteriolar hemodynamics in cremaster muscle of obese Zucker rats (OZR) to integrate existing knowledge into a greater understanding of impaired skeletal muscle perfusion. In OZR cremaster muscle, perfusion distribution at microvascular bifurcations (γ) was consistently more heterogeneous than in controls. However, while consistent, the underlying mechanistic contributors were spatially divergent as altered adrenergic constriction was the major contributor to altered γ at proximal microvascular bifurcations, with a steady decay with distance, while endothelial dysfunction was a stronger contributor in distal bifurcations with no discernible role proximally. Using measured values of γ, we found that simulations predict that successive alterations to γ in OZR caused more heterogeneous perfusion distribution in distal arterioles than in controls, an effect that could only be rectified by combined adrenoreceptor blockade and improvements to endothelial dysfunction. Intravascular (125)I-labeled albumin tracer washout from in situ gastrocnemius muscle of OZR provided independent support for these observations, indicating increased perfusion heterogeneity that was corrected only by combined adrenoreceptor blockade and improved endothelial function. These results suggest that a defining element of PVD in the metabolic syndrome may be an altered γ at microvascular bifurcations, that its contributors are heterogeneous and spatially distinct, and that interventions to rectify this negative outcome must take a new conceptual framework into account.     

Automated detection of the phase III slope during inert gas washout testing

We describe a method to determine the phase III slope for the purpose of calculating indexes of ventilation heterogeneity, S(acin) and S(cond), from the multiple breath nitrogen washout test (MBNW). Our automated method applies a recursive, segmented linear regression technique to each breath of the MBNW test and determines the best point of transition, or breakpoint, between each phase of the washout. A sample set of 50 MBNW tests (controls, asthma, and COPD) was used to establish the conditions in which the phase III slope obtained from the automated technique best matched that obtained by two manual interpreters. We then applied our technique to a test set of 30 subjects (with an even number of subjects in each of the above groups) and compared these results against the manual analysis of a third independent manual interpreter. Indexes of ventilation heterogeneity were determined using both methods and compared. The phase III slopes determined by the automatic technique best matched the manual interpreter when the phase III slope was calculated from the phase II-III transition point plus the addition of 50% of the phase II volume to the end of the expiration. Calculation of the indexes S(acin) and S(cond) showed no overall difference between analysis methods in either S(acin) (P = 0.14) or S(cond) (P = 0.59) when the set threshold was applied to our automated analysis. Our analysis method provides an alternate means for rapid quantification of the MBNW test, removing operator dependence without alteration in either S(acin) or S(cond).     

Numerical and experimental study of steady-state CO2 and inert gas washout

The predictions of a single-path trumpet-bell numerical model of steady-state CO2 and infused He and sulfur hexafluoride (SF6) washout were compared with experimental measurements on healthy human volunteers. The mathematical model used was a numerical solution of the classic airway convention-diffusion equation with the addition of a distributed source term at the alveolar end. In the human studies, a static sampling technique was used to measure the exhaled concentrations and phase III slopes of CO2, He, and SF6 during the intravenous infusion of saline saturated with a mixture of the two inert gases. We found good agreement between the experimentally determined normalized slopes (phase III slope divided by mixed expired concentration) and the numerically determined normalized slopes in the model with no free parameters other than the physiological ones of upper airway dead space, tidal volume, breathing frequency, and breathing pattern (sinusoidal). We conclude 1) that the single-path (Weibel) trumpet-bell anatomic model used in conjunction with the airway convection-diffusion equation with a distributed source term is adequate to describe the steady-state lung washout of CO2 and infused He and SF6 in normal lungs and 2) that the interfacial area separating the tidal volume fron from the functional residual capacity gas, through which gas diffusion into the moving tidal volume occurs, exerts a major effect on the normalized slopes of phase III.     

A delivery-independent blood flow effect on skeletal muscle fatigue

The hypothesis that hyperperfusion decreases muscle fatigue by increasing O2 and substrate delivery to the muscle was tested. Canine gastrocnemius-plantaris in situ preparations were stimulated at 5 Hz for 4 min during a free-flow control period and for 20 min during a pump-perfused experimental period. O2 delivery during these two periods was matched either by decreasing blood flow in animals breathing 100% O2 (high O2/low flow) [experimental-to-control ratio (E/C) = 0.97 + 0.02] or by increasing the blood flow in animals breathing 14% O2 (low O2/high flow) (E/C = 1.01 + 0.01). Plasma flow estimated from hematocrit to approximate substrate delivery was matched in the two contraction periods either by maintaining blood flow at the steady-state level (constant flow) (E/C = 0.98 + 0.10) or by increasing flow in animals with a dextran for 6% of blood volume exchange (dilute/high flow) (E/C = 1.02 + 0.02). E/C for initial developed tension was 1.00 + 0.02. Over 20 min, developed tension decreased 15.0 + 1.1% with low O2/high flow and 16.0 + 1.8% with dilute/high flow. Tension decreased by 28.0 + 3.0 and 27.8 + 1.5% with high O2/low flow and constant flow, respectively. Thus hyperperfusion decreased fatigue by a mechanism independent of increased O2 and substrate delivery.     

Effect of acute normovolemic hemodilution on distribution of blood flow and tissue oxygenation in dog skeletal muscle.

Acute normovolemic hemodilution (ANH) is efficient in reducing allogenic blood transfusion needs during elective surgery. Tissue oxygenation is maintained by increased cardiac output and oxygen extraction and, presumably, a more homogeneous tissue perfusion. The aim of this study was to investigate blood flow distribution and oxygenation of skeletal muscle. ANH from hematocrit of 36 +/- 3 to 20 +/- 1% was performed in 22 splenectomized, anesthetized beagles (17 analyzed) ventilated with room air. Normovolemia was confirmed by measurement of blood volume. Distribution of perfusion within skeletal muscle was determined by using radioactive microspheres. Tissue oxygen partial pressure was assessed with a polarographic platinum surface electrode. Cardiac index (3.69 +/- 0.79 vs. 4.79 +/- 0.73 l. min-1. m-2) and muscle perfusion (4.07 +/- 0.44 vs. 5.18 +/- 0.36 ml. 100 g-1. min-1) were increased at hematocrit of 20%. Oxygen delivery to skeletal muscle was reduced to 74% of baseline values (0.64 +/- 0.06 vs. 0.48 +/- 0.03 ml O2. 100 g-1. min-1). Nevertheless, tissue PO2 was preserved (27.4 +/- 1.3 vs. 29.9 +/- 1. 4 Torr). Heterogeneity of muscle perfusion (relative dispersion) was reduced after ANH (20.0 +/- 2.2 vs. 13.9 +/- 1.5%). We conclude that a more homogeneous distribution of perfusion is one mechanism for the preservation of tissue oxygenation after moderate ANH, despite reduced oxygen delivery.     

Calculating the distribution of ventilation-perfusion ratios from inert gas elimination data

It is well known that the major cause of hypoxemia in lung disease is ventilation-perfusion (VA/Q) inequality, but it has been extremely difficult to measure the distribution of ventilation-perfusion ratios except in terms of unrealistically simple (albeit useful) models. The multiple inert gas elimination technique provides considerable information concerning the shape, position, and dispersion of the VA/Q distribution, although it cannot precisely define all features of the distribution. Although there are many techniques for obtaining information about the distribution from inert gas elimination data, we have found the most flexible and useful approach to be a multicomponent analysis with enforced smoothing, sometimes known as ridge regression. This presentation describes in some detail the physiological and mathematical principles principles involved in the transformation of inert gas elimination data into a representative distribution of ventilation-perfusion ratios by enforced smoothing techniques. It is important to realize that with this approach and any other approach aimed at estimating the distribution of ventilation-perfusion ratios, the results must be properly interpreted.     

The critical role of VEGF in skeletal muscle angiogenesis and blood flow

VEGF (vascular endothelial growth factor) is well known as an important molecule in angiogenesis. Its inhibition is pursued as an anticancer therapy; its enhancement as therapy for tissue ischaemia. In the present paper, its role in skeletal muscle is explored, both at rest and after exercise. Muscle VEGF mRNA and protein are increased severalfold after heavy exercise. Whereas global VEGF knockout is embryonically lethal, muscle-specific knockout is not, providing models for studying its functional significance. Its deletion in adult mouse skeletal muscle: (i) reduces muscle capillarity by more than 50%, (ii) decreases exercise endurance time by approximately 80%, and (iii) abolishes the angiogenic response to exercise training. What causes VEGF to increase with exercise is not clear. Despite regulation by HIF (hypoxia-inducible factor), increased HIF on exercise, and PO2 falling to single digit values during exercise, muscle-specific HIF knockout does not impair performance or capillarity, leaving many unanswered questions.     

Regulation of canine skeletal muscle and hindlimb blood flow in acute anemia

Redistribution of blood flow away from resting skeletal muscles does not occur during anemic hypoxia even when whole body oxygen uptake is not maintained. In the present study, the effects of sympathetic nerve stimulation on both skeletal muscle and hindlimb blood flow were studied prior to and during anemia in anesthetized, paralyzed, and ventilated dogs. In one series (skeletal muscle group, n = 8) paw blood flow was excluded by placing a tourniquet around the ankle; in a second series (hindlimb group, n = 8) no tourniquet was placed at the ankle. The distal end of the transected left sciatic nerve was stimulated to produce a maximal vasoconstrictor response for 4-min intervals at normal hematocrit (Hct.) and at 30 min of anemia (Hct. = 14%). Arterial blood pressure and hindlimb or muscle blood flow were measured; resistance and vascular hindrance were calculated. Nerve stimulation decreased blood flow (p less than 0.05) in the hindlimb and muscle groups at normal Hct. Blood flow rose (p less than 0.05) during anemia and was decreased (p less than 0.05) in both groups during nerve stimulation. However, the blood flow values in both groups during nerve stimulation in anemic animals were greater (p less than 0.05) than those at normal Hct. Hindlimb and muscle vascular resistance fell significantly during anemia and nerve stimulation produced a greater increase in vascular resistance at normal Hct. Vascular hindrance in muscle, but not hindlimb, was less during nerve stimulation in anemia than at normal Hct.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioenergetics of contracting skeletal muscle after partial reduction of blood flow

The purpose ofthis study was to examine the bioenergetics and regulation ofO₂ uptake(O₂) and force productionin contracting muscle when blood flow was moderately reduced during asteady-state contractile period. Canine gastrocnemius muscle(n = 5) was isolated, and 3-minstimulation periods of isometric, tetanic contractions were elicitedsequentially at rates of 0.25, 0.33, and 0.5 contractions/s (Hz)immediately followed by a reduction of blood flow [ischemic (I)condition] to 46 ± 3% of the value obtained at 0.5 Hz with normal blood flow. TheO₂ of thecontracting muscle was significantly (P < 0.05) reduced during the Icondition [6.5 ± 0.8 (SE) ml · 100 g¹ · min¹]compared with the same stimulation frequency with normal flow (11.2 ± 1.5 ml · 100 g¹ · min¹),as was the tension-time index (79 ± 12 vs. 123 ± 22 N · g¹ · min¹,respectively). The ratio ofO₂ to tension-time indexremained constant throughout all contraction periods. Musclephosphocreatine concentration, ATP concentration, and lactate effluxwere not significantly different during the I condition compared withthe 0.5-Hz condition with normal blood flow. However, at comparable rates of O₂ andtension-time index, muscle phosphocreatine concentration and ATPconcentration were significantly less during the I condition comparedwith normal-flow conditions. These results demonstrate that, in thishighly oxidative muscle, the normal balance ofO₂ supply to force output wasmaintained during moderate ischemia by downregulation of forceproduction. In addition,1) the minimal disruption inintracellular homeostasis after the initiation of ischemia waslikely a result of steady-state metabolic conditions having alreadybeen activated, and 2) thedifference in intracellular conditions at comparable rates ofO₂ and tension-time index between the normal flow and I condition may have been due to altered intracellular O₂ tension.