Transcapillary Transport Research Articles

Ernest Henry Starling (1866–1927): The Scientist and the Man

The pre-eminent achievements of the English physician and physiologist Ernest Henry Starling were his quantitative explanation of the transcapillary transport of fluid, the discovery of the first hormone, secretin, and his formulation of the law of the heart. In some ways Starling was an outsider and he was the centre of several scientific and social controversies. However, throughout his life he stressed fundamental scientific attitudes and ideas with remarkable persistence and power, although also balance, and his scientific achievements have stood the test of time.

Delayed Transcapillary Delivery of Insulin to Muscle Interstitial Fluid After Oral Glucose Load in Obese Subjects

Obese subjects exhibit a delay in insulin action and delivery of insulin to muscle interstitial fluid during glucose/insulin infusion. The aim of the present study was to follow the distribution of insulin to skeletal muscle after an oral glucose load in obese subjects. We conducted an oral glucose tolerance test (OGTT) in 10 lean and 10 obese subjects (BMI 23 +/- 0.6 vs. 33 +/- 1.2 kg/m(2); P < 0.001). Insulin measurements in muscle interstitial fluid were combined with forearm arteriovenous catheterization and blood flow measurements. In the obese group, interstitial insulin was significantly (35-55%) lower than plasma insulin (P < 0.05) during the 1st h after the OGTT, whereas in lean subjects, no significant difference was found between interstitial and plasma insulin levels during the same time period. The permeability surface area product for glucose, representing capillary recruitment, increased in the lean group (P < 0.05) but not in the obese group (NS). Obese subjects had a significantly higher plasma insulin level at 90-120 min after oral glucose (398 +/- 57 vs. 224 +/- 37 pmol/l in control subjects; P < 0.05). The significant gradient between plasma insulin and muscle interstitial insulin during the first hour after OGTT suggests a slow delivery of insulin in obese subjects. The hindered transcapillary transport of insulin may be attributable to a defect in insulin-mediated capillary recruitment.

High interstitial fluid pressure — an obstacle in cancer therapy

Many solid tumours show an increased interstitial fluid pressure (IFP), which forms a barrier to transcapillary transport. This barrier is an obstacle in tumour treatment, as it results in inefficient uptake of therapeutic agents. There are a number of factors that contribute to increased IFP in the tumour, such as vessel abnormalities, fibrosis and contraction of the interstitial matrix. Lowering the tumour IFP with specific signal-transduction antagonists might be a useful approach to improving anticancer drug efficacy.

Volume-targeted therapy of increased intracranial pressure.

Fluid exchange across the intact blood-brain barrier (BBB) is counteracted by the low permeability to crystalloids (mainly Na+ and Cl-) combined with the high osmotic pressure (5,700 mm Hg) on both sides of the BBB. If the BBB is disrupted transcapillary water transport will be determined by the differences in hydrostatic and colloid osmotic pressure between the intra- and extracapillary compartments. Under these pathological conditions pressure autoregulation of cerebral blood flow is likely to be impaired and intracapillary hydrostatic pressure will depend on variations in systemic blood pressure. The volume targeted "Lund concept" can be summarized under four headings: A. Reduction of stress response and cerebral energy metabolism: B. Reduction of capillary hydrostatic pressure; C. Maintenance of colloid osmotic pressure and control of fluid balance: D. Reduction of cerebral blood volume. The efficacy of the protocol has been evaluated in experimental and clinical studies regarding the physiological and biochemical (utilizing intracerebral microdialysis) effects and the clinical experiences have been favourable.

PGE1 induced transcapillary transport of 51Cr-EDTA in rat skin measured by microdialysis.

Interstitial fluid pressure (P(if)) is a key determinant in increasing the transcapillary driving pressure, pulling fluid from the microcirculation into the interstitial space at the onset of acute inflammatory reactions and the oedema formation associated with these. Prostaglandin E1 (PGE1) induces lowering of P(if) in rat skin which increases transcapillary transport of 51Cr-EDTA into the center of a tumor as measured by microdialysis. The aim of this study was twofold: First, to evaluate and develop the microdialysis technique thoroughly with regard to its suitability for investigating transcapillary water transport in rat skin using 51Cr-EDTA as a tracer. Secondly, to evaluate the effect of PGE1 on transcapillary transport of 51Cr-EDTA. This study demonstrates that PGE1 increases transcapillary transport of 51Cr-EDTA into skin interstitium. There were no significant differences between the experimental probe and the control probe when calculations from the entire experiment (90 min) were compared. On the other hand, significant differences were observed by examining the experiment in smaller time intervals. PGE1 increased transcapillary transport of 51Cr-EDTA during the first 15 min when administered through the microdialysis probe. This observation suggests that increased blood flow and/or permeability-surface area product are responsible for raising the transcapillary transport of 51Cr-EDTA, i.e. the transport is diffusion limited. Administration of PGE1 through the probe rather than around the probe resulted in less scatter between experiments than when PGE1 was injected subcutaneously around the probe.

Delayed transcapillary transport of insulin to muscle interstitial fluid in obese subjects.

Insulin-resistant subjects have a slow onset of insulin action, and the underlying mechanism has not been determined. To evaluate whether a delayed transcapillary transport is part of the peripheral insulin resistance, we followed the kinetics of infused insulin and inulin in plasma and muscle interstitial fluid in obese insulin-resistant patients and control subjects. A total of 10 lean and 10 obese men (BMI 24 +/- 0.8 vs. 32 +/- 0.8 kg/m(2), P < 0.001) was evaluated during a hyperinsulinemic-euglycemic clamp (insulin infusion rate 120 mU. m(-2). min(-1)) combined with an inulin infusion. Measurements of insulin and inulin in plasma were taken by means of arterial-venous catheterization of the forearm and microdialysis in brachioradialis muscle combined with forearm blood flow measurements with vein occlusion pletysmography. The obese subjects had a significantly lower steady-state glucose infusion rate and, moreover, demonstrated a delayed appearance of insulin (time to achieve half-maximal concentration [T(1/2)] 72 +/- 6 vs. 46 +/- 6 min in control subjects, P < 0.05) as well as inulin (T(1/2) 83 +/- 3 vs. 53 +/- 7 min, P < 0.01) in the interstitial fluid. Also, the obese subjects had a delayed onset of insulin action (T(1/2) 70 +/- 9 vs. 45 +/- 5 min in control subjects, P < 0.05), and their forearm blood flow rate was significantly lower. These results demonstrate a delayed transcapillary transport of insulin and inulin from plasma to the muscle interstitial fluid and a delayed onset of insulin action in insulin-resistant obese subjects.

Sequential morphological and permeability changes in the rete capillaries during hyperglycaemia.

With the rete model of the eel swimbladder, we have studied the appearance and development of a microangiopathy during a 2-year period of hyperglycaemia. Hyperglycaemia was induced in the eel by chronic exposure to cold water. At 3-5 months, basement membrane thickness was twice the normal value and increased only slightly thereafter. Diffusion coefficients of permeability were measured in counter-current perfusion experiments for a variety of tracers that are believed to use different pathways of transcapillary transport. The permeability to sucrose was the first to significantly increase, at 6-8 months, followed by that of albumin, insulin, and inulin, at 9-11 months and that of sodium, at 18-24 months. The permeability to water and antipyrine remained stable throughout the study. The results indicate that in the rete model, chronic hyperglycaemia induces a rapid thickening of the capillary basement membrane and selective permeability increments in the various paths of transcapillary transport.

Mode of transcapillary transport of insulin and insulin analog NN304 in dog hindlimb: evidence for passive diffusion.

A defect in transcapillary transport of insulin in skeletal muscle and adipose tissue has been proposed to play a role in the insulin resistance that leads to type 2 diabetes, yet the mechanism of insulin transfer across the capillary endothelium from plasma to interstitium continues to be debated. This study examined in vivo the interstitial appearance of insulin in hindlimb using the fatty acid acylated insulin analog Lys(B29)-tetradecanoyl des-(B30) human insulin, or NN304, as a marker for insulin transport. If the insulin transport were a saturable process, then "swamping" the capillary endothelial insulin receptors with native insulin would suppress the subsequent appearance in interstitial fluid of the insulin analog NN304. This analog binds to insulin receptors with an affinity of about 50% of native insulin. Experimental conditions established a physiologic NN304 dose in the absence or presence of pharmacologic and saturating concentrations of regular human insulin. Euglycemic clamps were performed in dogs under inhalant anesthesia with deep hindlimb lymphatic sampling, representative of skeletal muscle interstitial fluid (ISF). In group 1 (n = 8), NN304 alone was infused (3.6 pmol center dot min(-1) center dot kg(-1)) from 60 to 360 min. In group 2 (n = 6), starting at time 0, human insulin was infused at a pharmacologic dose (60 pmol center dot min(-1) center dot kg(-1)) with the addition of NN304 infusion (3.6 pmol center dot min(-1) center dot kg(-1)) from 60 to 360 min. In group 3 (n = 4), the human insulin infusion was increased to a saturating dose (120 pmol center dot min(-1) center dot kg(-1)). Pharmacologic insulin infusion (group 2) established steady-state human insulin concentrations of 6,300 plus minus 510 pmol/l in plasma and 5,300 plus minus 540 pmol/l in ISF. Saturating insulin infusion (group 3) achieved steady-state human insulin concentrations of 22,000 plus minus 1,800 pmol/l in plasma and 19,000 plus minus 1,500 pmol/l in ISF. Total (bound and unbound) NN304 plasma concentrations rose from a steady state of 1,900 plus minus 110 (group 1) to 2,400 plus minus 200 pmol/l (group 2) and 3,100 plus minus 580 pmol/l (group 3), consistent with a competition-driven decline in NN304 clearance from plasma as the human insulin level increased (P < 0.05 by ANOVA). Steady-state interstitial NN304 concentrations also rose with increasing human insulin levels but did not achieve significance in comparison with analog alone (162 plus minus 15 vs. 196 plus minus 22 and 241 plus minus 53 pmol/l for group 1 versus groups 2 and 3, respectively; P = 0.20), yet the steady-state plasma:ISF ratio for NN304 remained essentially unchanged in the absence and presence of elevated human insulin levels (12.6 plus minus 1.2 vs. 12.4 plus minus 0.5 and 13.1 plus minus 1.5 for group 1 versus groups 2 and 3, respectively; P = 0.93). Last, NN304 rate of appearance in interstitial fluid (i.e., half-time to steady state) was similar between groups; mean half-time of 92 plus minus 4 min (NS between groups). In conclusion, appearance of the insulin analog NN304 in skeletal muscle interstitial fluid was constant whether in the absence or presence of human insulin concentrations sufficient to saturate the endothelial insulin receptors. These findings support the hypothesis, provided that the mechanism of insulin and NN304 transcapillary transport is similar, that transcapillary transport of insulin in skeletal muscle occurs primarily via a nonsaturable process such as passive diffusion via a paracellular or transcellular route.

Finite element model of antibody penetration in a prevascular tumor nodule embedded in normal tissue

We have developed a pharmacokinetic model for monoclonal antibodies (mAb) to aid in investigating protocols for targeting small primary tumors or sites of metastatic disease. The model describes the uptake of systemically-administered antibody by a prevascular spherical tumor nodule embedded in normal tissue. The model incorporates plasma kinetics, transcapillary transport, interstitial diffusion, binding reactions, and lymphatic clearance. Antigen internalization can easily be incorporated. Simulations obtained from a three-dimensional finite element analysis are used to assess errors in predictions from earlier models in which the influence of the normal tissue was collapsed into a boundary condition at the tumor surface. The model employing a Dirichlet boundary condition substantially overpredicted the mean total tumor mAb concentration at all times. Although the model with a concentration-dependent flux (composite) boundary condition underpredicted mAb concentration, the discrepancy with finite element results is only notable at early times. Sensitivity analyses were performed on mAb dose and on the coefficients for mAb diffusion in the tissue regions, since reported antibody diffusivity values have varied over 30-fold. The results of the study suggest that mAb diffusivity and mAb binding site density in tumors should have major influences on optimizing doses and scheduling of mAb administration in tumor targeting protocols.

Insulin insensitivity and delayed transcapillary delivery of insulin in oophorectomized rats treated with testosterone.

The importance of transcapillary insulin delivery as a regulated step was explored in an insulin resistant rat model. Oophorectomized female rats were exposed to testosterone (OVX + T) for 8 weeks and examined with insulin clamps, muscle microdialysis, and analyses of insulin distribution kinetics. The results were compared with those obtained in sham-operated control rats. After OVX + T, onset of glucose uptake in skeletal muscle was significantly (P < 0.001-0.05) delayed compared with controls as measured by the glucose infusion rate (GIR) during a euglycaemic, hyperinsulinaemic clamp (5 mU kg-1 min-1). The increase in interstitial insulin concentrations was also significantly (P < 0.05) delayed (15-20% lower) in OVX + T treated rats compared with control rats, but to such a small magnitude that this alone could not explain the late onset of the insulin effect. Skeletal muscle capillary density, examined histochemically, was diminished (P < 0.01-0.001) by 20-25% after treatment with OVX + T compared with control animals, as was the peripheral blood flow (P < 0.05) by 40-45%, measured with the microsphere technique. Insulin binding was reduced in proportion to the reduced (P < 0.01) vascular surface area by OVX + T treatment. Transcapillary transport rate of insulin, measured by comparisons of the kinetics of inulin and insulin spaces in muscle with time, tended (ns) to be lower after OVX + T compared with control rats (30-40%) as a reflection of the lower capillary surface area. The data suggest that the delayed onset of insulin action after OVX + T results from combined defects in the muscle cell at a postreceptor level and, to a lesser extent, from retarded transcapillary delivery of insulin.

Estimations of muscle interstitial insulin, glucose, and lactate in type 2 diabetic subjects.

Previous measurement of insulin in human muscle has shown that interstitial muscle insulin and glucose concentrations are approximately 30-50% lower than in plasma during hyperinsulinemia in normal subjects. The aims of this study were to measure interstitial muscle insulin and glucose in patients with type 2 diabetes to evaluate whether transcapillary transport is part of the peripheral insulin resistance. Ten patients with type 2 diabetes and ten healthy controls matched for sex, age, and body mass index were investigated. Plasma and interstitial insulin, glucose, and lactate (measured by intramuscular in situ-calibrated microdialysis) in the medial quadriceps femoris muscle were analyzed during a hyperinsulinemic euglycemic clamp. Blood flow in the contralateral calf was measured by vein plethysmography. At steady-state clamping, at 60-120 min, the interstitial insulin concentration was significantly lower than arterial insulin in both groups (409 +/- 86 vs. 1,071 +/- 99 pmol/l, P < 0.05, in controls and 584 +/- 165 vs. 1, 253 +/- 82 pmol/l, P < 0.05, in diabetic subjects, respectively). Interstitial insulin concentrations did not differ significantly between diabetic subjects and controls. Leg blood flow was significantly higher in controls (8.1 +/- 1.2 vs. 4.4 +/- 0.7 ml. 100 g(-1).min(-1) in diabetics, P < 0.05). Calculated glucose uptake was less in diabetic patients compared with controls (7.0 +/- 1.2 vs. 10.8 +/- 1.2 micromol. 100 g(-1).min(-1), P < 0.05, respectively). Arterial and interstitial lactate concentrations were both higher in the control group (1.7 +/- 0.1 vs. 1.2 +/- 0.1, P < 0. 01, and 1.8 +/- 0.1 vs. 1.2 +/- 0.2 mmol/l, P < 0.05, in controls and diabetics, respectively). We conclude that, during hyperinsulinemia, muscle interstitial insulin and glucose concentrations did not differ between patients with type 2 diabetes and healthy controls despite a significantly lower leg blood flow in diabetic subjects. It is suggested that decreased glucose uptake in type 2 diabetes is caused by insulin resistance at the cellular level rather than by a deficient access of insulin and glucose surrounding the muscle cell.

Lowering of tumoral interstitial fluid pressure by prostaglandin E(1) is paralleled by an increased uptake of (51)Cr-EDTA.

High intra-tumoral fluid pressure (TP(IF)) may impair uptake of anticancer drugs into tumors, contributing to poor efficiency in treatment of carcinomas. Here, we demonstrate that lowering of TP(IF) parallels increased transport of (51)Cr-EDTA (m.w. 341) into tumor interstitium. Introduction of 15 microg prostaglandin E(1) (PGE(1)) -methyl ester into the s.c. tissue surrounding transplanted rat colonic (PROb) carcinomas or chemically-induced rat mammary carcinomas, lowered TP(IF) by 30%. Transcapillary transport into the interstitium of PROb tumors quantified by microdialysis increased by 39.6% after PGE(1) treatment 40 min prior to administration of (51)Cr-EDTA (n=6; p<0.05) compared to vehicle (n=10). In mammary tumors, PGE(1) increased transport into the tumors by 86.9% over controls (n=16; p<0.05). Both tumors had well developed stroma containing collagen and hyaluronan. Our data demonstrate that adjuvant treatment with PGE(1) lowers TP(IF), and enhances transport into the tumors. This principle may be of value as adjuvant therapy in treatment of solid malignancies with currently used anticancer drugs.

Identificación de las principales proteínas de unión a IGF (IGFBP) en tejidos de rata normal

We investigated the presence of the main IGF-I binding proteins in rat tissues and the size of the complexes formed in each case. WLB and gel filtration chromatography were used to separate and identify four binding proteins: IGFBP-1 to IGFBP-4. In al1 the tissues studied, the presence of IGFBP-3 was detected, although its concentration seemed to change in each case, being most abundant in liver, kidney and heart, and less in lymphoid organs (spleen and thymus). IGFBP-1 and IGFBP-2 were found in liver and lung and also in heart and skeletal muscle, where their messenger RNAs, had not been previously reported, as is the case of the presence of IGFBP-4, identified in lung in the present study. In conclusion, our results show a typical profile for the IGFBPs, depending on the tissue, although it is not clear yet if they are the result of in situ synthesis or transcapillary transport. A better knowledge of their expression will give insight into their regulatory role on the IGF-I bioavailability in the different tissues.

Changes in blood-brain barrier permeability associated with insertion of brain cannulas and microdialysis probes

Blood-brain barrier (BBB) transcapillary transport was studied after insertion of cannulas and microdialysis probes into the brains of three groups of rats. Quantitative autoradiography was used to measure changes in BBB permeability around the insertion site. In the first group, BBB function was measured with 14 C -sucrose at times from immediately, and up to 28 days, after insertion of a microdialysis probe. BBB function was disrupted biphasically: a 19-fold increase in the influx constant ( K 1) of sucrose occurred immediately after insertion with a second 17-fold increase at 2 days, followed by a slow decline to 5 times normal values at 28 days. In the second group, 14 C -dextran (70 kDa) was used to measure BBB transcapillary transport; K 1 was increased 90-fold after probe insertion. In the 3rd group, 14 C -AIB ( α-aminoisobutyric acid) was used to evaluate BBB transport after insertion of a 27 gauge cannula, which was used to infuse 1 μl of saline over 5 min. The K 1 of AIB was increased 25 times control values. We conclude that BBB transcapillary transport function is disturbed in response to insertion of brain cannulas and/or microdialysis probes, that BBB dysfunction is maximal at the cannula or probe tip, varies with time after insertion, may persist for at least 28 days after insertion, and occurs over a wide molecular range of solutes. These results suggest caution when using microdialysis as a method to study normal BBB function, and suggest that microdialysis may overestimate the rate of transfer into and out of the brain.

Transcapillary Transport of Metaiodobenzylguanidine (MIBG) in Isolated Rat Heart

A better understanding of transcapillary transport for tracer metaiodobenzylguanidine (MIBG) is desirable for development of tracer kinetic models that yield meaningful estimates of neuronal uptake function from tissue radioactivity time courses. This study utilized a multiple-indicator approach in Langendorff-perfused rat hearts to define transport mechanisms and determine the capillary permeability-surface area (PSc) over a broad range of flow (F). Multiple injections within the same heart at different flows allowed characterization of the PSc/F relationship within the same heart. The coefficient of variation of E for multiple injections within the same hearts at constant flow was 6 ± 2% (3 to 6 injections in 9 hearts). In 10 hearts (4 to 6 injections per heart), flow was varied between 2.0–16.5 mL/min. PSc was found to be nearly proportional to flow in each heart ( r = 0.88 ± 0.14; slope = 0.23 ± 0.10; intercept = 11 ± 7 mL/min/g dry). Tissue hypoxia at low flows, as evidenced by enhanced lactate production, did not appear to influence the PSc/F relationship. Pharmacologic blockade of uptake-1 and uptake-2 had negligible affect on E or PSc as compared with flow-matched controls, although tissue retention was markedly reduced. The results show PSc of MIBG to be nearly proportional to flow but independent of specific neuronal and extraneuronal transport mechanisms and tissue hypoxia. The results are consistent with a passive diffusion process across the capillary endothelial barrier. The increase in PSc with increasing flow could reflect capillary recruitment and/or enhanced capillary permeability.

Contribution of the endothelium to transcapillary insulin transport in rat isolated perfused hearts.

Capillary endothelial cells are thought to limit the transport of insulin from the vascular to the interstitial space, resulting in attenuated hormonal action at target sites. This study examined the contribution of endothelial cells to the regulation of transcapillary insulin transport in rat hearts in vitro. Hearts were perfused with a protein-free buffer that resulted in the generation of a substantial amount of interstitial fluid (transudate) that was collected at the surface of ventricles. Insulin (0.05-1 U/l) was added to the perfusate, and its transfer kinetics to and clearance from the interstitium were analyzed from insulin measurements in transudate of hearts with intact or collagenase-disrupted endothelium. In endothelium-intact hearts (n = 5-8), the steady-state insulin concentration in transudate was 29 +/- 4, 30 +/- 2, 53 +/- 1, 103 +/- 6, and 97 +/- 4% of perfusate concentrations at 0.05, 0.1, 0.2, 0.5, and 1 U/l insulin, respectively. The corresponding apparent rate constants for transport (k(in)) increased from 0.03/min to -0.27/min, indicating a nonsaturable transport process. The transport rate for [3H]insulin (1.2 nmol/l; n = 5) was identical to an equimolar concentration of insulin (0.2 U/l), strongly indicating the same mode of transport. In endothelium-disrupted hearts (n = 3-5), the same perfusate/transudate concentration ratios were observed--that is, a gradient at low insulin concentrations (0.05-0.2 U/l) and complete equilibration at higher insulin concentrations, suggesting a contribution of reabsorption processes back into the vascular space in the generation of the gradient. Finally, inhibition of endothelial nitric oxide (NO) formation by NG-nitro-L-arginine (200 micromol/l) affected neither k(in) nor the extent of transendothelial insulin transport in the presence of an intact endothelium. We concluded that 1) capillary endothelial cells affect the transcapillary transport of insulin by slowing the transfer to the interstitium, 2) insulin is transported by a bidirectional convective transport rather than by a saturable receptor-mediated mechanism, and 3) endothelium-derived NO is without effect on transcapillary insulin transport in this model.

Reduction of Capillary Permeability in the Fructose-Induced Hypertensive Rat

Impaired insulin transcapillary transport and the subsequent decrease in insulin delivery to target organs have been suggested to play a role in insulin resistance. These defects were studied in fructose-fed rats, an animal model with insulin resistance. For this study, male Sprague-Dawley rats were fed with either a 60% fructose enriched (F) or a standard chow diet (N) for a total of 2, 4, or 8 weeks. Capillary permeability to albumin was assessed at the end of each dietary period by quantifying the extravasation of albumin-bound Evans blue (EB) dye in different organs. Unanesthetized animals were injected with Evans blue dye (20 mg/kg) in the caudal vein 10 min before being killed and EB dye was extracted by formamide from selected organs collected after exsanguination. As expected, rats had an increase in blood pressure upon feeding with fructose at 4 and 8 weeks (F, 149 ± 3 mm Hg; N, 139 ± 3 mm Hg; P < .05). Using this technique, we showed a 56% and a 51% reduction in capillary permeability in skeletal muscles at 4 and 8 weeks of fructose feeding, respectively (4 weeks: N, 44.5 ± 5.0 μg/g of dry tissue; F, 19.8 ± 4.2 μg/g of dry tissue; P < .01 and 8 weeks: N, 23.3 ± 3.7 μg/g of dry tissue; F, 11.3 ± 4.0 μg/g of dry tissue; P < .05). Similar changes were observed at 4 weeks in the thoracic aorta (N, 82.8 ± 8.8 μg/g of dry tissue; F, 53.0 ± 5.1 μg/g of dry tissue; P < .02) and skin (N, 36.0 ± 5.3 μg of dry tissue; F, 15.0 ± 2.3 μg/g of dry tissue; P < .02) and at 8 weeks in the liver (N, 107.5 ± 4.3 μg/g of dry tissue; F, 80.9 ± 3.2 μg/g of dry tissue; P < .01). In conclusion, fructose feeding is accompanied by a significant and selective reduction of Evans blue leakage primarily in skeletal muscle and liver, and transiently in the skin and aorta, consistent with a role for decreased tissue insulin delivery in insulin resistance.

Bronchial temperature as a key to the interior pulmonary capillary bed of anaesthetized dogs.

The terminal airways are separated from the surrounding pulmonary capillaries by a tissue layer of a few micrometers in thickness only. Therefore, it should be possible to gain information about in vivo transcapillary heat transport of the interior pulmonary vascular bed by recording the terminal bronchial temperature. For this purpose, we studied temperature-time curves in the pulmonary artery, bronchial system and the aorta of six anaesthetized dogs permanently instrumented for measuring pulmonary blood flow. Thermistors recorded temperature changes at the three locations after injection of 5 ml cold solution into the right atrium. From the observed temperature-time curves mean transit times between the three recording sites were calculated for various pulmonary blood flows (integral of delta Ttdt/integral of delta Tdt) (range 1.1-3.5 1/ min). We found that the temperature-time curves of the bronchial system resemble typical "dilution" curves and are interspaced between those in the pulmonary artery and those in the aorta. Regardless of pulmonary blood flow, mean transit times from the pulmonary artery to the distal bronchial system and from there to the aorta were about equal. We conclude that transcapillary heat transfer generates bronchial temperature-time curves which permit an estimation of the relation of precapillary to postcapillary mean transit times in the interior of the lung.

Competition between Polyanions in Glomerular Binding and Renal Clearance

This study tests the hypothesis that exogenous polyanions may accumulate in the glomerular capillary wall and thereby provide fixed negative charges that will be effective, through electrostatic interactions, in governing the transcapillary transport of charged molecules. We have tested the effects of high concentrations of dextran sulfate, heparin, and orosomucoid on the fractional clearance of albumin and dextran sulfate using the isolated perfused kidney technique. We demonstrate that all these exogenous polyanions are without effect on the fractional clearance of albumin. Augmentation of glomerular charge through the binding of dextran sulfate or orosomucoid is very small compared to the charge augmentation by albumin. These results agree with previous studies which demonstrate that electrostatic interactions governing glomerular transcapillary wall transport are negligible. This study also demonstrates that there is no plausible correlation between the fixed negative charge contributed by endogenous metabolically labeled glomerular heparan sulfate and the manifestation of apparent charge selectivity as determined with dextran sulfate. The results are also consistent with previous studies that the renal processing of both dextran sulfate and albumin is associated with specific cellular uptake.

The heart as a self-regulating system: integration of homeodynamic mechanisms*

In the past the study of mechanical and electrical properties of the heart has been disjointed with minimal overlap and unification. The fact remains that these features are tightly coupled and central to the functioning heart. The maintenance of adequate cardiac output relies upon the highly integrated autoregulatory mechanisms and modulation of cardiac myocyte function. Regional ventricular mechanics and energetics are dependent upon muscle fiber stress-strain rate, the passive properties of myocardial collagen matrix, adequate vascular perfusion, transcapillary transport and electrical activation pattern. Intramural hydraulic "loading" is regulated by coronary arterial and venous dynamics. All of these components are under the constant influence of intrinsic cardiac and extracardiac autonomic neurons, as well as circulating hormones. A brief overview of the putative regulation of these various components is presented in this paper.