[TMPRSS2-Erg/AR-V7: Prognostic value of tests in urine and biopsy rince material in prostate cancer]. / TMPRSS2-Erg/AR-V7 : valeur diagnostique des tests urinaires et sur liquides biopsiques dans le cancer prostatique.

INTRODUCTION: Nowadays, diagnostic biomarker research is oriented on a genomic characterisation of prostate cancer (PCa). This study evaluated diagnostic values of TMPRSS2-Erg fusion transcripts expression (TE) and androgen receptor variant 7 (AR-V7) on urine (tU) and biopsic rince material (tLRB) samples. MATERIALS AND METHODS: TE and AR-V7 have been tested by RT-PCR and RT-qPCR on urine and biopsies' rince liquid on 372 patients referred for prostate biopsies. RESULTS: Two hundred thirty-three patients (62%) were diagnosed with PCa. tU.AR-V7 was positive for 15 healthy patients (28%) and 30 patients diagnosed with PCa (37%). tLRB.AR-V7 was positive for 66 patients (42%) diagnosed with PCa. Concerning TE for patients diagnosed with PCa, tU was positive for 59 patients (54%) and tLRB for 132 (55%). TE and TE/AR-V7 combination were significantly associated with PCa (P<0.001), as tLRB.AR-V7 (P<0.001). Sensitivity and specificity for TE/AR-V7 combination for PCa were respectively: tU.TE/AR-V7 67% and 70%, tLRB.TE/AR-V7 68.8% and 71%, and, tUtLRB.TE/AR-V7 83% and 60%. There was no benefit for AR-V7 and TE association versus TE alone when comparing AUC. CONCLUSION: AR-V7 is not specific of PCa because of detection on healthy patients. This study did not managed to show a sufficient diagnostic value for TE/AR-V7 combination on urine and biospic rince material tests. LEVEL OF EVIDENCE: 3.

Epididymal Binder of SPerm genes and proteins: what do we know a decade later?

Binder of SPerm (BSP) proteins from ungulates (more specifically bull, bison, buffalo, stallion, boar, goat, and ram) have been extensively studied in the past 30 years. These proteins secreted by seminal vesicles constitute between 1 and 60% of total seminal plasma proteins depending on the species. In addition to sharing many biochemical characteristics such as the ability to bind to gelatin, glycosaminoglycans, choline phospholipids, and lipoproteins, they also share a main function: promoting sperm capacitation. Over the last 10 years, new members of the BSP superfamily have been discovered. These proteins found in bulls, humans, mice, and rabbits are expressed in the epididymides rather than in seminal vesicles and constitute only a minute percentage of the seminal plasma proteins. However, they share many characteristics with BSPs expressed by accessory glands including their structure, their ability to bind to the aforementioned BSP ligands, as well as their ability to promote sperm capacitation. More investigations need to be done on epididymal BSP proteins, but studies described in this review constitute a solid foundation toward deciphering the significance of epididymal BSP proteins in male fertility.

Implication of the human Binder of SPerm Homolog 1 (BSPH1) protein in capacitation.

Binder of SPerm (BSP) proteins are a family of proteins expressed exclusively in the male reproductive tract (seminal vesicles or epididymis) of several mammalian species. They are known to promote capacitation, a sperm maturation step essential for fertilization. Our recent studies have shown that in human, the Binder of SPerm Homolog 1 (BSPH1) is expressed solely in epididymal tissues. The goal of the current study was to characterize BSPH1 and evaluate its effect on different sperm functions. A human recombinant BSPH1 (rec-BSPH1) was produced, purified and refolded. Rec-BSPH1 was found to share many characteristics with other members of the BSP superfamily, as it was able to bind gelatin and heparin as well as capacitate sperm. Rec-BSPH1 had no effect on sperm acrosome reaction or any sperm motility parameters. Native BSPH1 was localized on the equatorial segment, post-acrosomal segment and neck of ejaculated human sperm. Rec-BSPH1, following incubation with washed ejaculated human sperm, exhibited binding patterns similar to the native protein. These results show that the human epididymal BSPH1 shares many biochemical and functional characteristics with BSP proteins secreted by seminal vesicles of ungulates, and behaves similarly to its murine epididymal orthologue BSPH1. This study of human BSPH1 brings us one step closer to understanding the importance of this protein in male fertility.

Dark matter results from 100 live days of XENON100 data.

We present results from the direct search for dark matter with the XENON100 detector, installed underground at the Laboratori Nazionali del Gran Sasso of INFN, Italy. XENON100 is a two-phase time-projection chamber with a 62 kg liquid xenon target. Interaction vertex reconstruction in three dimensions with millimeter precision allows the selection of only the innermost 48 kg as the ultralow background fiducial target. In 100.9 live days of data, acquired between January and June 2010, no evidence for dark matter is found. Three candidate events were observed in the signal region with an expected background of (1.8 ± 0.6) events. This leads to the most stringent limit on dark matter interactions today, excluding spin-independent elastic weakly interacting massive particle (WIMP) nucleon scattering cross sections above 7.0 × 10(-45) cm(2) for a WIMP mass of 50 GeV/c(2) at 90% confidence level.

Search for light dark matter in XENON10 data.

We report results of a search for light (≲10 GeV) particle dark matter with the XENON10 detector. The event trigger was sensitive to a single electron, with the analysis threshold of 5 electrons corresponding to 1.4 keV nuclear recoil energy. Considering spin-independent dark matter-nucleon scattering, we exclude cross sections σ(n)>7×10(-42) cm(2), for a dark matter particle mass m(χ)=7 GeV. We find that our data strongly constrain recent elastic dark matter interpretations of excess low-energy events observed by CoGeNT and CRESST-II, as well as the DAMA annual modulation signal.

First dark matter results from the XENON100 experiment.

The XENON100 experiment, in operation at the Laboratori Nazionali del Gran Sasso in Italy, is designed to search for dark matter weakly interacting massive particles (WIMPs) scattering off 62 kg of liquid xenon in an ultralow background dual-phase time projection chamber. In this Letter, we present first dark matter results from the analysis of 11.17 live days of nonblind data, acquired in October and November 2009. In the selected fiducial target of 40 kg, and within the predefined signal region, we observe no events and hence exclude spin-independent WIMP-nucleon elastic scattering cross sections above 3.4 × 10⁻44 cm² for 55 GeV/c² WIMPs at 90% confidence level. Below 20 GeV/c², this result constrains the interpretation of the CoGeNT and DAMA signals as being due to spin-independent, elastic, light mass WIMP interactions.

Limits on spin-dependent WIMP-nucleon cross sections from the XENON10 experiment.

XENON10 is an experiment to directly detect weakly interacting massive particles (WIMPs), which may comprise the bulk of the nonbaryonic dark matter in our Universe. We report new results for spin-dependent WIMP-nucleon interactions with 129Xe and 131Xe from 58.6 live days of operation at the Laboratori Nazionali del Gran Sasso. Based on the nonobservation of a WIMP signal in 5.4 kg of fiducial liquid xenon mass, we exclude previously unexplored regions in the theoretically allowed parameter space for neutralinos. We also exclude a heavy Majorana neutrino with a mass in the range of approximately 10 GeV/c2-2 TeV/c2 as a dark matter candidate under standard assumptions for its density and distribution in the galactic halo.

First results from the XENON10 dark matter experiment at the Gran Sasso National Laboratory.

The XENON10 experiment at the Gran Sasso National Laboratory uses a 15 kg xenon dual phase time projection chamber to search for dark matter weakly interacting massive particles (WIMPs). The detector measures simultaneously the scintillation and the ionization produced by radiation in pure liquid xenon to discriminate signal from background down to 4.5 keV nuclear-recoil energy. A blind analysis of 58.6 live days of data, acquired between October 6, 2006, and February 14, 2007, and using a fiducial mass of 5.4 kg, excludes previously unexplored parameter space, setting a new 90% C.L. upper limit for the WIMP-nucleon spin-independent cross section of 8.8x10(-44) cm2 for a WIMP mass of 100 GeV/c2, and 4.5x10(-44) cm2 for a WIMP mass of 30 GeV/c2. This result further constrains predictions of supersymmetric models.

Bioequivalence of abacavir generic and innovator formulations under fasting and fed conditions.

OBJECTIVE: Abacavir sulfate is a synthetic carbocyclic nucleoside analogue indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. The objective of the current study was to determine the bioequivalence between a generic formulation of abacavir and the innovator product. MATERIAL AND METHODS: A total of 80 subjects were randomly assigned to receive a single 300 mg oral dose of abacavir sulfate as the generic (Ranbaxy-Abacavir, Ranbaxy Laboratories Ltd., equivalent to 300 mg of abacavir) and innovator (Ziagen, GlaxoSmithKline) tablet formulations in 2-way crossover studies performed under fasting (n=40) and fed (n=40) conditions. Multiple blood samples were collected over 14 hours and plasma concentrations of abacavir were assayed using an LC/MS/MS method with a limit of quantitation of 25.0 ng/ml. Pharmacokinetic (PK) parameters were calculated using noncompartmental methods. RESULTS: Under fasting conditions, geometric mean area under the curve from time 0 to the last measurable concentration (AUC(0-t)), area under the curve extrapolated to infinity (AUC(0-infinity) and maximum plasma concentrations (Cmax) of abacavir for the generic (5565 ng x h/ml, 5668 ng x h/ml and 2526 ng/ml, respectively) and innovator (5675 ng x h/ml, 5770 ng x h/ml and 2528 ng/ml, respectively) products were very similar. Under fed conditions, mean values of AUC(0-t) AUC(0-infinity) and Cmax for the generic (4487 ng x h/ml, 4571 ng x h/ml and 1841 ng/ml, respectively) and innovator (4574 ng x h/ml, 4654 ng x h/ml and 1781 ng/ml, respectively) formulations were also very similar. Ratios of LSM and 90% confidence intervals of PK parameters between the 2 formulations were within 80.0 - 125.0% under fasting and fed conditions, suggesting that the 2 tablet formulations resulted in similar rate and extent of bioavailability. Adverse events for the generic and innovator products were similar in nature and frequency in the fasting and fed studies. CONCLUSIONS Based on the above results, the generic tablet formulation of abacavir developed by Ranbaxy should be equally effective as the innovator product.

Sodium intake, large artery stiffness, and proteoglycans in the spontaneously hypertensive rat.

Although the role of sodium in hypertension has been documented extensively, its effect on large arteries has not been well documented. We examined the effect of high-sodium (8%) diet and the diuretic indapamide (IND) on systemic hemodynamics and aortic wall structure and composition in collagen, elastin, and hyaluronan. Four groups of spontaneously hypertensive rats (SHR) were studied after 8 weeks: those on a normal diet (SHR), a high-sodium diet (SHR+NaCl), a normal diet with IND (SHR+IND), and a high-sodium diet with IND (SHR+NaCl+IND). Mean BP, which was not normalized with IND, was comparable for all groups. Systemic arterial compliance averaged 3.8, 2.5, 4.9, and 3.3 mL/mm Hg. 10(-3), respectively, for the SHR, SHR+NaCl, SHR+IND, and SHR+NaCl+IND groups (P<0.003 and <0.05 for NaCl and IND effects). Wall thickness increased only in the SHR+NaCl group (P<0.01). Aortic wall COL decreased from 16 116 in the SHR to 12 382 micrometer(2)/mm in the SHR+NaCl+IND (P<0.005) group. IND alone had no effect on elastin, but the elastin/collagen ratio was increased significantly. Aortic hyaluronan averaged 2343, 266, 3243, and 1052 micrometer(2)/mm, respectively, for the SHR, SHR+NaCl, SHR+IND, and SHR+NaCl+IND groups (P<0.0001 for NaCl and IND effects). Changes in systemic arterial compliance were significantly and positively correlated with aortic hyaluronan contents. Thus, high-sodium diet affects the structural and functional characteristics of large arteries independently of BP. A high-sodium diet, in addition to a diuretic regimen with IND, affects simultaneously aortic hyaluronan contents and large artery mechanical properties through pressure-independent mechanisms that remain to be defined.

Effects of tranexamic acid and aprotinin, two antifibrinolytic drugs, on PAF-induced plasma extravasation in unanesthetized rats.

Two antifibrinolytic drugs, tranexamic acid (TXA), and aprotinin (APR), are currently used to improve the recovery of patients following major surgery while reducing blood loss. Their mechanisms of action have yet to be fully understood. Here, we examined (1) the effects of TXA or APR on basal vascular permeability (VP) and (2) the effects of TXA or APR on platelet-activating factor (PAF)-induced increase of VP in normal unanesthetized rats. Evans blue dye (EB) bound to albumin was used as the marker of extravasation in selected tissues. In normal rats, PAF (1 microg/kg i.v.) increased VP in most selected tissues including bronchi, aorta, duodenum and pancreas without affecting blood pressure. TXA (up to 300 mg/kg i.v.) had no significant effect on basal VP in any tissues, while APR (30000 KIU/kg i.v.) decreased basal VP in 5 out of 8 tissues. Pre-treatment with TXA decreased PAF-induced increases of VP in the microcirculation of the thoracic and abdominal aorta, the duodenum and the pancreas, from 35% to 41%. TXA was mostly effective at an i.v. dose of 100 mg/kg with a 2 h of pre-treatment period. Pre-treatment with APR also reduced PAF-induced increases of VP in selected tissues by 35 to 61%. The i.v. dose of 30000 KIU/mg was optimal when injected at least 30 min before the administration of PAF + Evans blue. These results suggest that the beneficial effect of APR and TXA, following cardiopulmonary bypass (CPB) and other type of surgeries, may be attributed to the inhibition of plasma exudation mediated, at least in part, by PAF. Thus, TXA and APR may improve patients recovery by reducing the capillary leakage of albumin, associated with interstitial edema formation, and maintaining intravascular fluid volume.

The blood vessel, linchpin of diabetic lesions.

The morbidity and mortality associated with diabetes mellitus are essentially related to the vascular lesions that develop over time in this condition. Both the macrocirculation and microcirculation are involved, and as a consequence, vital organs such as the brain, retina, heart, and kidney and the limbs become damaged. Because microalbuminuria represents the earliest and probably most sensitive indication of endothelial dysfunction in diabetes mellitus, the results of pharmacologic intervention with angiotensin-converting enzyme inhibitors, which treat glomerular hypertension were the first indication of potential beneficial effects in reducing diabetic nephroplasty. The nature of endothelial dysfunction related to diabetes is probably not homogeneous, since microcirculation networks are affected at different periods and with variable intensity. This appears to be the case for the aorta, the heart, segments of the digestive tract, the skin, and the skeletal muscle, the largest consumer of insulin. Although the aorta and large arteries contain a small portion of the total blood volume, their distribution of blood flow (pulse pressure) to peripheral organs may affect endothelial function in the microcirculation. Changes in the structure of conduit arteries, partly responsible for the alteration in compliance characteristics, could well be related to the way these arteries are fed by the vasa vasorum system. This report describes a new in vitro approach to examine capillary permeability in normal and alloxan-induced diabetic rabbits. Preliminary results indicate that the size of terminal arterioles of the vasa vasorum (increased diameter) and the capillary permeability to albumin (markedly enhanced) in this specialized network are profoundly affected in the thoracic aorta obtained from diabetic animals. Albumin extravasation into the interstitial fluid compartment of the aorta is likely to lead to structural and physicochemical changes: in fact, removal of interstitial macromolecules via lymphatic drainage is poor in the blood vessel wall of large arteries. This experimental approach is likely to be useful in the exploration of medications affecting the structure and function of conduit vessels.

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 microg/g of dry tissue; F, 19.8 +/- 4.2 microg/g of dry tissue; P < .01 and 8 weeks: N, 23.3 +/- 3.7 microg/g of dry tissue; F, 11.3 +/- 4.0 microg/g of dry tissue; P < .05). Similar changes were observed at 4 weeks in the thoracic aorta (N, 82.8 +/- 8.8 microg/g of dry tissue; F, 53.0 +/- 5.1 microg/g of dry tissue; P < .02) and skin (N, 36.0 +/- 5.3 microg of dry tissue; F, 15.0 +/- 2.3 microg/g of dry tissue; P < .02) and at 8 weeks in the liver (N, 107.5 +/- 4.3 microg/g of dry tissue; F, 80.9 +/- 3.2 microg/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.

Aprotinin, an antifibrinolytic drug, attenuates bradykinin-induced permeability in conscious rats via platelets and neutrophils.

Two antifibrinolytic drugs, tranexamic acid (TXA) and aprotinin (APR), are used to improve the recovery of patients following cardiac surgery while reducing blood loss. Their mechanisms of action have yet to be fully understood. To investigate their possible mechanisms of action during cardiopulmonary bypass, we examined (i) the effects of TXA and APR on bradykinin (BK) induced vascular permeability (VP) in conscious rats, (ii) the roles of platelets and neutrophils in this reaction, and (iii) the effects of TXA or APR on BK responses in platelet- or neutrophil-depleted rats. Evans blue dye (EB) was used as the marker of extravasation. The animals were treated with antiplatelet serum for platelet depletion or with methotrexate for neutrophil depletion. In normal rats, BK increased VP in most tissues. Thrombocytopenia and neutropenia also increased basal VP. TXA had no significant effect whereas APR decreased basal VP. In the second series of experiments, APR significantly attenuated BK-induced increases in VP, whereas TXA was completely ineffective. Platelet depletion did not affect BK-induced increases of VP, except for a massive plasma exudation in the lung parenchyma. Neutrophil depletion also had no effect on BK-induced increases of VP, except for an attenuation in the duodenum. In the third and last series of experiments, TXA potentiated the effect of BK in the upper and lower bronchi of platelet-depleted rats, compared with the effects of TXA on BK in normal animals, except in the lung parenchyma, where TXA blocked the increase of VP induced by BK. APR also potentiated the effect of BK in the lower bronchi of platelet-depleted rats. Overall, the inhibitory effect of APR on the VP induced by BK in normal rats was attenuated in platelet-depleted rats. Like TXA, APR blocked the increase of VP induced by BK in the lung parenchyma of platelet-depleted rats. In neutrophil-depleted rats, TXA did not affect the permeabilizing response to BK. In those rats, the inhibitory effect of APR against BK increases of VP was attenuated. These results show that the beneficial effect of APR, but not TXA, following cardiac surgery may be attributed to the inhibition of plasma exudation mediated, in part, by BK. In addition, platelets and neutrophils do not appear to be involved in BK-mediated plasma exudation. However, both cell types are essential for the regulation of basal VP. Finally, the mechanism underlying the protective inhibitory effect of APR on BK-induced increases of VP involves, at least in part, platelets and neutrophils, since the inhibitory effect of APR is attenuated in thrombocytopenic and neutropenic rats. Both cell types are not involved in the action of TXA on VP. Therefore, maintaining platelet and neutrophil counts following cardiopulmonary bypass could enhance the protective effect of APR.

[Role of neutral endopeptidases in capillary dysfunctions of diabetic origin in rats]. / Rôle des endopeptidases neutres dans les dysfonctions capillaires d'origine diabétique chez le rat.

Among numerous complications associated with diabetes, the alterations of the normal properties of various microcirculation circuits lead to important dysfunctions which may contribute to target organ damage. As the endothelium plays a crucial role in the microcirculatory circuits, it is suggested that diabetes may influence both the physical and endocrine properties of that cell layer. In 1995, we reported an important increase in plasma extravasation in a model of diabetes in rats treated with streptozotocin. The increase of plasma extravasation was particularly significant in the pulmonary, skin and splanchnic areas. In that particular study, it was of interest that inhibitors of neutral endopeptidases, such as thiorphan, phosphoramidon and SQ 28,603 (specific inhibitor of the recombinant neutral endopeptidases2) corrected almost completely the increase of plasma extravasation induced by diabetes when compared with control rats. It is also worthy of note that the three above-mentioned inhibitors failed to normalize in any case the hyperglycaemia associated with the diabetes in these animals. The present document is a summary synthesis of the putative role of neutral endopeptidases and of the beneficial effects of the inhibitors of these enzymes in diabetes-induced plasma extravasation in the rat.

[Contribution of the vascular interstitial matrix to induced contraction by angiotensin II. In vitro studies on the rabbit aorta, mesenteric artery and vein]. / Contribution de la matrice interstitielle vasculaire à la contraction induite par l'angiotensine II. Etudes in vitro sur l'aorte, l'artère et la veine mésentériques du lapin.

This study examines the contribution of hyaluronan, a rich anionic glycoprotein, to angiotensin-II-induced contraction (AII: 10(-11) to 10(-8) M) of endothelium-free strips of aorta, mesenteric artery and vein obtained from normal rabbits. Tissues are treated with hyaluronidase (HYAL: 1 mg/ml) during 60 min before being mounted in organ baths superfused with normal Krebs solution for isotonic contraction. Isotonic contraction of the mesenteric artery to the four highest doses of AII is reduced by 50 to 60% following HYAL treatment, compared to the normal contraction curve (0.01 < p < 0.001). Isotonic contraction of the aorta and mesenteric vein to AII is not influenced by HYAL. Isometric contraction curves of the three tissues to AII are not modified by HYAL. In additional experiments, the Krebs solution was selectively enriched in calcium (3.8 mM/l) and in sodium (160 mEq/l) to verify if the effect of HYAL is associated with interstitial washing in the concentration of these cations, because of the hyaluronan digestion. In fact, the calcium-rich superfusion is associated with complete correction of the HYAL-induced reduction of the mesenteric artery isotonic contraction. The sodium-rich superfusion failed to normalize the depressed mesenteric artery contraction. Since HYAL only affected isotonic contraction of the resistance artery (mesenteric), it is likely that the interstitial space of this tissue contains more hyaluronan than the aortic or mesenteric vein matrix, or that HYAL only affected the smooth muscle cell population involved in the circular tonus of the resistance vessel. Correction of the abnormality by calcium enrichment of the Krebs solution suggests that a relative diminution and/or a redistribution of this important cation, obtained following the interstitial degradation of hyaluronan.

Comparison of the pre- and post-capillary vascular reactivity in the rat and guinea pig perfused mesenteric bed.

The present study reports the development and optimization of a new model by which the vasoactive properties of various agents can be monitored in the endothelium-intact pre- and post-capillary mesenteric vasculatures of the guinea pig. In contrast with the rat, the guinea pig pre-capillary mesenteric circulation responds to neurokinins via an endothelium-dependent vasodilation (ED50 for the NK-1 selective agonist, 20.2 pmol). In addition, in the rat as in the guinea pig mesenteric vasculature, kinins induced an endothelium-dependent vasodilation in the venous and arterial circuits. ED50 values for rat were arterial, 1.0 nmol, venous, 100 pmol; ED50 values for guinea pig were arterial, 5.5 pmol, venous, 1.9 pmol. The pharmacology of the receptors for these vasoactive agents (and others) as well as the localization of these entities is discussed. In addition, an interspecies comparison is made between the pre- and post-capillary vascular reactivity in the mesenteric circuit of the rat and guinea pig. Our studies should elucidate the pharmacodynamic properties of vasoactive agents in the pre- and post-capillary circulation and shed further light on the contribution of these agonists in hydrostatic force changes and in plasma extravasation phenomena.

Consequences of alteration in capillary permeability.

In this review paper, three aspects related to alteration in capillary permeability, based on a series of recent observations from this laboratory, are examined. Firstly, the determinants of capillary extravasation, which include pre- and post-capillary resistances in different microcirculation networks, as well as endothelial permeability per se, are described with particular reference to the heterogeneous character of both regulatory components, reported by this and other groups. Secondly, the endothelium-interstitium relationship, responsible in part for the maintenance of the interstitial compartment physicochemical characteristics, is introduced as an important factor in regulating the traffic of vital nutrients delivered to the cell mass, and the removal of waste products from the cellular compartment to the microcirculation, for ultimate excretion. Examined in this manner, it appears that modulation of capillary permeability is essential for the maintenance of cellular life, yet the neurohumoral mechanisms involved in the control of microcirculation networks are just starting to be identified. A number of morbid conditions characterized by multiorgan involvement exhibit a common pathophysiological denominator which involves endothelium-interstitium relationships, as illustrated in experimental animal models of arterial hypertension, diabetes mellitus, heart failure, and degenerative renal diseases. Enhanced capillary permeability associated with local interstitial edema in specific organs, such as the heart and the kidney, in arterial hypertension and diabetes mellitus, as well as decreased permeability in peripheral tissues, such as the skeletal muscle and the skin, in congenital cardiomyopathy, have been documented. It is likely that alteration in the characteristics of interstitial matrix composition contributes to target organ damage in these examples of systemic disorders from different etiologies. Thirdly, the recent identification of autocoids and hormones involved in the direct and indirect control of capillary permeability has led to the development of pharmacological tools capable of modulating pre- and post-capillary vascular tonus, as well as endothelial permeability. Angiotensin II antagonism, bradykinin B1-receptor inhibition, and modulation of eicosanoid production, in particular thromboxane A2, are associated in some of the above-described disorders, with normalization of capillary permeability defects, and occasionally with improvement in organ function. The eventual development of agents capable of directly controlling the physicochemical characteristics of the interstitial matrix should be of interest, not only for preventing the development of irreversible matrix structural alterations but also for facilitating the traffic of metabolites between capillaries and the cell mass of vital organs.