Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Permeability”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,261 records · Page 70Linked to original sources
PubMed1992

Kinetics of urea and water permeability activation by vasopressin in rat terminal IMCD.

The vasopressin-regulated urea carrier and the vasopressin-regulated water channel are distinct transporters present in the apical membrane of the inner medullary collecting duct (IMCD) cells. To assess whether these transporters may be activated by common mechanisms, we investigated the time course of increase of urea and water permeability in response to vasopressin in isolated perfused terminal IMCD segments. The permeability responses were determined through the use of a specially designed continuous-flow fluorometer for rapid analysis of collected tubule fluid samples. The time courses of activation of the two transporters by vasopressin were virtually identical. Both urea and water permeability displayed a rapid initial increase for the first 10 min followed by a slower secondary response lasting at least 30 additional min. The lag periods between vasopressin addition and the initial rise in permeability were the same for urea (34.2 +/- 8.8 s) and water (34.8 +/- 8.9 s) transport activation. Furthermore, the initial rate of permeability increase (normalized by the total increase) was not significantly different for the two transport processes. The lag periods for the increase in urea permeability in response to 8-bromoadenosine 3',5'-cyclic monophosphate and vasopressin were not significantly different. The results are consistent with the view that the rate-limiting step in vasopressin-induced activation is the same for both the urea carrier and water channel and may lie at a step beyond generation of adenosine 3',5'-cyclic monophosphate.

Animals↗
PubMed1998

Water and solute permeabilities of medullary thick ascending limb apical and basolateral membranes.

The medullary thick ascending limb (MTAL) reabsorbs solute without water and concentrates NH4+ in the interstitium without a favorable pH gradient, activities which require low water and NH3 permeabilities. The contributions of different apical and basolateral membrane structures to these low permeabilities are unclear. We isolated highly purified apical and basolateral MTAL plasma membranes and measured, by stopped-flow fluorometry, their permeabilities to water, urea, glycerol, protons, and NH3. Osmotic water permeability at 20 degrees C averaged 9.4 +/- 0.8 x 10(-4) cm/s for apical and 11.9 +/- 0.5 x 10(-4) cm/s for basolateral membranes. NH3 permeabilities at 20 degrees C averaged 0.0023 +/- 0.00035 and 0.0035 +/- 0.00080 cm/s for apical and basolateral membranes, respectively. These values are consistent with those obtained in isolated perfused tubules and can account for known aspects of MTAL function in vivo. Because the apical and basolateral membrane unit permeabilities are similar, the ability of the apical membrane to function as the site of barrier function arises from its very small surface area when compared with the highly redundant basolateral membrane.

Ammonia↗
PubMed2000

Angiotensin II increases vasopressin-stimulated facilitated urea permeability in rat terminal IMCDs.

Angiotensin II receptors are present along the rat inner medullary collecting duct (IMCD), although their physiological role is unknown. Because urea is one of the major solutes transported across the terminal IMCD, we measured angiotensin II's effect on urea permeability. In the perfused rat terminal IMCD, angiotensin II had no effect on basal urea permeability but significantly increased vasopressin-stimulated urea permeability by 55%. Angiotensin II, both without and with vasopressin, also increased the amount of (32)P incorporated into urea transporter (UT)-A1 in inner medullary tissue exposed to these hormones ex vivo. Because angiotensin II activates protein kinase C, we tested the effect of staurosporine (SSP). In the absence of angiotensin II, SSP had no effect on vasopressin-stimulated urea permeability in the perfused terminal IMCD. However, SSP completely and reversibly blocked the angiotensin II-mediated increase in vasopressin-stimulated urea permeability. SSP and chelerythrine reduced the angiotensin II-stimulated (32)P incorporation into UT-A1 in inner medullary tissue exposed ex vivo. We conclude that angiotensin II increases vasopressin-stimulated facilitated urea permeability and (32)P incorporation into the 97- and 117-kDa UT-A1 proteins via a protein kinase C-mediated signaling pathway. These data suggest that angiotensin II augments vasopressin-stimulated facilitated urea transport in the rat terminal IMCD and may play a physiological role in the urinary concentrating mechanism by augmenting the maximal response to vasopressin.

Angiotensin II↗
PubMed1982

Alveolar epithelium permeability to small solutes: developmental changes.

To determine whether alveolar epithelium permeability to small lipid-insoluble solutes changes during development we measured transport across the blood-gas barrier in isolated Ringer-perfused lungs from prenatal, 1-day-old, 4-wk-old, and adult rabbits. Radioactive test molecules, one of which was always sucrose, were dissolved in Ringer solution and instilled into the trachea of degassed lungs. Samples taken from recirculating perfusate were used to calculate permeability-surface area (PS) products. Results were expressed as the ratio (PS)/(PS)sucrose, and as absolute permeability. Lungs from 4-wk-old rabbits were studied most thoroughly; the (PS)/(PS) sucrose ratios obtained are urea 4.0, erythritol 1.3, mannitol 0.98, L-glucose 1.4, and D-glucose 5.6. These and other data imply that the most lipid-insoluble molecules (erythritol, mannitol, L-glucose, and sucrose) are transported by a nonselective bulk process. Urea transport is primarily through lipid membranes; D-glucose seems to involve a special process. Sucrose and L-glucose permeability decreased during development, but their relative permeabilities did not change. Small lipid-insoluble solutes apparently do not cross the alveolar epithelium through small water-filled pores, and their permeability decreases as the animal matures.

Animals↗
PubMed1990

Silica directly increases permeability of alveolar epithelial cells.

Alveolar epithelial cell injury and increased alveolar-capillary membrane permeability are important features of acute silicosis. To determine whether silica particles contribute directly to this increased permeability, we measured paracellular permeability of rat alveolar epithelium after exposure to silica, in vitro, using markers of the extracellular space. Silica (Minusil) markedly increased permeability in a dose- and time-dependent manner. This was not the result of cytolytic injury, because lactate dehydrogenase release from monolayers exposed to silica was not increased. Pretreatment of the silica with serum, charged dextrans, or aluminum sulfate blocked the increase in permeability. Scanning electron microscopy demonstrated adherence of the silica to the surface of the alveolar epithelial cells. Thus silica can directly increase permeability of alveolar epithelium.

Alum Compounds↗
PubMed1990

Relationships between permeable vessels, nerves, and mast cells in rat cutaneous neurogenic inflammation.

Electrical stimulation of rat sensory nerves produces cutaneous vasodilation and plasma protein extravasation, a phenomenon termed "neurogenic inflammation". Rat skin on the dorsum of the paw developed neurogenic inflammation after electrical stimulation of the saphenous nerve. In tissue sections, the extravasation of the supravital dye monastral blue B identified permeable vessels. Mast cells were identified by toluidine blue stain. Permeable vessels were significantly more dense in the superficial 120 microns of the dermis than in the deeper dermis, whereas mast cells were significantly more frequent in the deeper dermis. The relationships between nociceptive sensory nerve fibers, permeable vessels, and mast cells were examined by indirect immunohistochemistry for calcitonin gene-related peptide (CGRP), neurokinin A (NKA), and substance P (SP). CGRP-, NKA-, and SP-containing nerves densely innervated the superficial dermis and appeared to innervate the vessels that became permeable during neurogenic inflammation. In contrast, mast cells were not associated with either permeable vessels or nerve fibers. These data suggest that electrical stimulation of rat sensory nerves produces vascular permeability by inducing the release of neuropeptides that may directly stimulate the superficial vascular bed. Mast cells may not be involved in this stage of cutaneous neurogenic inflammation in rat skin.

Animals↗
PubMed1990

Thrombin's enzymatic activity increases permeability of endothelial cell monolayers.

Human alpha-thrombin increases the permeability of bovine pulmonary artery endothelial cell (CCL-209) monolayers. To determine if this increase is via an enzymatic or receptor-mediated mechanism, enzymatically active forms of alpha-thrombin and enzymatically inactive forms with cell binding activity were incubated with the monolayers. Enzymatic forms included alpha-thrombin and two digestion products, zeta-thrombin (chymotryptic product with 89% clotting activity) and gamma-thrombin (tryptic product). Enzymatically inactive forms included D-Phe-Pro-Arg-chloromethylketone-(PPACK) alpha-thrombin and diisopropylphosphorofluoridate-(DIP) alpha-thrombin. Cell binding activity of alpha- and PPACK-alpha-thrombin was demonstrated to be similar to each other and comparable to that cited in the literature for DIP-alpha-thrombin. gamma-Thrombin, on the other hand, did not compete for binding of 125I-labeled alpha-thrombin. All enzymatic forms of alpha-thrombin increased endothelial permeability as assessed by the clearance of 125I-albumin across the monolayers. Coincubation of PPACK, an enzymatic site inhibitor, with alpha- or gamma-thrombin prevented the increase in permeability, further indicating that alpha-thrombin increased permeability by its enzymatic activity. Both enzymatically inactive forms of alpha-thrombin with high-affinity binding activity had no effect on permeability. To further examine whether cell binding activity of alpha-thrombin contributed to the increased permeability, a sulfated COOH-terminal fragment of hirudin (hirugen) that binds to the anion-binding site of alpha-thrombin but, unlike hirudin, does not interact with the catalytic site was coincubated with alpha-thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Chloromethyl Ketones↗
PubMed1993

HEPES buffer perfusate alters rabbit lung endothelial permeability.

N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) has been shown to cause changes in cultured endothelial cells and smooth muscle function at concentrations from 5 to 25 mM. To determine whether HEPES also affects vascular permeability, the effects of two buffers, HEPES and phosphate, were compared in isolated perfused rabbit lungs. Hemodynamic parameters and vascular protein permeability-surface area products (PS) were measured after perfusion with the buffers. Endothelial permeability was measured for an anionic and a cationic albumin to assess the charge effects of the zwitterion buffer. With HEPES, there were no changes in vascular pressure or resistance but permeability was affected. Cationic albumin permeability increased with 12 mM HEPES (8.7phosphate-->30(12) mM HEPES x ml.min-1.g dry lung-1 x 10(-2)) as did the anionic albumin PS (2.7phosphate-->3.52(12) mM HEPES). The cationic PS returned to baseline (8.1(60) mM HEPES) at 60 mM HEPES, but the anionic PS did not change from the 12 mM HEPES (4.01(60) mM HEPES). In summary, we find that HEPES is not innocuous. Although hemodynamic parameters did not change, endothelial permeability was increased when HEPES was used at normal concentrations. Therefore, HEPES should be used with caution as a physiological buffer in perfused organ systems.

Animals↗
PubMed1997

Airway and alveolar permeability and surface liquid thickness: theory.

The thickness of airway surface liquid (ASL) can be calculated as the ratio of the permeability coefficient of an absorbed inert tracer to the percentage rate in which it decreases in content in the airway lumen. The percentage clearance of radiolabeled diethylenetriaminepentaacetic acid (DTPA) from human airways or lungs has been measured many times, with a mean value of 1.04 +/- 0.25 (SD) %/min. Rates of clearance from animal lungs of most species give values of the same order, although they are lower in the sheep and higher in the dog. Permeability coefficients have not been measured simultaneously with percentage clearances and not at all for human tissues. Values for mannitol and sucrose, of which the former gives a permeability coefficient approximately 25% greater than that for sucrose and DTPA in airway tubes and isolated mucosal sheets from experimental animals, give a mean approximately 7.1 x 10(-7) cm/s. This corresponds to thickness of ASl of approximately 20-150 microns for various species. The assumptions underlying this estimate are discussed. It is concluded that ASL thickness in vivo may be considerably greater than in vitro measurements involving rapid freezing of the airway wall. Estimates of alveolar permeability suggest that either it is very considerably lower than that of the airway epithelium, that methods to measure alveolar permeability mainly reflect airway permeability, or both.

Animals↗
PubMed1997

Role for anions in pulmonary endothelial permeability.

beta-Adrenergic stimulation reduces albumin permeation across pulmonary artery endothelial monolayers and induces changes in cell morphology that are mediated by Cl- flux. We tested the hypothesis that anion-mediated changes in endothelial cells result in changes in endothelial permeability. We measured permeation of radiolabeled albumin across bovine pulmonary arterial endothelial monolayers when the extracellular anion was Cl-, Br-, I-, F-, acetate (Ac-), gluconate (G-), and propionate (Pr-). Permeability to albumin (Palbumin) was calculated before and after addition of 0.2 mM of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), which reduces permeability. In Cl-, the Palbumin was 3.05 +/- 0.86 x 10(-6) cm/s and fell by 70% with the addition of IBMX. The initial Palbumin was lowest for Pr- and Ac-. Initial Palbumin was higher in Br-, I-, G-, and F- than in Cl-. A permeability ratio was calculated to examine the IBMX effect. The greatest IBMX effect was seen when Cl- was the extracellular anion, and the order among halide anions was Cl- > Br- > I- > F-. Although the level of extracellular Ca2+ concentration ([Ca2+]o) varied over a wide range in the anion solutions, [Ca2+]o did not systematically affect endothelial permeability in this system. When Cl- was the extracellular anion, varying [Ca2+]o from 0.2 to 2.8 mM caused a change in initial Palbumin but no change in the IBMX effect. The anion channel blockers 4-acetamido-4'-isothiocyanotostilbene-2, 2'-disulfonic acid (0.25 mM) and anthracene-9-carboxylic acid (0.5 mM) significantly altered initial Palbumin and the IBMX effect. The anion transport blockers bumetanide (0.2 mM) and furosemide (1 mM) had no such effects. We conclude that extracellular anions influence bovine pulmonary arterial endothelial permeability and that the pharmacological profile fits better with the activity of anion channels than with other anion transport processes.

1-Methyl-3-isobutylxanthine↗
PubMed2003

Rho inhibition decreases TNF-induced endothelial MAPK activation and monolayer permeability.

Our laboratory previously demonstrated that MAPK activation is an important signal during cytokine-induced endothelial permeability (Nwariaku FE, Liu Z, Terada L, Duffy S, Sarosi G, and Turnage R. Shock 18: 82-85, 2002). Because GTP-binding proteins have been implicated in MAPK activation, we now hypothesize that the GTP-binding protein Rho is a mediator of TNF-induced MAPK activation and increased endothelial permeability. Transmonolayer permeability was assessed in human lung microvascular cells by measuring transmonolayer electrical resistance. MAPK activity was assessed by using a phospho-specific immunoprecipitation kinase assay and by comparing Western blots for phospho-MAPK with total MAPK. MAPK inhibitors used were SB-202190 and PD-098059, whereas Clostridium botulinum C3 transferase was used as a Rho inactivator. Rho-associated coiled-coil kinase was inhibited with Y-27632. TNF increased pulmonary endothelial permeability in vitro and caused a rapid, sustained increase in endothelial p38 and extracellular signal-regulated kinase MAPK activity. Inhibition of p38 and extracellular signal-regulated kinase MAPK with SB-202190 and PD-098059, respectively, decreased TNF-induced endothelial permeability. C3 transferase attenuated TNF-induced MAPK activation and blocked TNF-induced endothelial permeability. Finally, inhibition of Rho-associated coiled-coil kinase with Y-27632 prevented both MAPK activation and TNF-induced decreases in transmonolayer resistance. Rho acts upstream of mitogen-activated protein kinases in mediating TNF-induced pulmonary endothelial leak.

ADP Ribose Transferases↗
PubMed2002

Selected contribution: Hyperthermia-induced intestinal permeability and the role of oxidative and nitrosative stress.

The purpose of this study was to characterize intestinal permeability changes over a range of physiologically relevant body temperatures in vivo and in vitro. Initially, FITC-dextran (4,000 Da), a large fluorescent molecule, was loaded into the small intestine of anesthetized rats. The rats were then maintained at approximately 37 degrees C or heated over 90 min to a core body temperature of approximately 41, approximately 41.5, or approximately 42.5 degrees C. Permeability was greater in the 42.5 degrees C group compared with the 37, 41, or 41.5 degrees C groups. Histological analysis revealed intestinal epithelial damage in heated groups. Everted intestinal sacs were then used to further characterize hyperthermia-induced intestinal permeability and to study the potential role of oxidative and nitrosative stress. Increased permeability to 4,000-Da FITC-dextran in both small intestinal and colonic sacs was observed at a temperature of 41.5-42 degrees C compared with 37 degrees C, along with widespread intestinal epithelial damage. Administration of antioxidant enzyme mimics or a nitric oxide synthase inhibitor did not reduce permeability due to heat stress, and tissue concentrations of a lipid peroxidation product were not altered by heat stress, suggesting that oxidative and nitrosative stress were not likely mediators of this phenomenon in vitro. In conclusion, hyperthermia produced increased permeability and marked intestinal epithelial damage both in vivo and in vitro, suggesting that thermal disruption of epithelial membranes contributes to the intestinal barrier dysfunction manifested with heat stress.

Animals↗
PubMedDate not supplied

Intestinal permeability before and after ibuprofen in families of children with Crohn's disease.

BACKGROUND: Members of a subset of first-degree relatives of adults with Crohn's disease have been shown to have an increased baseline intestinal permeability and/or an exaggerated increase in intestinal permeability after the administration of acetylsalicylic acid. PURPOSE: To determine intestinal permeability in unaffected first-degree relatives of children with Crohn's disease before and after the administration of an ibuprofen challenge. METHODS: Lactulose-mannitol ratios, a measure of intestinal permeability, were determined in 14 healthy control families (41 subjects) and 14 families with a child with Crohn's disease (36 relatives, 14 probands) before and after ingestion of ibuprofen. An upper reference limit was defined using the control group as mean +/- 2 SD. RESULTS: The proportion of healthy, first-degree relatives with an exaggerated response to ibuprofen (20%, 95% CI 7% to 33%) was significantly higher than controls (P = 0.003). The exaggerated response was more common among siblings than among parents of pediatric probands. CONCLUSIONS: Members of a subset of first-degree relatives of children with Crohn's disease have an exaggerated increase in intestinal permeability after ibuprofen ingestion. These findings are compatible with there being a genetic link between abnormalities of intestinal permeability and Crohn's disease.

Adolescent↗
PubMed2001

Helicobacter pylori infection increases mucosal permeability of the stomach and intestine.

It is important to study the effect of Helicobacter pylori infection on the permeability of the intestine. Permeability was evaluated by oral sucrose tolerance test using sucrose 25 g in 200 ml of water. Existence of H. pylori itself was associated with increased permeability of sucrose. Also, the permeability of sucrose increased as polymorphonuclear and lymphocyte infiltration increased. The increase of mucosal permeability suggests that antigens like protein penetrate into the body and result in systemic reactions. Thus, it is important to study the implication of increased permeability in relation not only to gastric diseases but also certain systemic diseases.

Adult↗
PubMedDate not supplied

Human and rabbit corneal endothelial permeability after different chemical forms of glutathione.

This study aimed to compare the effects of reduced glutathione (GSH) with those of S-(1,2-dicarboxyethyl)glutathione (DCE-GS) (in rabbits and humans), and different concentrations of the latter (in humans), on corneal endothelial permeability when added to solutions bathing the isolated cornea. Inulin/dextran permeability was determined from stromal- to endothelial-facing surfaces of de-epithelialized corneas. The bathing solution was modified Opeguard(R)-MA (MOMA), an ocular irrigating solution, to which either GSH or another intrinsic tripeptide, DCE-GS, was added. Paired corneas were used to compare either different combinations of GSH with DCE-GS (rabbit or human) or various concentrations of DCE-GS from 0.25 to 2.0 mM (human). Endothelial cyclic AMP levels were determined in cultured rabbit cells. MOMA alone resulted in approximately the same permeability as MOMA + 0.3 mM GSH while the use of 2 mM DCE-GS significantly reduced rabbit (40% maximum, p < 0.00001) and human (30% maximum, p < 0.01) corneal permeability. Human corneal endothelial permeability remained reduced through a range of concentrations of DCE-GS from 0.25 to 2.0 mM DCE-GS. Tissue-cultured rabbit corneal endothelium showed an increase in cyclic AMP after DCE-GS or GSH. DCE-GS potentially offers a viable alternative to GSH for inclusion in ocular irrigating or corneal preservative solutions since it maintains human corneal endothelial permeability at a lower, stable value relative to non-DCE-GS-containing solutions.

Aged↗
PubMed2003

Acute stress results in skin corticotropin-releasing hormone secretion, mast cell activation and vascular permeability, an effect mimicked by intradermal corticotropin-releasing hormone and inhibited by histamine-1 receptor antagonists.

BACKGROUND: Mast cells play an important role in allergic inflammation by releasing vasoactive molecules, proteases and cytokines. Corticotropin-releasing hormone (CRH) and its structural analogue urocortin (Ucn) were shown to trigger skin mast cell activation and vascular permeability. We investigated the effect of acute stress on rat skin vascular permeability and CRH secretion, as well as the effect of intradermal CRH, and that of two histamine-1 receptor antagonists, azelastine and olopatadine, on vascular permeability. METHODS: Rats were stressed by restraint and vascular permeability was assessed by extravasation of (99)Tc-gluceptate, while mast cell activation was determined by skin rat mast cell protease-1 (RMCP-1) content. Skin CRH content was evaluated by ELISA. The effect of intradermal injection of CRH and Ucn, as well as that of two histamine-1 receptor antagonists, azelastine and olopatadine, was assessed by Evan's blue extravasation. Purified rat peritoneal mast cells (RPMCs) were also pretreated with azelastine (24 microM) or olopatadine (133 microM) for 5 min before challenge with compound 48/80 (0.5 microg/ml) for 30 min. Histamine secretion was measured fluorometrically. Intracellular Ca(2+) ions were evaluated in RPMCs loaded with calcium crimson and stimulated with compound 48/80. RESULTS: Acute stress increased skin vascular permeability and CRH content, while it decreased RMCP-1. Intradermal injection of CRH or Ucn induced substantial Evan's blue extravasation that was inhibited by pretreatment with azelastine (24 microM) and olopatadine (133 microM). Both antihistamines also inhibited histamine release and intracellular increase of Ca(2+) ions from RPMCs stimulated by compound 48/80. CONCLUSIONS: These results indicate that acute stress increases skin CRH that can trigger mast cell-dependent vascular permeability, effects inhibited by certain histamine-1 receptor antagonists, possibly acting to reduce intracellular Ca(2+) ion levels.

Acute Disease↗
PubMed2004

Steady-state brain concentrations of antihistamines in rats: interplay of membrane permeability, P-glycoprotein efflux and plasma protein binding.

The purpose of this study was to measure the in vivo brain distribution of antihistamines and assess the influence of in vitro permeability, P-glycoprotein (Pgp) efflux, and plasma protein binding. Six antihistamines (acrivastine, chlorpheniramine, diphenhydramine doxylamine, fexofenadine, terfenadine) were selected based on previously reported in vitro permeability and Pgp efflux properties and dosed intravenously to steady-state plasma concentrations of 2-10 micromol/l in rats. Plasma and brain concentrations were measured by LC/MS/MS, and protein binding determined by ultrafiltration. Doxylamine, diphenhydramine and chlorpheniramine had brain-to-plasma concentration ratios of 4.34 +/- 1.26, 18.4 +/- 2.35 and 34.0 +/- 9.02, respectively. These drugs had high passive membrane permeability (>310 nm/s), moderate protein binding (71-84%) and were not Pgp substrates; features that yield high CNS penetration. In contrast, acrivastine and fexofenadine had low brain-to-plasma ratios of 0.072 +/- 0.014 and 0.018 + 0.002, consistent with low passive membrane permeability for both compounds (16.2 and 66 nm/s, respectively) and Pgp efflux. Finally, terfenadine had a brain-to-plasma ratio of 2.21 +/- 1.00 even though it underwent Pgp-mediated efflux (in vitro ratio = 2.88). Terfenadine's high passive permeability (285 nm/s) overcame the Pgp-mediated efflux to yield brain-to-plasma ratio >1. The brain-to-unbound plasma ratio was 22-fold higher suggesting that protein binding (96.3% bound) limited terfenadine's brain distribution. In conclusion, passive membrane permeability, Pgp-mediated efflux and/or high plasma protein binding influence the in vivo brain distribution of antihistamine drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Cyclic-GMP-mediated decrease in permeability of human umbilical and pulmonary artery endothelial cell monolayers.

Endothelial cell contraction plays a pivotal role in the increased extravasation of fluid and macromolecules in vascular leakage. Previous studies have indicated that elevation of the adenosine 3',5'-cyclic monophosphate (cAMP) concentration can improve the endothelial barrier function. In analogy with smooth muscle cell contraction, which is inhibited by both cAMP and guanosine 3',5'-cyclic monophosphate (cGMP), we have compared the role of cAMP and cGMP in the regulation of the permeability of human endothelial cell monolayers. The cellular cGMP concentration was elevated 3- to 5-fold after addition of 10(-7) M atrial natriuretic peptide (ANP) or 10(-4) M sodium nitroprusside (SNP), both under basal and thrombin-stimulated conditions. After exposure to thrombin, cGMP generation by ANP or SNP or addition of 8-bromo-cGMP significantly suppressed the increase in permeability. Inhibition of nitric oxide production with 10(-4) M NG-nitro-L-arginine methyl ester increased the permeability of endothelial monolayers in the majority of the tested cultures, an effect that could be counteracted by addition of 8-bromo-cGMP or ANP. An increase of cAMP upon the addition of forskolin reduced the permeability in all endothelial cell strains under basal conditions and after exposure to thrombin. The forskolin- and 8-bromo-cGMP-mediated decreases in permeability were accompanied by increases in transendothelial electrical resistance. These in vitro data indicate that, in addition to cAMP, cGMP can act as a potent fine-regulator of endothelial permeability.

8-Bromo Cyclic Adenosine Monophosphate↗