Biomedical subjects

A Tedgui

Publications and source records attributed to A Tedgui.

At least 91 records · Page 5Linked to original sources

PubMed1996

Endothelial permeability under physiological and pathological conditions.

Due to their special position at the tissue-blood interface, the endothelial cells are endowed with two mechanisms for handling plasma molecules: one, receptor-mediated endocytosis, which supplies nutrients for the cell's own metabolic needs; the other, direct transendothelial transport of material from plasma to the intima of arteries. Under normal physiological conditions, the latter transendothelial pathway is far more important than the endocytic one. Routes for exchange of both small and large plasma molecules include the clefts between adjacent endothelial cells (paracellular) and plasmalemmal vesicles. Paracellular transport is restricted to molecules smaller than 4 nm in diameter, and is the pathway for water filtration. Larger molecules, as large as 30 nm in diameter, are transported through plasmalemmal vesicles. Changes in endothelial permeability occur during inflammation, hypertension or diabetes.

Biological Transport↗

PubMed1996

Acute haemodynamic responses and inhibition of tumour necrosis factor-alpha by pentoxifylline in rats with cirrhosis.

1. Although pentoxifylline has been shown to reduce portal hypertension, the mechanism for this is unclear. Since pentoxifylline decreases tumour necrosis factor-alpha production and since this cytokine may induce vasodilatation per se, a pentoxifylline-induced decrease in tumour necrosis factor-alpha production may limit arterial vasodilatation and decrease portal pressure. The aim of the present study was to examine the effects of pentoxifylline administration on plasma tumour necrosis factor-alpha concentration and haemodynamics in normal and cirrhotic rats. 2. In both groups, systemic and splanchnic haemodynamics and plasma tumour necrosis factor-alpha concentrations were measured before and 120 min after the administration of saline or pentoxifylline (20 mg/kg intravenous bolus). 3. In cirrhotic rats, pentoxifylline significantly decreased portal pressure (24 +/- 13%) and tributary blood flow (33 +/- 30%). On the other hand, pentoxifylline significantly increased vascular resistance in portal and hepatic arterial territories. Systemic haemodynamics were not altered. In normal rats, pentoxifylline significantly decreased portal pressure but induced no other significant changes in splanchnic or systemic haemodynamics. In cirrhotic rats, plasma tumour necrosis factor-alpha concentrations were significantly reduced after pentoxifylline administration but not after saline administration. No significant correlations were found between pentoxifylline-induced changes in tumour necrosis factor-alpha levels and changes in splanchnic haemodynamics. In normal rats, plasma tumour necrosis factor-alpha concentrations significantly decreased after pentoxifylline or saline administration. 4. This study shows that in rats with cirrhosis, pentoxifylline induces a decrease in both portal pressure and plasma tumour necrosis factor-alpha concentrations. These reductions were not correlated however.

Animals↗

PubMed1996

Role of NO in flow-induced remodeling of the rabbit common carotid artery.

Flow-induced changes in vessel caliber tend to restore baseline wall shear stress (WSS) and have been reported to be endothelium-dependent. To investigate the role of endothelium-derived nitric oxide (NO) in the adaptive increase in artery diameter in response to a chronic increase in blood flow, an arteriovenous fistula was constructed between the left common carotid artery (CCA) and the external jugular vein in 22 New Zealand White rabbits, and NO synthesis was inhibited in 14 animals by long-term administration of NG-nitro-L-arginine-methyl ester (L-NAME) in drinking water given for 4 weeks. The remaining 8 animals served as controls. Mean arterial blood pressure was not significantly altered by L-NAME treatment (91 +/- 2 in control versus 98 +/- 3 mm Hg in L-NAME-treated rabbits). Blood flow significantly increased in the left CCA in both groups but was lower in L-NAME-treated than control animals (106.1 +/- 10.7 versus 196.2 +/- 32.3 mL/min, P < .003). The diameter of the flow-loaded left CCA also increased significantly in both groups compared with the right CCA (2.15 +/- 0.12 and 2.54 +/- 0.1 mm, respectively, P < .02), but the increase was less in the L-NAME-treated than the control group (3.24 +/- 0.09 and 4.64 +/- 0.17 mm, respectively, P < .0001). The diameter of the anastomosed veins was also increased but to a much lesser degree in L-NAME-treated animals than in controls (4.14 +/- 0.29 versus 7.94 +/- 0.51 mm, P < .0001). As a result of artery enlargement, WSS was normalized in the flow-loaded left CCA of the control group (8.87 +/- 0.77 dynes/cm2) regardless of blood flow values. In L-NAME-treated animals, however, WSS was only partially regulated, the mean value being significantly increased (18.7 +/- 2.2 dynes/cm2, P < .006). Moreover, a highly significant positive correlation between WSS and blood flow was obtained in L-NAME-treated animals (r = .84, P < .0001). We also found remodeling of the artery wall, with a larger increase in the medial cross-sectional area associated with an increased number of smooth muscle cells, in the control group compared with the L-NAME-treated group (0.75 +/- 0.09 versus 0.49 +/- 0.04 mm2 and 4504 +/- 722 versus 2717 +/- 282 cells/mm2, P < .03). We conclude that NO plays a role in the increase of vessel caliber in response to chronic increase in blood flow. As yet unidentified additional metabolic processes appear to be necessary for a complete regulatory response.

Administration, Oral↗

PubMed1996

Pressure and angiotensin II synergistically induce aortic fibronectin expression in organ culture model of rabbit aorta. Evidence for a pressure-induced tissue renin-angiotensin system.

Aortic fibronectin (FN) expression is augmented in hypertension. Increasing evidence suggests that both angiotensin II (Ang II) and mechanical factors may induce vascular remodeling in response to hypertension. We have previously shown that, in vitro, increased transmural pressure enhances FN expression in rabbit aortic media. To investigate the existence of a link between the effects of pressure and Ang II and to explore the mechanisms underlying such a relationship, we quantified the effect of Ang II and Ang II inhibitors on the pressure-dependent FN expression in a 3-day organ culture model of rabbit aorta using immunolabeling analysis and detected FN mRNAs by in situ hybridization. A dose-dependent effect of Ang II on FN expression was observed at both 80 and 150 mm Hg but not at 0 mm Hg (relaxed vessels). One mumol/L Ang II increased the media cross-sectional surface, showing FN expression from 7.9 +/- 0.7% (n = 9) to 18.9 +/- 1.1% (n = 4) at 80 mm Hg (P < .01) and from 17.4 +/- 1.8% (n = 9) to 56.6% +/- 3.6 (n = 4) at 150 mm Hg (P < .001). In situ hybridization revealed that Ang II and pressure upregulated FN mRNA expression. Losartan, an AT1 antagonist, not only blocked the Ang II effect but also inhibited the transmural pressure effect. Angiotensin-converting enzyme inhibition abolished the pressure-dependent FN expression and significantly diminished the effect of pressure in the presence of Ang II. The effect of renin-angiotensin system inhibitors was specific for FN, since neither bFGF nor laminin expression was affected by these agents. Taken together, the results demonstrate that (1) the effect of transmural pressure is mediated by the stimulation of a local renin-angiotensin system, resulting in a net Ang II production in the culture medium, (2) transmural pressure and Ang II act synergistically to enhance vascular FN expression, (3) AT1 receptors mediate both the effects of pressure and of exogenous Ang II, and (4) the effect of Ang II on FN expression is regulated at a pretranslational level.

Angiotensin II↗

PubMed1996

Effects of pressure-induced stretch and convection on low-density lipoprotein and albumin uptake in the rabbit aortic wall.

The effects of pressure-driven convection and vessel wall stretching in the pressure-related changes in low-density lipoprotein (LDL) and albumin transport across the arterial wall were studied in vitro in freshly excised rabbit thoracic aorta held at in vivo length and pressurized at 70, 120, or 160 mm Hg for 30 minutes. External rigid polyester sleeves of various diameters (4, 5, or 6 mm) were passed around half of the arterial segments in order to prevent vessel distension during pressurization. The intraluminal solution contained 131I-LDL and 125I-albumin. The transmural distribution of relative concentrations of LDL (CLDL) and albumin (Calb) across the wall was determined in wrapped and unwrapped segments using a serial frozen-sectioning technique. In the unwrapped segments, Calb increased uniformly between 70 and 120 mm Hg (P < .0001) but did not change significantly between 120 and 160 mm Hg (0.0063 +/- 0.0009 [n = 4], 0.0520 +/- 0.0055 [n = 9], and 0.0620 +/- 0.0071 [n = 12], respectively). In contrast, CLDL increased markedly both between 70 and 120 mm Hg (P < .001) and between 120 and 160 mm Hg (P < .05) (0.0025 +/- 0.0005 [n = 4], 0.0234 +/- 0.0029 [n = 9], and 0.0393 +/- 0.0056 [n = 12], respectively), with the increase being much more pronounced in the inner than in the outer media. In the segments wrapped with the 4-mm sleeves, both CLDL and Calb did not vary significantly between 70, 120, and 160 mm Hg. In the segments wrapped with the 5-mm sleeves, CLDL increased significantly between 120 and 160 mm Hg, whereas Calb did not vary significantly with increasing pressure. Our results demonstrate that (1) pressure-induced stretching of the arterial wall is a major determinant of arterial mass transport, and (2) pressure-driven convection accentuates LDL accumulation in the inner media, which may explain enhanced atherosclerosis in hypertension.

Animals↗

PubMed1995

Influence of temperature on neutrophil trafficking during clinical cardiopulmonary bypass.

BACKGROUND: The adhesion of neutrophils to endothelial cells and their subsequent transendothelial migration play a major role in inflammatory damage elicited by cardiopulmonary bypass (CPB) because these events are linked to the release of cytotoxic proteases and oxidants. However, the patterns of neutrophil trafficking in relation to systemic temperature during clinical CPB have not yet been characterized. METHODS AND RESULTS: Twenty case-matched patients undergoing warm (31.8 +/- 0.4 degrees C) or cold (26.3 +/- 0.5 degrees C, P < .0001 versus warm) bypass were studied. Blood samples were simultaneously collected from the right and left atria before, at the end of, and 30 minutes after CPB. Plasma levels of C3a, P- and E-selectins, elastase, and interleukin-8 were determined by immunoassays. The results demonstrate: (1) a rise in C3a, reflecting complement activation, (2) a fall in soluble E-selectin consistent with an increased adhesiveness of activated neutrophils, (3) a rise in soluble P-selectin expected to enhance endothelial adhesion of these neutrophils, (4) a rise in elastase, suggesting an adhesion-triggered neutrophil degranulation, and finally (5) a rise in interleukin-8 that is likely to promote transendothelial migration of adherent neutrophils. All of these changes occurred in the two groups of patients and were significant compared with prebypass values. However, in none of the groups was there a significant difference between right and left atrial values for any of the markers. The single difference between cold and warm bypass patients was a significant reduction of elastase release in the cold group (P < .001 versus the warm group). CONCLUSIONS: Clinical CPB is associated with biological changes suggesting the occurrence of neutrophil trafficking. Hypothermia provides only partial protection through a reduced release of elastase. Overall, these results reinforce the rationale for the development of therapeutic strategies targeted at blunting the neutrophil-mediated component of bypass-induced inflammatory damage.

Body Temperature↗

PubMed1995

Effects of inhibition of nitric oxide synthesis on TNF alpha serum levels in E. coli endotoxemic rats.

We investigated the effects of nitric oxide (NO) synthesis inhibition on mortality rate and TNF alpha serum levels in rats inoculated with E. Coli endotoxin (30 mg/kg i.v.) Pre-treatment of endotoxemic rats with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis by both the constitutive and the inducible isoforms of the NO synthase, did not change the mortality rate but significantly reduced TNF alpha serum levels. By contrast, administration of aminoguanidine, a more specific inhibitor of the inducible NO synthase, did not modify serum TNF alpha. These results suggest that, in E. Coli endotoxemic rats, NO synthetized by the constitutive isoform of the NO synthase positively modulates TNF alpha synthesis.

Amino Acid Oxidoreductases↗

PubMed1995

Normal and pathological aspects of mass transport across the vascular wall.

The rapid progress in cardiovascular surgery during the past 10 years has been matched by a complementary increase in the understanding of underlying cellular and molecular aspects of normal and pathological physiology of blood vessels. This review focuses on one aspect of vascular biology, namely the transport of macromolecules and water across the vascular wall, with particular attention to the role of endothelial permeability, and offers a bridge between the basic biological sciences and clinical care.

Animals↗

PubMed1995

Pentoxifylline selectivity inhibits tumor necrosis factor synthesis in the arterial wall.

Pentoxifylline (PTX) has been reported to potentially inhibit tumor necrosis factor (TNF) synthesis by monocytes/macrophages. Because inflammatory processes involve both leukocytes and vascular cells, we tested the effects of PTX on TNF and interleukin-6 (IL-6) production by the vessel wall in response to lipopolysaccharide (LPS). Rings of rat thoracic aorta were incubated for 24 h in DMEM containing antibiotics and 1% fetal calf serum in the presence of 1 microgram/ml LPS. TNF and IL-6 were biologically assayed using L-M fibroblast cytotoxicity and B9 hybridoma cell proliferation, respectively. Maximal LPS-induced production of TNF and IL-6 by the aorta was 0.77 +/- 0.04 and 23.3 +/- 3.5 x 10(3) U/mg dry weight, respectively. The addition of PTX dose-dependently suppressed the production of TNF by 26 +/- 7%, 58 +/- 6%, and 85 +/- 9% at 10, 100, and 1,000 microM, respectively. This effect was selective for TNF, because the production of IL-6 was not affected by any dose of PTX, suggesting a selective gene regulation of TNF and IL-6 in vascular cells. These results may have clinical implications. PTX may be useful in vascular inflammatory diseases, in which serum TNF levels have been shown to be correlated with the severity of the disease.

Animals↗

PubMed1995

Increased production of tumor necrosis factor and interleukin-6 by arterial wall of aged rats.

Plasma cytokine levels are enhanced in aged animals and in elderly people. Vascular cells are known to be both targets and sources of cytokines. To investigate the effect of aging on vascular cytokine synthesis, we studied tumor necrosis factor (TNF), interleukin-6 (IL-6), and prostacyclin (PGI2) production by the arterial wall using organoid culture of aorta from 10- (n = 8) and 30-mo-old (n = 8) rats, after activation by lipopolysaccharide (LPS). Biological activity of TNF and IL-6 was measured in supernatant from incubated vessels. 6-Ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), a stable metabolite of PGI2, a secondary inflammatory mediator, was measured using enzyme immunoassay. In the absence of LPS, TNF production was undetectable in most animals and was not significantly increased in the aged group. By contrast IL-6 and 6-keto-PGF1 alpha productions, in the absence of LPS, were significantly greater in 30- (8,140 +/- 1,350 U/micrograms DNA and 23.2 +/- 6.4 ng/micrograms DNA, respectively) than in 10-mo animals (3,060 +/- 350 U/micrograms DNA and 8.4 +/- 1.6 ng/micrograms DNA, P < 0.01 and P < 0.05, respectively). LPS-induced production of TNF, IL-6, and 6-keto-PGF1 alpha was significantly increased in old rats, being increased respectively by 3.2-, 3.5-, and 2.4-fold at 1 ng/ml LPS, compared with the production in young rats. Because TNF and IL-6 are capable of regulating vascular cell function such as proliferation protein synthesis and contractility, these cytokines might play a major role in age-related remodeling of arteries and age-related vascular diseases.

6-Ketoprostaglandin F1 alpha↗

PubMed1995

Control of carotid vasomotor tone by local renin-angiotensin system in normotensive and spontaneously hypertensive rats. Role of endothelium and flow.

To investigate the relation between the tissue renin-angiotensin system (RAS) and the local vasomotor tone of large arteries, we used in vitro isolated carotid arteries from 14-week-old Wistar-Kyoto rats (WKY; n = 80) and spontaneously hypertensive rats (SHR; n = 80). Diameters were measured with the use of an ultrasonic echo-tracking system (12 MHz) under flow (2 mL/min) (F+) or no-flow (Fo) conditions, with intact endothelium (Endo+) or after endothelium removal (Endo-). The role of tissue RAS was assessed by incubating isolated carotid arteries with an angiotensin-converting enzyme inhibitor (ACE I; lisinopril, 10(-6) mol/L) or with a specific antagonist of angiotensin II AT1 receptors (AT1A; losartan, 10(-6) mol/L). In addition, maximal dilation of carotid arteries was measured after poisoning with KCN (100 mg/L). In all experiments, KCN significantly increased carotid diameters (WKY, 23 +/- 0.9%; SHR, 19 +/- 0.8%; P < .001 versus control conditions). In intact carotid arteries, flow caused significant dilation in WKY (7 +/- 0.5%, P < .001) but had no effect in SHR. In the presence or absence of flow, ACE I and AT1A induced similar dilations in both strains, and a specific antagonist of bradykinin B2 receptors (Hoe 140, 10(-7) mol/L) had no effect on ACE I-induced dilation. After endothelium removal, carotid artery diameters were significantly increased (P < .001) in both strains, although more in SHR (13 +/- 0.8%) than in WKY (8 +/- 1.1%) (P < .001). Also, flow did not modify the diameter of deendothelialized vessels and ACE I had no effect in either strain.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1995

Differential effects of pressure and flow on DNA and protein synthesis and on fibronectin expression by arteries in a novel organ culture system.

Structural adaptation of the blood vessel wall occurs in response to mechanical factors related to blood pressure and flow. To elucidate the relative roles of pressure, flow, and medium composition, we have developed a novel organ culture system in which rabbit thoracic aorta, held at in vivo length, can be perfused and pressurized at independently varied flow and pressure for several days. Histology and histomorphometry, as well as scanning electron microscopy, revealed a well-preserved wall structure. In arteries perfused and pressurized at 80 mm Hg, endothelial injury led to a 2-fold increase in [3H]thymidine incorporation in the media, which peaked at 3 to 5 days and returned to baseline level at 6 to 8 days. In intact endothelialized vessels cultured for 3 days under no-flow conditions, pressure per se had no effect on DNA synthesis. In contrast, in the presence of serum, total protein synthesis, as assessed by [35S]methionine incorporation into the media, was enhanced 6-fold at 150 mm Hg compared with vessels pressurized at 0 or 80 mm Hg. In intact vessels perfused at a constant flow of 40 mL/min for 3 days, DNA synthesis was unchanged regardless of the pressure level when vessels were cultured in the presence of serum but increased 8-fold at both 80 and 150 mm Hg in the absence of serum. Unlike DNA synthesis, total protein synthesis was enhanced 12-fold by flow regardless of the presence or absence of serum. Expression of fibronectin was markedly enhanced at high transmural pressure, and serum potentiated its expression in the arterial wall. This novel organ culture system of perfused and pressurized vessels allowed identification of differential effects of pressure, flow, and serum on DNA and total protein synthesis, including cellular fibronectin expression.

Animals↗

PubMed1995

[Does temperature in extracorporeal circulation affect neutrophil-endothelium interactions?].

The increasing interest in "warm" aerobic cardioplegia requires a critical reevaluation of the systemic effects of the associated normothermic cardiopulmonary bypass (CPB). As activated neutrophils seem to be essential mediators of the inflammatory response to CPB via the cytotoxicity of the products that are released during their adhesion to endothelial cells, the authors undertook a study of the influence of temperature on the interaction between the neutrophils and the endothelium in 95 patients undergoing warm (31-33.5 degrees C, n = 49) and cold (26-27 degrees C, n = 46) CPB surgery. Blood sampling was performed before, during and after CPB. The following markers of neutrophil-endocardium interaction were analysed: complement activation (C3a), cytokine production (tumor necrosis factor alpha, interleukines 1, 6 and 8, and interleukin-1 receptor antagonist); endothelial expression of cytokine-dependent [intercellular adhesion molecule (ICAM)] and cytokine-independent (P-selectin) adhesion molecules (P-selectin); expression of cytokine molecules on the surface of polynuclear neutrophils (CD11a, CD11b, CD11c); and finally, endothelial adhesion and transendothelial migration of neutrophils (interleukin 8 and elastase). The results showed that, irrespective of temperature, CPB was associated with changes strongly suggestive of phenomena of transendothelial adhesion and migration. Moreover, normothermia increased the intensity of the inflammatory response as shown by increased cytokine production, earlier expression of neutrophil adhesion molecules and increased elastase production.

Aged↗

PubMed1994

Elevated temperature accelerates and amplifies the induction of nitric oxide synthesis in rat macrophages.

Evidence has accrued that nitric oxide (NO) is an effector molecule in cell-mediated immunity, and it is generally agreed that fever is beneficial to host defence. Therefore, the role of elevated temperature in the induction of NO synthesis was examined in rat peritoneal macrophages activated by lipopolysaccharide (LPS). When macrophages were incubated in vitro at 40 degrees C, the time between macrophage activation and the induction of NO synthesis, as assessed by nitrite accumulation in the medium, was shortened as compared with incubation at 37 degrees C, and nitrite accumulation was markedly enhanced by 2.6- and 1.8-fold after 6 and 9 h of LPS activation, respectively. These results suggest that elevated temperature may contribute to enhance host defence by accelerating and amplifying the induction of NO synthesis in macrophages.

Animals↗

PubMed1994

[Effects of angiotensin II and pressure on cellular fibronectin in the vascular wall in organotypic culture].

Fibronectin is a dimeric glycoprotein found in the extracellular matrix of most tissues, which can influence processes, including cell growth, adhesion and migration. Fibronectin synthesis has been shown to be overexpressed in hypertension. However, the respective effects of humoral factors, including angiotensin II, versus mechanical factors in vascular remodeling have not yet been clarified. To study fibronectin de novo synthesis in the arterial wall, we have developed a new model for organ culture of rabbit thoracic aorta. Arteries held at their in vivo length were incubated and perfused (40 ml/min) in DME medium containing antibiotics, supplemented with 20% fetal calf serum or with 5% bovine serum albumin. In a series of experiments, angiotensin II (10(-6) M) and indomethacin (10(-5) M) were added to culture media. Vessels were pressurized at 0, 80 or 150 mmHg, and kept for 3 days in incubator at 37 degrees C under 5% CO2. De novo synthesis of fibronectin was detected by immunofluorescence using anti-cellular fibronectin antibodies (1/200). In the absence of angiotensin II and serum, fibronectin was expressed in the sub-endothelium at 80 mmHg, and in the inner media at 150 mmHg. In the presence of serum, fibronectin expression was increased by the high pressure. When angiotensin II was added, a gradient of fibronectin became apparent in the inner media at 80 mmHg with a marked expression at the luminal side. Angiotensin II markedly enhanced fibronectin expression at 150 mmHg, the protein being detected in almost the whole media. Our results indicate that both angiotensin II and transmural pressure can induce fibronectin expression in the arterial wall, and both act synergically.

Angiotensin II↗

PubMed1994

Does normothermia during cardiopulmonary bypass increase neutrophil-endothelium interactions?

BACKGROUND: The use of warm blood cardioplegia is usually associated with that of warm cardiopulmonary bypass (CPB). Little is known, however, about the effect of temperature during bypass on neutrophil-endothelium interactions, which are currently considered a key component of the inflammatory response to CPB. METHODS AND RESULTS: Twenty-five patients operated on under CPB were studied. Core temperature during bypass was kept normothermic (33.5 degrees C to 37 degrees C) in 14 and lowered to 28 degrees C to 30 degrees C in the 11 remaining patients. The two groups were otherwise comparable. Arterial blood samples were collected before CPB and 30 minutes, 4 hours, and 24 hours thereafter. Samples were assayed for interleukin-1 receptor antagonist (IL-1ra), soluble intercellular adhesion molecule 1 (sICAM-1), and elastase, which are markers of cytokine production, cytokine-upregulated endothelial ligands for neutrophil adhesion molecules, and degranulation secondary to adhesion of neutrophils to endothelial cells, respectively. IL-1ra levels (mean +/- SEM) peaked 4 hours after bypass and were significantly higher in the warm group (87,926 +/- 24,067 versus 18,090 +/- 5798 mg/L, P < .02). Peak values of sICAM-1, which occurred 24 hours after bypass, were correspondingly higher in warm patients (414 +/- 74 versus 298 +/- 23 micrograms/L in cold patients). In keeping with these data, warm patients released significantly more elastase at both the 30-minute (703 +/- 101 versus 349 +/- 55 micrograms/L, P < .01) and 4-hour (627 +/- 116 versus 324 +/- 31 micrograms/L, P < .03) post-CPB study points. CONCLUSIONS: Temperature profoundly affects neutrophil-endothelium interactions, which leads one to question the use of systemic normothermia in patients at higher risk of suffering from postbypass inflammation-mediated organ damage.

Body Temperature↗

PubMed1994

A potential mechanism of vasodilation after warm heart surgery. The temperature-dependent release of cytokines.

Peripheral vasodilation is a common feature of warm heart surgery and creates clinical concerns when pressor agents become necessary because of the potential for some of these drugs to adversely affect flow through newly engrafted arterial and venous bypass conduits. The possible role of a temperature-dependent production of cytokines in the pathogenesis of this vasodilation was investigated in a two-part study. In part I, lipopolysaccharide-activated peritoneal rabbit macrophages (5 x 10(6)/ml) were incubated at 30 degrees or 37 degrees C up to 9 hours and the concentration of tumor necrosis factor released in the supernatant was serially measured by a bioassay. Tumor necrosis factor production was found to increase over time for each of the two temperatures of incubation but was significantly higher throughout the observation period in normothermic experiments than in those done at 30 degrees C. Part II was a prospective clinical study involving 30 patients who underwent either cold (core temperature 28 degrees to 30 degrees C, n = 15) or warm (37 degrees C, n = 15) cardiopulmonary bypass and in whom serum levels of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 were measured by enzyme-linked immunosorbent assays at 2, 4, 10, and 24 hours after bypass. Cytokine levels were found to be consistently higher in patients having normothermic bypass. Differences between the two groups were significant 2 hours after bypass for tumor necrosis factor alpha and interleukin-6 (p < 0.02 and p = 0.0001, respectively) and 4 and 10 hours after bypass for interleukin-1 beta (p < 0.01 and p < 0.04, respectively). The incidence of vasodilation necessitating vasopressor support was twofold higher in the normothermic group (six patients versus three in the hypothermic group). Taken as a whole, patients supported by pressor agents had significantly higher cytokine levels after bypass than those who did not require pressor therapy. Our results suggest that vasodilation occurring with warm heart operation is, at least partly, mediated by a temperature-dependent release of cytokines. Vasodilation might therefore be mitigated by simply allowing the core temperature to drift during bypass. Our recent clinical experience suggests that this "tepid" heart surgery (32 degrees to 34 degrees C) effectively blunts most of the vasodilatory response to strictly normothermic bypass without compromising maintenance of myocardial aerobiosis during arrest.

Animals↗

PubMed1993

Age-related changes in endothelial permeability and distribution volume of albumin in rat aorta.

Age-related changes in macromolecular transport across the arterial wall were investigated in 10-, 20-, and 30-mo-old WAG/Rij rats. Animals were injected with 125I- and 131I-labeled albumin, 90 and 5 min before they were killed, respectively. The transmural distribution of relative concentration of tracers in the aortic wall was obtained using en face serial sectioning technique. The apparent endothelial permeability to albumin calculated from the distribution of 5-min 131I-labeled albumin concentrations was significantly enhanced in 20- and 30-mo-old rats compared with 10-mo-old rats. The apparent distribution volume of albumin within the media, estimated as the mean medial 125I-labeled albumin concentration, was not significantly changed in 20-mo-old rats but was significantly decreased in the 30-mo-old animals. These age-related changes in the macromolecular transport suggest that the entry of plasma macromolecules in the aged arterial wall might be enhanced, whereas the efflux through the media may be impeded, possibly contributing to their trapping in the subendothelium.

Aging↗