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PubMed1988

Stereoselective effect of diltiazem on endothelium-dependent relaxations in canine femoral arteries.

Experiments were designed to analyze potential interactions between voltage-dependent calcium channel blockers and endothelium-dependent vascular responses. Rings of canine femoral artery were suspended for isometric force recording in organ chambers and contracted with prostaglandin F2 alpha. Removal of the endothelium had no effect on relaxations induced by d-cis-diltiazem (active stereoisomer), verapamil or nimodipine. When rings with endothelium were first partially relaxed with acetylcholine or the calcium ionophore A23187 the concentration-relaxation curve to d-cis-diltiazem (but not to verapamil or nimodipine) was significantly shifted to the right. Partial relaxation of femoral arterial rings without endothelium by sodium nitroprusside had no effect on relaxations evoked by diltiazem. Pretreatment with diltiazem (10(-6) M) had no effect on endothelium-dependent relaxations to acetylcholine in femoral artery rings. D-cis-Diltiazem partially reversed the relaxation induced by acetylcholine in a bioassay system, in which a ring of canine coronary artery without endothelium was superfused by solution passing through a segment of femoral artery with endothelium. D-cis-Diltiazem relaxed the bioassay ring when infused downstream of the perfused femoral artery with, or upstream of a femoral artery without endothelium. The effect of diltiazem was stereoselective (the less active l-cis-diltiazem had no effect). Verapamil did not reverse the relaxation induced by acetylcholine and did not affect the reversal induced by diltiazem. These findings indicate that diltiazem specifically antagonizes the production and/or the release of endothelium-derived relaxing factor(s) stimulated by acetylcholine or A23187 in canine femoral arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Mechanism underlying the inhibitory interaction between the nitrovasodilator SIN-1 and the endothelium.

Experiments were designed to determine the influence of the endothelium on the relaxing potency of the nitrovasodilator SIN-1. Rings of coronary arteries were suspended for isometric-tension recording in organ chambers filled with modified Krebs-Ringer bicarbonate solution, aerated with 95% O2-5% CO2 and warmed to 37 degrees C. The experiments were performed in the presence of indomethacin and propranolol in order to inhibit cyclooxygenase and beta-adrenoceptors, respectively. In rings contracted with prostaglandin F2 alpha, SIN-1 caused concentration-dependent relaxations that were increased following endothelium removal. In rings denuded of endothelium, the relaxations evoked by SIN-1 were not affected by NG-monomethyl-L-arginine (L-NMMA, which inhibits the production of endothelium-derived relaxing factor), or by superoxide dismutase and catalase (scavengers of oxygen-derived free radicals), or by L-NMMA plus superoxide dismutase and catalase. In rings with endothelium, relaxations evoked by SIN-1 were increased significantly by L-NMMA or by superoxide dismutase and catalase, and were increased further by the combination of L-NMMA plus superoxide dismutase and catalase. The difference in potency of SIN-1 between arterial rings with and without endothelium was reduced by either L-NMMA or by superoxide dismutase and catalase, and was abolished by the combination of L-NMMA plus superoxide dismutase and catalase. Therefore, the inhibitory interaction between SIN-1 and the endothelium may result from an endothelium-dependent production of oxygen-derived free radicals that may inactivate the nitric oxide generated by SIN-1, and from an inhibitory interaction between SIN-1 and endothelium-derived relaxing factor, released under basal conditions.

Analysis of Variance↗
PubMed2005

Hydrogen peroxide is an endothelium-dependent contracting factor in rat renal artery.

In addition to endothelium-derived relaxing factor and hyperpolarizing factor, vascular endothelium also modulates smooth muscle tone by releasing endothelium-derived contracting factor(s) (EDCF), but the identity of EDCF remains obscure. We studied here the involvement of hydrogen peroxide (H2O2) in endothelium-dependent contraction (EDC) of rat renal artery to acetylcholine (ACh). ACh (10(-6), 10(-5), and 10(-4) M) induced a transient contraction of rat renal artery with intact endothelium in a concentration-related manner, but not in the artery with endothelium removed. In phenylephrine-precontracted renal arteries, ACh induced an endothelium-dependent relaxation response at lower concentrations (10(-8)-10(-6) M), and a relaxation followed by a contraction at higher concentrations (10(-5) M). Inhibition of nitric oxide synthase by N(omega)-nitro-L-arginine (10(-4) M) enhanced the EDC to ACh. Catalase (1000 U ml(-1)) reduced the EDC to ACh. H2O2 (10(-6), 10(-5), and 10(-4) M) induced a similar transient contraction of the renal arteries as ACh, but in an endothelium-independent manner. Inhibition of NAD(P)H oxidase and cyclooxygenase by diphenylliodonium chloride and diclofenac greatly attenuated ACh-induced EDC, while inhibition of xanthine oxidase (allopurinol) and cytochrome P450 monooxygenase (17-octadecynoic acid) did not affect the contraction. Antagonist of thromboxane A2 and prostaglandin H2 receptors (SQ 29548) and thromboxane A2 synthase inhibitor (furegrelate) attenuated the contraction to ACh and to H2O2. In isolated endothelial cells, ACh (10(-5) M) induced a transient H2O2 production detected with a fluorescence dye sensitive to H2O2 (2',7'-dichlorofluorescein diacetate). The peak concentration of H2O2 was 5.1 x 10(-4) M at 3 min and was prevented by catalase. Taken together, these results show that ACh triggers H2O2 production through NAD(P)H oxidase activation in the endothelial cells, and that ACh and H2O2 share the same signaling pathway in causing smooth muscle contraction. Therefore, H2O2 is most likely the EDCF in rat renal artery in response to ACh stimulation.

Acetylcholine↗
PubMedDate not supplied

Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: a scanning microscopy evaluation.

Cardiotoxicity is a serious side effect of treatment of malignant diseases with 5-fluorouracil (5-FU). The underlying pathophysiologic mechanism remains unclear but clinical data suggest that the endothelium of coronary arteries may be involved. Experimental studies indicate that the endothelium is especially susceptible to 5-FU and support the hypothesis that a thrombogenic effect of 5-FU, secondary to its direct toxic effect on the endothelium, is one of the pathophysiologic mechanisms behind 5-FU-induced cardiotoxicity. In the present study we evaluate the role of antithrombotic treatment with dalteparin as protection against the thrombogenic effect of 5-FU on the vascular endothelium in a rabbit model. The effects on the vascular endothelium of 5-FU, dalteparin, and the combination of these two substances were evaluated with scanning electron microscopy 1, 3, 7, 14, and 30 days after treatment and compared with a control group. Very severe damage to the endothelium was seen in 5-FU-treated animals, often leading to intima disruption and denudation of underlying structures, with accompanying platelet accumulation and fibrin formation. The most extensive damage was observed on Day 3 after treatment. The cytotoxic effect of 5-FU was partly reversible. The combination of 5-FU and dalteparin gave lower scores on Day 3 because of less evidence of thrombotic events. However, the reversibility of the endothelial damage was poorer in this group, as well as in the group that received dalteparin alone. The findings support the hypothesis that antithrombotic treatment with dalteparin can protect against the thrombogenic effect of 5-FU, secondary to its direct toxic effect on the vascular endothelium. However, the study indicates that dalteparin per se has a toxic effect on the endothelium that is different from that of 5-FU.

Animals↗
PubMed1996

The endothelium-dependent response of human hepatic artery after preservation with the UW solution.

The University of Wisconsin's (UW) solution has been used commonly for current liver transplantation. However, its effect on the vascular endothelium remains unclear. Experiments were designed to study the effects. Human hepatic arteries harvested from patients with hepatocellular carcinoma undergoing liver resection were preserved in 4 degree C physiological solution (group 1, the content showed on the text) and UW solution (group 2) for 1 hr. Segments of preserved and control (group 3) hepatic arteries were suspended in organ chamber to measure the isometric force. The relaxations to acetylcholine (ACH) and adenosine diphosphate in segments of hepatic artery with endothelium were significantly greater than those segments without endothelium. The maximal relaxation to ACH in arterial segments with endothelium of group 2 was significantly different from those of group 1 and 3 (group 1 to group 3, 82 +/- 2%, 57 +/- 6%, and 83 +/- 4% of the initial tension contracted by neoepinephrine (3 X 10-7 mole/l, P < 0.05). The maximal relaxation to adenosine diphosphate was similar to the response to ACH. Perfusate hypoxia (oxygen tension 30 +/- 5 mmHG) caused endothelium-dependent contraction of the arterial segments (group 1 to group 3, 233 +/- 32%, 276 +/- 35%, and 251 +/- 40% of the initial tension, P < 0.05). Endothelium-independent relaxation and contraction of human hepatic artery to sodium nitroprusside and norepinephrine were not altered by UW solution. In summary, the impaired endothelium-dependent relaxation by UW solution and prominent endothelium-dependent contraction to hypoxia of human hepatic artery would favor vasospasm and thrombus formation after liver transplantation.

Adenosine↗
PubMed1996

Effects of lumbar sympathectomy on the properties of both endothelium and smooth muscle cells of the canine femoral artery and autogenous vein grafts under poor runoff conditions.

The purpose of this study was to determine whether or not a lumbar sympathectomy would modulate the functions of the endothelium, in terms of endothelium-derived relaxing factor (EDRF), under poor distal runoff conditions. First, a poor distal runoff model was developed in the canine right and left femoral arteries. After 5 weeks, a unilateral left sympathectomy was performed from L-3 to L-6. In experiment I, changes in blood flow and endothelium-dependent responses were examined in the canine femoral artery 5 weeks after the lumbar sympathectomy. In experiment II, 5 weeks after the development of a poor runoff model, a unilateral left sympathectomy was performed and both femoral veins were also grafted to the femoral arteries on both sides. Then after 4 weeks, endothelium-dependent responses and intimal thickening of both autogenous vein grafts were examined. The endothelium-dependent responses were examined by mechanical tension recording. In both experiments, the mean blood flow of the left femoral arteries (denervated, 92.2 +/- 47.1 ml/min) and vein grafts (denervated, 100.0 +/- 35.4 ml/min) was significantly higher than that of the right femoral arteries (innervated, 46.9 +/-25.7 ml/min) and vein grafts (innervated, 50.0 +/- 20.1 ml/min) (P < 0.01). In experiment I, the endothelium-dependent relaxations to acetylcholine, ADP, and A23187 were comparable between the right and left femoral arteries. In experiment II, the endothelium-independent contractions to acetylcholine and endothelium-dependent relaxations to ADP and A23187 were all comparable between the right and left vein grafts. In addition, the intimal thickening of the vein graft was comparable between the two groups (denervated, 95.6 +/- 10.8 microm; innervated, 105.0 +/- 15.0 microm). In both experiments, the NE-induced contractions and SNP-induced relaxations were closely similar between the two groups, irrespective of the flow change. These results suggest that lumbar sympathectomy does not alter endothelial function in terms of EDRF, although mean blood flow of the denervated femoral arteries and vein grafts was significantly higher than that of the innervated femoral arteries and vein grafts. These results suggest that continuous vasodilation following sympathectomy may be a more potent factor with respect to regulation of vascular tonus than physiologic regulation of EDRF.

Acetylcholine↗
PubMed1987

Palytoxin-induced endothelium-dependent relaxation in the isolated rat aorta.

The effects of a potent marine toxin, palytoxin (PTX), were investigated on the contractile responses in the isolated rat aorta with or without endothelium. PTX in the concentrations of 10(-13)-10(-11) mol/l showed little effect on the resting tension of the vessel with or without endothelium. PTX, 10(-10) mol/l, induced a small contraction in the aorta without endothelium but not in the aorta with endothelium. When added during the sustained contraction induced by 10(-7) mol/l norepinephrine, 10(-12) mol/l PTX sometimes (6 out of 43 strips) augmented the norepinephrine-induced contraction whereas 10(-11)-10(-10) mol/l PTX induced a biphasic response which was composed of a transient augmentation followed by a relaxation. These effects of PTX were not observed in the aorta without endothelium. Influences of atropine (10(-6) mol/l), indomethacin (2.5 X 10(-5) mol/l), methylene blue (5 X 10(-6) mol/l), hydroquinone (10(-4) mol/l), phenidone (5 X 10(-5) mol/l), hemoglobin (10(-6) mol/l) and p-bromophenacyl bromide (5 X 10(-5) mol/l) on the PTX (10(-10) mol/l) induced responses were examined. Methylene blue, hydroquinone, phenidone, hemoglobin and p-bromophenacyl bromide inhibited both the PTX-induced augmentation and relaxation of the norepinephrine-induced contraction. The endothelium-dependent relaxation due to 3 X 10(-7) mol/l carbachol was inhibited by atropine, methylene blue, hydroquinone, phenidone, hemoglobin and p-bromophenacyl bromide. These results suggest that PTX acts on the endothelium, modifies the synthesis or release of endothelium-derived relaxing factor and thus changes the contractile response to norepinephrine in rat aorta.

Acrylamides↗
PubMed1987

Lectin histochemistry of mammalian endothelium.

Lectin-histochemical studies were performed on formalin-fixed, paraffin-embedded tissues from ten mammalian species to demonstrate the pattern of carbohydrate residues in vascular endothelium. Ten different biotinylated lectins were used as probes and avidin-biotin-peroxidase complex (ABC) was used as visualant. Ricinus communis agglutinin-I (RCA-I) and wheat germ agglutinin (WGA) stained vascular endothelium in all species. Peanut agglutinin (PNA) stained vascular endothelium in all species only after preincubation with neuraminidase. Bandeirea simplicifolia agglutinin-I (BS-I) stained vascular endothelium in all species but human, while Ulex europeus agglutinin-I (UEA-I) stained only human endothelium. Individual differences in staining of human vascular endothelium were noted with BS-I and succinylated-WGA (SWGA). Similarly, individual differences in staining of animal vascular endothelium were noted with soybean agglutinin (SBA) after preincubation with neuraminidase. Finally, Concanavalia ensiformis agglutinin (Con A), Dolichos biflorus agglutinin (DBA) and Lens culinaris agglutinin (LCA) did not stain vascular endothelium in any of the species studied.

Animals↗
PubMed1999

Evidence for a contribution of store-operated Ca2+ channels to NO-mediated endothelium-dependent relaxation of guinea-pig aorta in response to a Ca2+ ionophore, A23187.

A23187 (6S-[6alpha,8beta,9beta,11alpha]-5-(methylamino) -2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]-1,7- dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazolecarboxylic acid, calcimycin), an antibiotic Ca2+ ionophore, produces an endothelium-dependent vascular relaxation. In the present study, pharmacological features were functionally characterized of endothelium-dependent relaxant response of guinea-pig aorta to A23187, especially focusing on the possible Ca2+ source and Ca2+ mobilization mechanisms in endothelial cells responsible for the vasorelaxant response to the Ca2+ ionophore. A23187-induced endothelium-dependent relaxation was suppressed profoundly by N(G)-nitro-L-arginine (L-NNA; 3 x 10(-4) M) or calmidazolium (3 x 10(-5) M), suggesting that nitric oxide (NO) produced by the enhanced activation of Ca2+/calmodulin-dependent endothelial NO synthase (eNOS) is largely responsible for the relaxant response of this artery to A23187. In the Ca2+-free solution without EGTA, NO-mediated endothelium-dependent relaxation induced by A23187 was almost abolished, which suggests that Ca2+ entry from extracellular space into endothelial cells plays the key role in the A23187-induced functional vasorelaxation. On the other hand, SK&F96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole; 5 x 10(-5) M) and Ni2+ (3 x 10(-4) M), both of which inhibit capacitative Ca2+ influx through store-operated Ca2+ channels (SOCCs), attenuated significantly NO-mediated endothelium-dependent relaxation by A23187. Furthermore, A23187-induced endothelium-dependent relaxation was suppressed more strongly than endothelium-independent relaxation induced by SIN-1 (3-morpholino-sydnonimine), an NO donor, when aortic preparation was preconstricted with high KCl instead of agonistic stimulation (prostaglandin F2alpha). These findings suggest that NO-mediated endothelium-dependent relaxant response of guinea-pig aorta to A23187 is preceded by the increase in endothelial cytosolic free Ca2+ concentration ([Ca2+]cyt) due to the enhanced Ca2+ influx from extracellular space. In the enhanced Ca2+ entry leading to the stimulation of eNOS and NO-mediated functional relaxant response of guinea-pig aorta to A23187, activation of SOCCs but not the Ca2+ entry through plasma membrane Ca2+-specific routes made by A23187 seems to play the predominant role. It is most likely that A23187 acts primarily at the Ca2+ store sites in endothelial cells, which subsequently depletes stored Ca2+ to activate SOCCs via unidentified mechanisms.

Animals↗
PubMed1989

Alpha 2-adrenoceptors and endothelium-derived relaxing factor.

The endothelium can release potent vasodilator substances, in particular prostacyclin and endothelium-derived relaxing factor. The triggers for the release of endothelium-derived relaxing factor include increases in levels of shear stress, neurotransmitters, autacoids, platelet products, and hormones. The endothelium-dependent response to catecholamines involves stimulation of alpha 2-adrenoceptors on the endothelial cells. Indeed, in a number of blood vessels, selective alpha 2-adrenergic agonists cause endothelium-dependent relaxations. These are seen most typically in blood vessels with long-term exposure to high flows and high partial pressures of oxygen. In addition to the release of endothelium-derived relaxing factor, alpha 2-adrenergic agonists can stimulate postjunctional (postsynaptic) alpha 2-adrenoceptors on vascular smooth muscles. These receptors, which are more abundant in hypertensive blood vessels, activate the contractile process. However, the alpha 2-adrenergic vasoconstrictors act as partial agonists (with a limited receptor reserve) and hence their vasoconstrictor response is very sensitive to functional antagonists such as endothelium-derived relaxing factor. Thus, the presence of endothelial cells can blunt the vasoconstrictor response to these substances not only because of an augmented release of endothelium-derived relaxing factor but also because the vasoconstriction that they induce is particularly susceptible to the inhibitory effect of the factor.

Animals↗
PubMed1989

Roles of calcium and the endothelium in the relaxations produced by 5'-N-ethylcarboxamidoadenosine (NECA).

The aim of the present investigation was to evaluate the endothelium dependency in the relaxations by the adenosine analog, 5'-N-ethylcarboxamidoadenosine (NECA), and the requirement for extracellular calcium in endothelium-dependent and independent relaxations. In prostaglandin F2 alpha (PGF2 alpha)-contracted bovine coronary arteries with intact endothelium, bradykinin produced relaxations in calcium medium but not in calcium-free medium. Removal of the endothelium abolished the relaxing response to bradykinin. In calcium medium, NECA produced similar relaxations in coronary arteries with intact and mechanically disrupted endothelium. The relaxation-response curves for NECA were shifted to the right in parallel in calcium free medium. Sodium nitroprusside produced concentration-dependent relaxations which were endothelium-independent. Removal of calcium from the bathing medium caused partial but significant attenuation of these relaxations. The results indicated that in bovine coronary artery, relaxations induced by NECA were endothelium-independent. Also bradykinin-induced relaxations are totally dependent on calcium whereas the endothelium-independent relaxing agents such as NECA and sodium nitroprusside require calcium only partially for their relaxations.

Adenosine↗
PubMed1990

Differential modulation by basilar and mesenteric endothelium of angiotensin-induced contraction in canine arteries.

The contraction of ring segments of canine mesenteric and basilar arteries in response to angiotensins II and III was investigated. Removal of the mesenteric endothelium resulted in markedly intensified contraction in response to angiotensin II but did not affect the contractile response to angiotensin III. This angiotensin II-induced contraction was augmented by indomethacin (10(-5) M) and by methylene blue (5 X 10(-6) M) in the intact rings. These findings suggest that mesenteric endothelium modulates the vasoconstriction induced by angiotensin II but not that induced by angiotensin III. They also indicate that the mesenteric endothelium may contain relaxing factors such as prostacyclin or endothelium-derived relaxing factor as mediators. In contrast with mesenteric endothelium, removal of the basilar endothelium produced a much reduced contraction in response to either angiotensin. Acetylcholine, which caused a dose-dependent contraction in the basilar artery, elicited only a low-grade response if the functional endothelium was absent. These results suggest that basilar endothelium may release a contracting factor. It is possible that the main modulator of the peripheral arteries is a relaxing factor but that of the cerebral arteries is a contracting factor.

Acetylcholine↗
PubMed1994

Endothelium-dependent, nitric oxide-mediated inhibition of angiotensin II-induced contractions in rabbit aorta.

The role of endothelium in angiotensin II-induced contractions of the rabbit aorta and the mechanism involved were investigated. Destruction of the endothelium significantly shifted the concentration-response curve for angiotensin II to the left in a non-parallel manner and enhanced the maximal response. The EC50 and Emax values obtained from the rings with and without functional endothelium were 2.44 +/- 0.13 x 10(-9) M, 4.50 +/- 0.45 g and 1.21 +/- 0.14 x 10(-9) M (n = 8, P < 0.05), 5.73 +/- 0.55 g (n = 8, P < 0.05), respectively. Indomethacin (10(-5) M) did not significantly alter the concentration-dependent response to angiotensin II in the presence of endothelium. Three inhibitors of nitric oxide synthase (NG-monomethyl-L-arginine; NG-nitro-L-arginine, and NG-nitro-L-arginine methyl ester) at 10(-4) M caused a similar endothelium-dependent potentiation of angiotensin II-induced contractions in the aortic rings with, but not in those without endothelium. These effects were reversed by L-arginine (3 x 10(-3) M) but not by D-arginine (3 x 10(-3) M). Angiotensin II in a concentration range of 10(-16) to 10(-6) M did not relax the endothelium-intact rings precontracted with phenylephrine (2 x 10(-7) M). In the presence of endothelium, the angiotensin II subtype 2 receptor antagonist, 1-[(4-amino-3-methylphenyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro- 1H- imidazol[4,5-C]pyridine-6-carboxylic acid (PD 123177), caused neither relaxation of the rings precontracted with phenylephrine nor alteration of the concentration-response curve for angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

Is endothelium necessary for transmural pressure-induced contractions of bovine truncal lymphatics?

The purpose of this study was to investigate the role of the endothelium in regulating lymphatic contractile activity in bovine mesenteric truncal lymphatics. To test the effects of endothelial denudation on lymphatic pumping, bovine lymphatics were suspended in an organ bath preparation with the vessels cannulated at both inflow and outflow ends. By raising the heights of the Krebs reservoir and the outflow catheters appropriately, a transmural pressure could be applied to the vessels. The relationship between transmural pressure and fluid pumping is expressed as a bell-shaped curve with pumping increasing up to a peak pressure (between 8 and 12 cm H2O), and declining at pressures above this level. We compared pressure/flow curves in endothelium-intact and endothelium-denuded vessels. Chemical methods to remove the endothelium were attempted (collagenase and dispase) but were unsuccessful since they resulted in inhibition of all contractile activity including that induced with KCl. A technique using suture silk (3-O to 6-O) threaded into PE 50 or PE 20 polyethylene catheters with a loop at one end proved to be effective. By passing the catheter with its exposed loop of silk through the lymphatic ducts and imparting a twisting motion, we were able to remove the endothelium and preserve the smooth muscle responses to KCl. Transmission electron microscopy as well as silver staining techniques confirmed that all of the endothelium had been removed leaving the subendothelium and smooth muscle undamaged. We established that removal of the endothelium had no effect on lymphatic pumping. Pumping could not have occurred without the normal function of the one-way valves indicating that the denudation procedures did not damage these elements. Maximum flow rates and the transmural pressures that induced peak flows were similar in the two groups. We conclude that the pumping activity of bovine mesenteric truncal lymphatics in response to transmural pressure changes does not depend on an intact endothelium.

Animals↗
PubMed1990

Comparison of the immunological properties of rat cerebral and aortic endothelium.

The immunological properties of cerebral microvascular endothelium were directly compared with those of an extra-cerebral endothelium in vitro. Lymphocyte adhesion to cerebral endothelium is normally low, but is sensitive to induction by interferon-gamma (IFN gamma) and tumour necrosis factor-alpha (TNF alpha). Conversely adhesion to aortic endothelium is normally much higher but it is only marginally sensitive to induction by cytokines. Adhesion to both cell types is Ca2+ and Mg2+ dependent. Mitogen-activated lymphocytes bind more strongly to both endothelia, but adhesion to aortic endothelium is not enhanced further by activation of the endothelium. The observed low binding of lymphocytes to brain endothelium and its rapid induction by cytokines suggest a mechanism to explain why lymphocyte accumulation in brain is normally very low but rapidly increases during immune responses. Both cell types express similar levels of class I major histocompatibility complex (MHC) molecules, and this is enhanced by IFN gamma with similar responsiveness to different levels of IFN gamma. MHC class II molecules are absent from these cells but may be induced: although both endothelia respond to similar levels of cytokines, the surface density induced on brain endothelium is approximately 2- to 3-fold higher at all levels of IFN gamma.

Animals↗
PubMed1996

Control of lymphocyte adhesion to brain and aortic endothelium: ICAM-1, VCAM-1 and negative charge.

Lymphocyte adhesion to CNS endothelium is low by comparison with non-CNS endothelium. It has been proposed that this could be due to the high surface charge of brain endothelium, or a low constitutive expression of adhesion molecules. In this study we compared the influence of these factors on lymphocyte adhesion to BEC and aortic endothelium (AEC) in culture. Brain endothelium expresses very low levels of VCAM-1, and lower levels of ICAM-1 than aortic endothelium. The negative charge differed between the endothelia, but this had a minimal effect on lymphocyte adhesion. The anionic sites were, however, more stable on brain endothelium, remaining unchanged after endothelial cell activation with cytokines, while redistribution was observed on cytokine-activated aortic endothelium.

Animals↗
PubMed2001

Distribution and role of Na(+)/K(+) ATPase in endocardial endothelium.

OBJECTIVE: In mammalian cardiomyocytes, alpha isoforms of Na(+)/K(+) ATPase have specific localisation and function, but their role in endocardial endothelium is unknown. METHODS: Different alpha isoforms in endocardial endothelium and cardiomyocytes of rabbit were investigated by measuring contractile parameters of papillary muscles, by RT-PCR, by Western blots and by immunocytochemistry. RESULTS: Inhibition of Na(+)/K(+) ATPase by decreasing external K(+) from 5.0 to 0.5 mmol/l caused biphasic inotropic effects. The maximal negative inotropic effect at external K(+) of 2.5 mmol/l was significantly larger in +EE muscles (with intact endocardial endothelium) than in -EE muscles (with endocardial endothelium removed) (-22.5+/-2.4% versus -5.9+/-4.0%, n=7, P<0.05). Further decrease of K(+) to 0.5 mmol/l caused endothelium-independent positive inotropy (27.8+/-11.8% for +EE versus 18.6+/-11.3% for -EE, n=7, P>0.05). Inhibition of Na(+)/K(+) ATPase either by dihydro-ouabain (10(-9) to 10(-4) mol/l, n=4) or by K(+) decrease following inhibition of Na(+)-H(+) exchanger by dimethyl-amiloride (50 micromol/l, n=6) caused endothelium-independent positive inotropic effects only. RT-PCR and Western Blot demonstrated alpha(1) and alpha(2) Na-K-ATPase isoforms in cardiomyocytes, but only alpha(1) in cultured endocardial endothelial cells. Immunohistochemistry showed that alpha(1) in endocardial endothelium was predominantly present at the luminal side of the cell (n=7) and that alpha(1) and alpha(2) displayed different localisation in cardiomyocytes. CONCLUSIONS: These results suggested that negative and positive inotropic effects of Na(+)/K(+) ATPase inhibition in +EE muscles could be attributed to inhibition of endocardial endothelial alpha(1) and muscle alpha(2) isoform, respectively. Accordingly, the endocardial endothelial alpha(1) isoform of Na(+)/K(+) ATPase may contribute to blood-heart barrier properties of this endothelium and may control cardiac performance via endothelial Na(+)/H(+) exchange.

Animals↗
PubMed1999

Impairment of G-protein-mediated signal transduction in the porcine coronary endothelium during rejection after heart transplantation.

BACKGROUND: Endothelial dysfunction is an early event leading to atherosclerosis. It also occurs after orthotopic heart transplantation and can be used to predict the development of intimal hyperplasia in the coronary artery wall. The present study was designed to assess the time course and specific alterations underlying endothelial dysfunction due to rejection after heart transplantation. METHODS: A porcine model of heterotopic heart transplantation was used. Preoperative serum typing for the class I antigen of the swine lymphocyte alloantigen was performed to ensure compatibility for this antigen. This permitted survival of the graft with a low grade rejection without immunosuppression. Rings (with or without endothelium) of epicardial coronary arteries of native and transplanted hearts were studied in organ chambers filled with modified Krebs-Ringer bicarbonate solution and compared 1, 30 and 60 days after transplantation. RESULTS: Myocardial contractility was normal in all grafts studied at 60 days after transplantation and all coronary arteries were patent. Myocardial biopsies showed the progression of rejection from day 1 to day 60 after implantation. All endothelium-dependent relaxations were normal one day after transplantation. Endothelium-dependent relaxations to serotonin and to the alpha 2-adrenergic agonist UK14304 (which both activate receptors coupled to Gi-proteins) and to sodium fluoride (a direct activator of G-proteins) were decreased 30 days after transplantation, while those to the calcium ionophore, A23187, and bradykinin were shifted to the right and those to ADP were normal. At 60 days, endothelium-dependent relaxations mediated by the Gi-protein pathway were decreased further while the concentration-relaxation curves to the other agonists were further shifted to the right. Endothelium-independent relaxations to the nitric oxide donor, Sin-1, were progressively reduced at 30 and 60 days, but maximal relaxations were maintained at 60 days. Histomorphometric studies showed a progressive increase in the percentage of coronary rings with intimal thickening from day 1 to day 60 after transplantation. CONCLUSIONS: The progressive endothelial dysfunction reported in this model of accelerated coronary atherosclerosis after transplantation without immunosuppression involves preferentially the pertussis-toxin-sensitive Gi-protein-mediated pathway. Endothelium-independent relaxations are decreased at 60 days, as are all other endothelium-dependent relaxations. Decreased endothelium-dependent vasodilatation may contribute to the development of coronary graft vasculopathy.

Adenosine Diphosphate↗