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PubMed1988

Endothelium-dependent modulation of angiotensin II-induced contraction in blood vessels.

The influence of endothelium on angiotensin II-induced contraction was investigated in rings of rat aorta, bovine coronary artery, bovine intrapulmonary artery and bovine intrapulmonary vein. Destruction of endothelium significantly enhanced angiotensin II-induced contraction in rat aorta and bovine coronary artery, but not in bovine intrapulmonary artery and bovine intrapulmonary vein. Indomethacin (10(-5) M) did not alter angiotensin II-induced contraction in rat aorta or bovine coronary artery. However, hemoglobin (10(-5) M) or methylene blue (10(-5) M) significantly enhanced angiotensin II-induced contraction in rat aorta and bovine coronary artery with, but not without, endothelium. Intimal rubbing did not affect stimulation of phosphoinositide hydrolysis by angiotensin II in rat aorta. The findings demonstrate that angiotensin II-induced contraction in vascular rings can be modulated by endothelium. However, the effect of endothelium apparently depends upon the species and vascular bed from which the vessel is isolated. Results obtained using inhibitors suggest that in rat aorta and bovine coronary artery release of endothelium-derived relaxant factor (EDRF), rather than cyclooxygenase products, is involved in mediating the inhibitory influence of endothelium. Further, similar stimulation of phosphoinositide hydrolysis in intimally rubbed and unrubbed rat aorta suggests that EDRF does not modulate angiotensin II-induced contraction in this vessel by inhibiting angiotensin II stimulation of phosphoinositide hydrolysis.

Angiotensin II↗
PubMed1989

The endothelium modulates adrenergic neurotransmission to canine pulmonary arteries and veins.

We tested the postulate that endothelium-derived relaxing factor (EDRF) modulates adrenergic neuroeffector transmission in isolated canine pulmonary arteries and veins, using the technique of superfusion and measurement of the efflux of [2-14C]NE during transmural nerve stimulation at 1, 2, 4, 8, 16 and 32 Hz for 10 and 30 min. In endothelium-rubbed artery and vein the contractile responses to low frequency nerve stimulation were enhanced, when compared to those from endothelium rubbed blood vessels. Transmural nerve stimulation of endothelium competent arteries and veins for 10 min released less [2-14C]NE than denuded arteries and veins, especially at 1, 2 and 4 Hz, with smaller differences evident at higher frequencies (16 and 32 Hz) of stimulation. Superfusion of endothelium rubbed blood vessels with effluent from canine thoracic aorta decreased the release of [2-14C]NE during nerve stimulation. These findings suggest that the endothelium and EDRF can inhibit release of adrenergic neurotransmitter from canine pulmonary arteries and veins. The endothelium may act as an endogenous modulator of adrenergic neurotransmission to canine vascular smooth muscle.

Acetylcholine↗
PubMed1989

Inhibitory effect of ethanol on endothelium-dependent vascular responsiveness.

The effect of ethanol was studied on the endothelium-dependent vascular responses in isolated rat aortic strips. Ethanol depressed the endothelium-dependent relaxation induced by acetylcholine and ATP but not that induced by the calcium ionophore, A23187. Endothelium-independent relaxation in response to sodium nitroprusside, a soluble guanylate cyclase activator, was not depressed by ethanol. On the other hand, ethanol significantly enhanced the contractile response to clonidine, an alpha 2-adrenoceptor agonist, in endothelium-intact strips and depressed it in endothelium-denuded strips. These results suggest that ethanol can inhibit endothelium-dependent relaxation by acting on endothelial cells but not on smooth muscle cells, and can also suppress an inhibitory effect of the endothelium on alpha 2-adrenoceptor-mediated vasoconstriction.

Acetylcholine↗
PubMed1990

5-Hydroxytryptamine does not release endothelium-derived relaxing factor in rat isolated coronary arteries.

Removal of the endothelium from isolated rat proximal and distal coronary artery segments shifted the 5-HT concentration-response curve to the left without affecting, the maximal contractile response. 5-HT had no relaxing effect in 10(-5) M prostaglandin F2 alpha-precontracted vessels with an intact endothelium in the presence of 10(-5) M ketanserin. The spontaneous myogenic tone increased in both proximal and distal coronary artery segments after the endothelium had been removed. Indomethacin (10(-5) M) reduced the response of the proximal coronary artery segments to 5-HT by 35% but indomethacin had no effect on the 5-HT concentration-response curve of the distal coronary artery segments. Indomethacin relaxed precontracted (40 mM potassium) proximal coronary artery segments independently of the presence of the endothelium, suggesting a non-specific relaxing effect of indomethacin in these arteries. It is concluded that rat coronary artery endothelium is unresponsive to 5-HT because it lacks 5-HT1 receptors. The increased 5-HT sensitivity and spontaneous myogenic tone of endothelium-denuded rat coronary arteries is probably due to the elimination of the relaxing stimulus mediated by spontaneously released endothelium-derived relaxing factor.

Acetylcholine↗
PubMed1993

Endothelium-dependent component in the contractile responses of human omental arteries to adrenergic stimulation.

The present study was designed to investigate the influence of endothelium-derived nitric oxide on the contractile responses of isolated human omental arteries to electrical field stimulation and noradrenaline. We measured isometric tension in artery rings obtained from portions of human omentum during the course of abdominal operations (32 patients). Electrical field stimulation induced frequency-dependent contractions which were abolished by tetrodotoxin (10(-6) M) and prazosin (10(-6) M), thus indicating that this effect was due to noradrenaline released from adrenergic nerves acting on alpha 1-adrenoceptors. The increases in tension induced by electrical field stimulation were of greater magnitude in arteries denuded of endothelium. NG-Nitro-L-arginine (L-NAME, 10(-4) M) potentiated the contractile response to electrical field stimulation in artery rings with endothelium but did not influence the contractile responses of endothelium-denuded arteries. The potentiation induced by L-NAME was completely reversed by L-arginine (10(-4) M), but not by D-arginine (10(-4) M). Contractile responses to noradrenaline were similar in arteries with and without endothelium. L-NAME (10(-4) M) had no significant effect on the contractile responses to noradrenaline. Our results suggest that electrical field stimulation releases endothelium-derived nitric oxide which inhibits the contractile responses of human omental arteries. The constrictor responses to noradrenaline are not modulated by the endothelium.

Adult↗
PubMed1993

Endothelium-dependent vasodilator responses of the isolated mesenteric bed are preserved in long-term streptozotocin diabetic rats.

Endothelium-dependent and endothelium-independent responses to exogenous vasoactive substances were compared in isolated, perfused mesenteric beds from control rats and in rats subjected to prolonged (15-17 weeks) streptozotocin induced diabetes. The main aim of the study was to determine whether the prolonged period of diabetes altered vascular endothelial function, and thereby modified vascular responsiveness to vasoconstrictors or vasodilators. Noradrenaline induced vasoconstriction was not significantly altered in preparations from diabetic rats compared to control. Vasodilator responses to acetylcholine (ACh) and ATP were endothelium-dependent, since they were greatly reduced or abolished after endothelium removal by perfusion with 0.1% Triton-X 100. The vasodilator action of these agents was fully preserved in the diabetic animals. Sodium nitroprusside produced a vasodilation which was endothelium-independent, this vasodilation was also preserved in the diabetic animal. We conclude that prolonged streptozotocin-induced diabetes does not reduce the ability of the mesenteric vascular endothelium to release vasodilator substances, nor does it alter the responsiveness of the bed to exogenous endothelium-independent vasodilator sodium nitroprusside or vasoconstrictor noradrenaline.

Acetylcholine↗
PubMed1993

Endothelium-independent pressor effect of big endothelin-1 and its inhibition by phosphoramidon in rat mesenteric artery.

We asked whether or not the endothelium plays a functional role in the conversion of big endothelin-1 to endothelin-1 in the perfused rat mesenteric artery. In endothelium-denuded preparations, big endothelin-1 produced a much more potent pressor effect than in intact preparations. Phosphoramidon suppressed the big endothelin-1-induced pressor action without affecting the action of endothelin-1, irrespective of the presence or absence of the endothelium. The amounts of immunoreactive-endothelin in the perfusate during perfusion of endothelium-denuded preparations with big endothelin-1 were extremely low compared with those observed in intact preparations and were not significantly suppressed by the metalloproteinase inhibitor, phosphoramidon, in contrast to the case with intact preparations. When synthetic endothelin-1 was perfused in the endothelium-denuded mesentery, the peptide disappeared from the perfusate more rapidly than with intact preparations, suggesting that endothelin-1 generated from big endothelin-1 is effectively trapped by vascular smooth muscle cells in the endothelium-denuded preparation. Our results suggest that the endothelium is not essential for the conversion of big endothelin-1 to endothelin-1, in rat mesenteric artery.

Animals↗
PubMed1991

Humoral factor mediates acetylcholine-induced endothelium-dependent relaxation of chicken aorta.

A superfusion cascade system was used to determine whether endothelium-dependent vasorelaxation induced by acetylcholine (ACh) is mediated by a humoral factor(s) in the domestic fowl. An abdominal aorta (5 cm in length) with intact endothelium, excised from the donor bird, was mounted in an organ bath and perfused with avian Ringer solution. The vasorelaxing activity of the effluent was determined by an endothelium-denuded aortic ring (bioassay ring) equilibrated and precontracted with phenylephrine (PHE) (10(-6) M). The effluent (containing PHE) from the donor aorta with intact endothelium did not significantly change the PHE-induced tension of the bioassay rings. ACh (10(-6) M), when added to the perfusion medium that runs through the control polyethylene tubing, produced further contraction of the PHE-precontracted endothelium-denuded bioassay rings, whereas ACh caused relaxation of the rings when added to the perfusate that passes through the endothelium-intact donor aorta. The ACh-induced relaxation of the bioassay ring was slightly potentiated by superoxide dismutase (100 U/ml). Hemoglobin (10(-5) M) increased the basal tension of the bioassay rings and completely inhibited the ACh-induced relaxation of the rings. These results suggest that ACh-induced relaxation of fowl aorta is, at least partially, mediated by a humoral factor(s) that resembles endothelium-derived relaxing factor demonstrated in mammals.

Acetylcholine↗
PubMed1996

Expression of VCAM-1 in rabbit iliac arteries is associated with vasodilator dysfunction of regenerated endothelium following balloon injury.

Previous studies have demonstrated impaired endothelium-dependent vasodilation following balloon injury of the rabbit iliac artery, suggesting dysfunction of the regenerated endothelium. More recently, expression of vascular cell adhesion molecule-1 (VCAM-1) has been shown up to 4 weeks in a different injury model of the rabbit aorta, suggesting sustained inflammatory activation of endothelium following injury. The aim of the present study was to combine the examination of VCAM-1 expression, as a marker of cellular activation, and the assessment of endothelium-dependent relaxation to test the hypothesis that different forms of altered endothelial function are concurrently present in the chronic phase following experimental balloon angioplasty. New Zealand White rabbits fed either a standard (n = 7) or a 1% cholesterol (n = 8) diet, underwent balloon injury of the iliac artery 5 weeks following the initiation of the diet. Four weeks after balloon injury, control and balloon-injured arteries were harvested for in vitro studies of vascular reactivity, for morphometric analysis and for immunocytochemical staining with Rb 1/9 monoclonal antibody directed against VCAM-1 and with CD 31 monoclonal antibody for the identification of endothelial cells. The combination of balloon injury and hypercholesterolemia resulted in a marked impairment of endothelium-dependent relaxation to acetylcholine and in a pronounced intimal proliferation compared to control or either intervention alone. Control rings of rabbits fed a normal diet did not reveal positive staining for VCAM-1. Balloon-injured rings of the animals fed a normal diet showed focal areas of positive staining in the superficial cell layer overlying intimal lesions. In the group fed a high cholesterol diet, control rings and ballooned rings showed positive staining for VCAM-1 in cells overlying intimal lesions. In all groups the superficial cell layers were identified as endothelial cells by positive staining for CD 31. In conclusion, the present study shows that regenerated endothelium following mechanical arterial injury reveals expression of VCAM-1 together with impaired receptor-mediated vasodilator capacity. Thus, the expression of VCAM-1 and the impairment of endothelium-dependent relaxation may represent different features of endothelial dysfunction following balloon injury which may actively influence the proliferative lesion of restenosis after balloon angioplasty.

Acetylcholine↗
PubMed1996

RGD-containing peptides induce endothelium-dependent and independent vasorelaxations of rat aortic rings.

Peptides containing the extracellular matrix peptide cell attachment sequence RGD possess potent, endothelium-dependent vasorelaxant properties. In the present study, the ability of RGD-containing peptides to cause vasorelaxation in the presence and absence of a functional endothelium was examined in rat aortic rings along with the ability of RGD-containing peptides to increase cGMP production in these vessels. The active RGD-containing peptide GRGDNP induced rapid relaxation in endothelium-intact, norepinephrine contracted rat aortic rings. When the endothelium was removed, RGD-containing peptides produced a slow relaxation of contracted rings which took approx. 40 min to reach maximum relaxation. Control RGD peptides were without effect either in the presence or absence of a functional endothelium. While acetylcholine and sodium nitroprusside stimulated cGMP production in endothelium-intact and denuded aortic segments, neither the control RGD peptide nor the active GRGDNP increased cGMP in these vessels when compared to controls upon either short (30 s) or long (45 min) incubation times. These data indicate that relaxations of rat aortic rings in response to RGD-containing peptides occur both in the presence and absence of an intact endothelium and that cGMP is likely not the sole mediator of these responses.

Acetylcholine↗
PubMed1992

Histamine H1-receptors mediate endothelium-dependent relaxation of rat isolated pulmonary arteries.

Histamine has been reported to cause endothelium-dependent relaxation of vascular smooth muscle and vasodilation. This study was undertaken to examine the inhibitory effects of histamine on cylindrical segments of extrapulmonary arteries isolated from male Sprague Dawley rats. In arterial segments precontracted with phenylephrine (10 microM), histamine (0.1-100 microM) elicited concentration-dependent relaxation responses. Removal of the endothelium or pretreatment with methylene blue (10 microM) abolished relaxation responses to low concentrations of histamine and markedly inhibited those caused by histamine at concentrations greater than 1 microM. Incubation of endothelium-intact arterial segments with pyrilamine (1 microM) caused a significant rightward shift of the histamine concentration-response curves. Treatment of the segments with cimetidine (100 microM) or indomethacin (10 microM) only minimally antagonized histamine-induced relaxation in arteries with endothelium. Residual relaxation responses observed in arteries stripped of endothelium were unaffected by pretreatment with cimetidine, indomethacin, or pyrilamine. The results suggest that the inhibitory effect of histamine in rat pulmonary arteries is mediated predominantly by activation of H1-receptors on the endothelium and the subsequent release of endothelium-derived relaxing factor(s).

Animals↗
PubMed2006

Mechanisms underlying ATP-induced endothelium-dependent contractions in the SHR aorta.

In mature spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats, acetylcholine, the calcium ionophore A 23187 and ATP release endothelium-derived contracting factor (EDCF), cyclooxygenase (COX) derivatives that activate thromboxane-endoperoxide (TP) receptors on vascular smooth muscle. The EDCFs released by acetylcholine have been identified as prostacyclin and prostaglandin (PG) H(2) while in response to A 23187 thromboxane A(2), along with the two other prostaglandins, contributes to the endothelium-dependent contractions. The purpose of the present study was to identify the EDCFs produced by ATP. Isometric tension and the release of prostaglandins were measured in isolated aortic rings of WKY rats and SHR. ATP produced the endothelium-dependent release of prostacyclin, thromboxane A(2) and PGE(2) (PGI(2)>>TXA(2)> or =PGE(2)>PGF(2alpha)) in a similar manner in aorta from WKY rats and SHR. In SHR aortas, the release of thromboxane A(2) was significantly larger in response to ATP than to acetylcholine while that to prostacyclin was significantly smaller. The inhibition of cyclooxygenase with indomethacin prevented the release of prostaglandins and the occurrence of endothelium-dependent contractions. The thromboxane synthase inhibitor dazoxiben selectively abolished the ATP-dependent production of thromboxane A(2) and partially inhibited the corresponding endothelium-dependent contractions. U 51605, a non-selective inhibitor of PGI-synthase, reduced the release of prostacyclin elicited by ATP but induced a parallel increase in the production of PGE(2) and PGF(2alpha), suggestive of a PGH(2)-spillover, which was associated with the enhancement of the endothelium-dependent contractions. Thus, in the aorta of SHR, endothelium-dependent contractions elicited by ATP involve the release of thromboxane A(2) and prostacyclin with a possible contribution of PGH(2).

Acetylcholine↗
PubMed2006

Leukemia-stimulated bone marrow endothelium promotes leukemia cell survival.

Extensive endothelial cell proliferation and marked neovascularization are the most pronounced microenvironmental changes consistently observed in the bone marrow (BM) of patients with acute lymphoblastic leukemia (ALL). It is not known whether ALL cells induce this phenotype and whether they receive critical signals from the tumor-associated BM endothelium. Here, we show that leukemia cells actively stimulate BM endothelium, promote de novo angiogenesis, and induce neovascularization in the leukemic BM. Soluble factors, present in the leukemic BM microenvironment, promote the proliferation, migration, and morphogenesis of BM endothelial cells, which are critical processes in tumor angiogenesis. We also show in vitro that leukemia cells display directional motion towards assembled BM endothelium and following adherence exhibit cell polarization, pseudopodia, and ultrastructural features that suggest the existence of leukemia-endothelium cross-talk. Finally, we show that BM endothelium promotes leukemia cell survival through a mechanism mediated through the anti-apoptotic molecule bcl-2. These studies indicate that ALL cells actively recruit BM endothelium and mediate the leukemia-associated neovascularization observed in ALL. Therefore, disruption of interactions between leukemia cells and BM endothelium may constitute a valid therapeutic strategy.

Animals↗
PubMed2006

Effect of lithium on endothelium-dependent and neurogenic relaxation of rat corpus cavernosum: role of nitric oxide pathway.

INTRODUCTION: Some studies have reported erectile dysfunction in patients receiving lithium through a mechanism that has not yet been defined. The aim of the present study was to verify the effect of acute lithium administration on the nonadrenergic noncholinergic (NANC)- and endothelium-mediated relaxation of rat isolated corpus cavernosum. MATERIALS AND METHODS: The isolated rat corporeal strips were precontracted with phenylephrine hydrochloride (7.5 microM) and electrical field stimulation (EFS) was applied at different frequencies (2, 5, 10, and 15 Hz) to obtain NANC-mediated relaxation or relaxed by adding cumulative doses of acetylcholine (10nM-1mM) to obtain endothelium-dependent relaxation in the presence or absence of lithium (0.3, 0.5, 1, and 5mM). Also, effects of combining lithium (0.3mM) with 30 nM and 0.1 nM L-NAME (an NO synthase inhibitor) on NANC- and acetylcholine-mediated relaxation was investigated, respectively. Moreover, effects of combining lithium (1mM) with 0.1mM and 10 microM L-arginine (a precursor of NO) on NANC- and endothelium-mediated relaxation was assessed, respectively. Also, the effect of lithium (1mM) on relaxation to sodium nitroprusside (SNP; 1nM-1mM), an NO donor, was investigated. RESULTS: The NANC-mediated relaxation was significantly (P<0.001) reduced by 1 and 5mM, but not by 0.3 and 0.5mM lithium. Lithium significantly (P<0.001) attenuated the maximum response to acetylcholine in a concentration-dependent manner. Combination of lithium (0.3mM) with 30 and 0.1 nM L-NAME, which separately had a minimum effect on NANC- and endothelium-mediated relaxation, significantly (P<0.001) reduced the NANC- and endothelium-mediated relaxation, respectively. Although L-arginine at 10 microM and 0.1mM did not alter the relaxant responses to acetylcholine and EFS, it improved the inhibition by lithium (1mM) of relaxant responses to acetylcholine and EFS, respectively. Also, SNP produced similar concentration-dependent relaxations from both groups. DISCUSSION: Our experiments indicated that lithium likely by interfering with NO pathway in both endothelium and nitrergic nerve can result in impairment of both the endothelium- and NANC-mediated relaxation of rat corpus cavernosum.

Acetylcholine↗
PubMed2005

CXCR 3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow.

T cells infiltrating the inflamed liver express high levels of CXCR 3 and show enhanced migration to CXCR 3 ligands in chemotactic assays. Moreover, CXCR 3 ligands are up-regulated on hepatic endothelium at sites of T-cell infiltration in chronic hepatitis, and their presence correlates with outcome of inflammatory liver disease. We used a flow-based adhesion assay with human hepatic endothelium to investigate the function of CXCR 3 on lymphocyte adhesion to and transmigration through hepatic endothelium under physiological conditions of blood flow. To more accurately model the function of in vivo activated CXCR 3(high) lymphocytes, we isolated T cells from human liver tissue and studied their behavior in flow-based adhesion assays. We demonstrate that CXCR 3 not only promoted the adhesion of effector T cells to endothelium from flow but also drove transendothelial migration. Moreover, these responses could be stimulated either by endogenous CXCR 3 ligands secreted by the endothelium or by exogenous CXCR 3 ligands derived from other cell types and presented by the endothelium. This study thus demonstrates that activation of CXCR 3 promotes lymphocyte adhesion and transendothelial migration under flow and that human hepatic endothelium can present functionally active chemokines secreted by other cell types within the liver.

Biliary Tract↗
PubMed1997

Effects of lung preservation with Euro-Collins and University of Wisconsin solutions on endothelium-dependent relaxations.

BACKGROUND: This study compares the effect of lung preservation using flush perfusion of Euro-Collins or University of Wisconsin solution on the pulmonary vascular function of endothelium-dependent and endothelium-independent relaxations. METHODS: Rings of canine intrapulmonary arteries were studied after 6 hours of cold ischemia in Euro-Collins or University of Wisconsin preservation solution. Endothelium-dependent and endothelium-independent relaxations were induced in organ chamber experiments. To also study pulmonary resistance vessels, endothelium-dependent relaxations were induced in in vitro perfused intact rabbit lungs. RESULTS: In the organ chamber experiments, a moderate but significant (p < 0.05) reduction in endothelium-dependent relaxations were found in the perfused and stored vessels. In perfused rabbit lungs, a decrease in the endothelial response occurred immediately after perfusion with Euro-Collins solution. However, a recovery and overshooting response was found after preservation with either solution and 6 hours of cold ischemia. A significant increase in the sensitivity of smooth muscle cells to nitric oxide was shown in both preparations. CONCLUSIONS: Both crystalloid perfusion fluids cause a decrease in endothelial function during the perfusion procedure. In contrast, endothelial function is well preserved during the ischemic time. University of Wisconsin solution induced a higher sensitivity of the vascular smooth muscle to the endothelium-derived relaxing factor nitric oxide. A reduction in pulmonary vascular resistance after University of Wisconsin preservation may be of importance in subsequent clinical lung transplantation.

Adenosine↗
PubMed2003

Endothelium-dependent and -independent relaxation and VASP serines 157/239 phosphorylation by cyclic nucleotide-elevating vasodilators in rat aorta.

Endothelium-dependent vasodilation is thought to be mediated primarily by the NO/cGMP signaling pathway whereas cAMP-elevating vasodilators are considered to act independent of the endothelial cell layer. However, recent functional data suggest that cAMP-elevating vasodilators such as beta-receptor agonists, adenosine or forskolin may also be endothelium-dependent. Here we used functional and biochemical assays to analyze endothelium-dependent, cGMP- and cAMP-mediated signaling in rat aorta. Acetylcholine and sodium nitroprusside (SNP) induced a concentration-dependent relaxation of phenylephrine-precontracted aorta. This response was reflected by the phosphorylation of the vasodilator-stimulated phosphoprotein (VASP), a validated substrate of cGMP- and cAMP-dependent protein kinases (cGK, cAK), on Ser(157) and Ser(239). As expected, the effects of acetylcholine were endothelium-dependent. However, relaxation induced by the beta-receptor agonist isoproterenol was also almost completely impaired after endothelial denudation. At the biochemical level, acetylcholine- and isoproterenol-evoked cGK and cAK activation, respectively, as measured by VASP Ser(239) and Ser(157) phosphorylation, was strongly diminished. Furthermore, the effects of isoproterenol were repressed by eNOS inhibition when endothelium was present. We also observed that the relaxing and biochemical effects of forskolin were at least partially endothelium-dependent. We conclude that cAMP-elevating vasodilators, i.e. isoproterenol and to a lesser extent also forskolin, induce vasodilation and concomitant cyclic nucleotide protein kinase activation in the vessel wall in an endothelium-dependent way.

Acetylcholine↗
PubMed1997

Non-specific inhibition by human lipoproteins of endothelium dependent relaxation in rat aorta may be attributed to lipoprotein phospholipids.

OBJECTIVE: In vitro incubation of low-density lipoprotein (LDL) is reported to attenuate endothelium dependent relaxation mediated by acetylcholine (ACh) while not affecting endothelium-independent relaxation. This study was designed to examine the effects of other lipid-carrying lipoproteins as well as to study their effects on responses mediated by endothelium dependent agonists other than ACh. METHODS: The effects of human LDL, very-low-density lipoprotein (VLDL) and high density lipoprotein (HDL) on endothelium-dependent relaxation by ACh, histamine and the calcium ionophore, A23187, and endothelium-independent relaxation by sodium nitroprusside (SNP) were investigated is rat isolated aortic rings. The effects of combined LDL and HDL incubation on responses mediated by ACh were also examined. Control experiments included experiments examining the effects of bovine serum albumin on responses mediated by ACh. Thiobarbituric-acid-reactive substances (TBARS) measured before and after organ bath incubation indicated little oxidation of the lipoproteins used. RESULTS: Maximal responses to ACh were inhibited by LDL, VLDL and HDL (0.02 and 0.2 mg protein/ml), to histamine by LDL (0.2 mg protein/ml), VLDL (0.02 and 0.2 mg protein/ml) and HDL (0.02 mg protein/ml) and to A23187 by LDL (0.2 mg protein/ml). VLDL (0.2 mg protein/ml) and HDL (0.02 and 0.2 mg protein/ml). A small but significant correlation (r = 0.54, P = 0.01) was observed between the level of inhibition of the endothelium-dependent responses and lipoprotein phospholipid concentration in the organ bath but not between the level of inhibition and cholesterol (free and esterified) or triglyceride concentrations. Responses to SNP were unaffected by LDL, VLDL and HDL. Combined incubation of tissues with LDL (0.2 mg protein/ml) and HDL (0.2 mg protein/ml) significantly increased maximal responses to ACh (pre-lipoproteins 81.8 +/- 5.7 vs plus-LDL/HDL 100 +/- 0.0; P < 0.05). Bovine serum albumin had no effect on the maximal responses to ACh. CONCLUSIONS: We conclude that inhibition by human lipoproteins of endothelium-dependent agonists occurs with LDL, HDL and VLDL and suggest that this may be due to the phospholipid content of each lipoprotein. However, combined incubation of HDL with LDL negates this effect and an increased maximal response to ACh is reported.

Acetylcholine↗