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PubMed1991

Endothelium-dependent production of prostacyclin in human internal mammary artery.

The internal mammary artery (IMA) has become the conduit of choice in coronary artery bypass surgery because of superior long-term patency. It had been shown that IMA graft could release prostacyclin. Prostacyclin is a potent vasodilator and also can inhibit platelet aggregation. To determine the role of human IMA endothelium in production of prostacyclin, we tested the reactivity of segments of human IMA to hypoxia in vitro. Human IMAs were harvested during coronary artery bypass surgery. Prostacyclin was measured from fluid in the organ baths by radioimmunoassay of its major hydrolytic product 6-keto-prostaglandin F1 alpha. Rings (4 mm in length) of IMA, with and without endothelium, were suspended in organ baths containing physiologic salt solution. Rings were contracted with norepinephrine, and exposed to hypoxia (pO2 35 +/- 5 mmHg) for 15 minutes then reoxygenated. In segments with endothelium, hypoxia induced a transient relaxation followed by contraction. The transient relaxation was associated with a significantly increased production of 6-keto-prostaglandin-F1 alpha (from 34.1 +/- 2.7 pg/ml prehypoxia to 51.6 +/- 6.7 pg/ml during hypoxia, mean +/- SEM, p less than 0.05). This transient relaxation was blocked by indomethacin but not by NG-monomethyl-L-arginine (L-NMMA) and free radical scavengers (superoxide dismutase, catalase and deferoxamine). However, in segments without endothelium, the prehypoxia (14.7 +/- 0.9) and during hypoxia (15.5 +/- 1.4) level of 6-keto-prostaglandin F1 alpha were not increased and were significantly lower than those with endothelium. This study demonstrated that endothelium of IMA grafts could release prostacyclin either in a basal condition or upon stimulation of hypoxia. This ability possibly contributes to its long-term patency.

Cell Hypoxia↗
PubMed1991

Response of rat thoracic aortic rings to thromboxane mimetic U-46,619: roles of endothelium-derived relaxing factor and thromboxane A2 release.

Studies were designed to test the role of the endothelium and endogenous release of thromboxane (Tx) A2 in the contractile response of rat thoracic aortic rings to the TxA2/prostaglandin (PG) H2 mimetic, U-46,619. U-46,619 caused a dose-dependent contraction of rings with endothelium (mean ED50 = 6.54 +/- 3.02 x 10(-9) M; n = 13) which was abolished by the TxA2/PGH2 receptor antagonist, SQ-29,548. Removal of endothelium greatly potentiated (P less than .05) the contractile response to U-46,619 (ED50 = 4.78 +/- 2.14 x 10(-10) M; n = 14). On addition to the organ bath, oxyhemoglobin (10(-6) M), an inhibitor of endothelium-derived relaxing factor, increased vascular smooth muscle contraction in response to U-46,619 and abolished the difference in response between rings with endothelium (ED50 = 6.63 +/- 0.38 x 10(-11) M) and those without (ED50 = 5.13 +/- 0.18 x 10(-11) M). Vascular contraction with U-46,619 (10(-7] was associated with release of immunoreactive TxB2 and 6-keto PGF1 alpha as well as increased conversion of [14C]arachidonate to [14C]TxB2 and 6-keto-[14C]PGF1 alpha. To test the role of endogenous TxA2 in response to U-46,619, the TxA2 synthetase inhibitor UK-38,485 (10(-6) M) was added directly to the organ bath; this diminished (P less than .05) the contractile responses to U-46,619 of rings with and without endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Inhibition of endothelium-dependent relaxations by phorbol myristate acetate in canine coronary arteries: role of a pertussis toxin-sensitive G-protein.

Activation of protein kinase C by phorbol esters inhibits the endothelium-dependent relaxations evoked by certain stimuli. The release of endothelium-derived relaxing factor can be evoked by a number of distinct subcellular processes, including activation of a pertussis toxin-sensitive G-protein. The aim of the present study was to determine whether or not the inhibitory effect of phorbol esters on endothelial function was associated with inhibition of the pertussis toxin-sensitive pathway. Rings of canine coronary artery were suspended for isometric tension recording in organ chambers filled with modified Krebs-Ringer bicarbonate solution, gassed with 95% O2-5% CO2 (37 degrees C). Treatment of arterial rings with pertussis toxin (100 ng/ml) or with phorbol myristate acetate (PMA, 10(-8) M) inhibited the endothelium-dependent relaxations produced by UK 14,304, an alpha-2 adrenergic agonist, leukotriene C4 or by NaF, a direct activator of G-proteins, but did not affect the endothelium-dependent relaxations produced by bradykinin or by A23187. If the arterial rings were first treated with pertussis toxin, PMA (10(-8) M) no longer inhibited the endothelium-dependent relaxations to NaF. Increasing the concentration of PMA (to 3 X 10(-8) and 10(-7) M) caused inhibition of responses to bradykinin. At higher concentrations, PMA (3 X 10(-7) and 10(-6)) also inhibited the relaxations evoked by A23187. The endothelium-independent relaxations evoked by nitroglycerin were not affected by PMA (10(-8) to 10(-6)).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Control of lymphocyte migration into brain: selective interactions of lymphocyte subpopulations with brain endothelium.

We have determined whether particular lymphocyte populations bind preferentially to cerebral endothelium, using adhesion assays and a new method for in situ staining of adherent lymphocytes. B cells bind more strongly than T cells, an effect enhanced by lymphocyte activation or endothelial cell stimulation with interferon-gamma (IFN-gamma) or tumour necrosis factor-alpha (TNF-alpha). This is not equated with levels of CD18 expression on the lymphocytes. CD8+ T cells bound more efficiently than CD4+ cells under all conditions. To determine whether there was a population of cells which selectively homes to the brain, we compared adhesion of cervical lymph nodes cells to brain endothelium, with adhesion of lymphocytes from other nodes. In 50% of the experiments there was significantly enhanced binding of activated cervical lymph cells to cerebral endothelium but not to control (aortic) endothelium. This effect was seen using both normal and IFN-gamma-activated endothelium. The explanation for this finding is that cervical lymph nodes frequently, but not invariably, contain higher proportions of CD8+ cells and B cells than other lymph nodes. These data imply that selective adhesion of lymphocytes to brain endothelium is related to the subpopulations involved and this may be reflected in the cell types seen in immunological lesions of the brain, and in the relative proportions of the subpopulations seen in cervical lymph nodes.

Animals↗
PubMed1990

Decrease in endothelium-dependent relaxation and levels of cyclic nucleotides in aorta from rabbits with alloxan-induced diabetes.

To investigate the influence of diabetes mellitus on vascular relaxation response, acetylcholine (ACh)-induced relaxation and production of cyclic GMP and cyclic AMP in aortic rings with endothelium were compared between alloxan-induced diabetic and control rabbits. ACh-induced relaxation was significantly attenuated in the aortic rings of diabetic rabbits. Concentration-response curve for ACh-induced relaxation in the aortic rings of control rabbits was shifted to the right by the pretreatment with hemoglobin, and this concentration-response curve was almost identical to that in the aorta from diabetic rabbits. Sodium nitroprusside (SNP)-induced relaxation in the aortic rings without endothelium from diabetic rabbits was similar to that in the aortic rings without endothelium from control rabbits. Basal levels of cyclic GMP and ACh-induced production of cyclic GMP were markedly lower in diabetic rabbits than those in control rabbits. On the other hand, there were no differences in basal and ACh-induced production of cyclic AMP between diabetic and control aorta. These results suggest that impairment of endothelium but not guanylate cyclase activity may be occurred in the aorta of diabetic rabbits. This impairment leads to the decrease in production of cyclic GMP through the attenuation of endothelium-derived relaxing factor (EDRF) release, and this may be responsible for the decreased endothelium-dependent relaxation of ACh.

Acetylcholine↗
PubMed1990

Proinflammatory and procoagulant effects of herpes simplex infection on human endothelium.

Atherosclerotic lesions have been reported to contain herpes simplex virus (HSV) genomic material. This and other evidence suggests that latent viral infection may be an atherogenic trigger. Moreover, active HSV lesions manifest histologically marked fibrin deposition in microvessels. Our laboratory tested in vitro whether HSV infection would cause human umbilical vein endothelial cells to become procoagulant and attract inflammatory cells. Early infection of human endothelial cells with HSV-1 alters the surface conformation as detected by merocyanine 540 staining. The efficiency of prothrombinase complex assembly increases, resulting in a two- to threefold accelerated rate of thrombin generation on the cell surface of virally infected endothelium. HSV infection of endothelium results in a marked increase in thrombin-induced platelet adhesion with a concomitant decrease in prostacyclin secretion in response to thrombin. Viral infection enhances coagulation by decreasing endothelial thrombomodulin expression and subsequent activation of protein C. Viral infection also induces tissue factor in human endothelial cells within 4 hours of infection. Not only does the endothelial monolayer become procoagulant when infected with HSV, it also becomes a more adherent surface for granulocytes. Resting and stimulated granulocyte adherence is enhanced twofold on virally infected endothelium. Enhanced adhesion is accompanied by excessive granulocyte-mediated lysis of 51Cr-labeled HSV-infected endothelium and endothelial cell detachment from its substrate. Exaggerated endothelial detachment correlated with poor binding of infected endothelial cells to substratum matrix proteins. Resuspended virus-infected cells bound significantly less well to tissue culture containers coated with fibronectin, laminin, and type IV collagen. HSV-infected endothelium alters the anticoagulant properties of the endothelium causing it to become procoagulant.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Adhesion↗
PubMed1990

Endothelium-dependent contraction induced by platelet-derived substances in canine basilar arteries.

The supernatant obtained from platelet-suspension incubated with thrombin caused contractions in both intact and endothelium-removed canine basilar arteries. Cyproheptadine (5 x 10(-7) M), which reduced the serotonin-induced contraction to about 20%, attenuated the supernatant-induced contraction to 51% in intact arteries and to 24% in endothelium-removed arteries. In both absence and presence of cyproheptadine, the supernatant-induced contraction of intact arteries was significantly larger than that of endothelium-removed arteries. The cyproheptadine-resistant contraction by the supernatant of intact arteries was attenuated by aspirin, OKY-046 (a thromboxane A2 synthetase inhibitor) and ONO-3708 (a thromboxane A2 antagonist), whereas such contraction of endothelium-removed arteries was not affected by these agents. The concentrations of serotonin, ATP and ADP in the supernatant used here were approximately 3, 67 and 44 micrograms/ml, respectively. The mixed solution of serotonin, ATP and ADP, at the same concentrations as the supernatant, also induced cyproheptadine-resistant, endothelium-dependent contractions in intact arteries. The contraction induced by the mixed solution in intact arteries was also attenuated by aspirin, OKY-046 and ONO-3708. The present experiments indicate that the supernatant causes endothelium-dependent contraction in canine cerebral arteries and that platelet-derived ATP and ADP contribute to this contraction.

Adenosine Diphosphate↗
PubMed1986

Interaction of gangliosides with fibronectin in the mobilization of capillary endothelium. Possible influence on the growth of metastasis.

Mobilization of the capillary endothelium is one of the first events observed during angiogenesis, and the study of conditions that control or influence the mobilization of the endothelium in vitro has been assumed to offer information relevant to the understanding of angiogenesis in vivo. In vitro mobilization of the bovine capillary endothelium was substantially enhanced by addition of gangliosides to the culture medium. Optimal mobilization was obtained when the endothelium incorporated the gangliosides first and was then seeded on fibronectin anchored to collagen type I. Preincubation of the capillary endothelium with gangliosides, trisialoganglioside in particular, doubled the amount of fibronectin bound to the cells and enhanced the migration about 5-fold. 'Blockage' of ganglioside binding with cholera toxin or gamma-interferon substantially reduced migration. Rabbit corneas, treated in vivo with a variety of angiogenesis effectors to induce neovascularization, consistently showed an increase in sialic acid content just prior to the time the tissue would be penetrated by the capillaries. This finding was interpreted to indicate that an increment of the ganglioside content of the capillary endothelial cell membranes may play a determinant role in the mobilization of the capillary endothelium in vivo as shown here to take place in vitro. Since the formation of a tumor from a micrometastasis requires formation of new capillaries and highly metastasizing tumors very frequently have high levels of sialic acid on the cell surface, it is hypothesized that production and shedding of gangliosides from the surface of neoplastic cells may be a factor in promoting angiogenesis and metastatic growth.

Animals↗
PubMed1987

Biphasic release of endothelium-derived relaxing factor(s) by acetylcholine from perfused canine femoral arteries. Characterization of muscarinic receptors.

Experiments were designed to compare the release of endothelium-derived relaxing factor(s) in response to various muscarinic receptor agonists from canine femoral arteries mounted in organ chambers or perfused in a bioassay system. In rings of femoral arteries, suspended for isometric tension recording in organ chambers, acetylcholine induced endothelium-dependent relaxations during contractions evoked by prostaglandin F2 alpha. Atropine and pirenzepine antagonized these relaxations in a competitive manner, atropine with a higher affinity (KB = 1.9 X 10(-9) M) than pirenzepine (KB = 5.4 X 10(-7) M). Carbachol and McN-A-343 also evoked endothelium-dependent relaxations, and pirenzepine inhibited these responses with a similar low potency. The order of relative potency of the agonists in organ chamber studies was acetylcholine = carbachol much greater than McN-A-343. Isolated segments of femoral arteries with endothelium were perfused (2 ml/min) with modified Krebs-Ringer-bicarbonate solution containing indomethacin; the perfusate was bioassayed for endothelium-derived relaxing factor(s) by means of a ring of coronary artery without endothelium. When infused above but not below the femoral artery, low concentrations (10(-8)-10(-7) M) of acetylcholine caused transient relaxations of the bioassay ring contracted with prostaglandin F2 alpha; higher concentrations of acetylcholine caused sustained decreases in tension. Atropine inhibited the two phases of the concentration-relaxation curve with similar potencies. Pirenzepine inhibited both phases in a competitive manner but exhibited significantly higher potency against the first- (ED50, 1.9 X 10(-9) M) than against the second-phase responses (ED50, 2.1 X 10(-7) M). Compound McN-A-343 induced only transient decreases in tension, whereas carbachol caused sustained relaxations.(ABSTRACT TRUNCATED AT 250 WORDS)

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1989

Vascular responsiveness of constant flow perfused arteries with intact endothelium.

We have devised a perfused artery preparation, in which one can conveniently assess vasoactivity to agents (a) in the presence and absence of a functionally intact endothelium within the same vessel, and (b) when added to the luminal or abluminal (i.e., adventitial) surface of the vessel. Moreover, utilizing stainless steel cannulas of various calibers, one can routinely perfuse vessels ranging from less than 1 mm to over 4 mm in internal diameter. By moderating the pulsatile nature of the constant flow perfusion, one can retain a functionally intact endothelium (i.e., at totally damped perfusion) or one can abolish endothelial modulation of vasoactive agents (i.e., a pulsatile perfusion). The integrity of the endothelium was confirmed by histological methods. Using perfused cat carotid arteries preconstricted with U-46619, a stable prostaglandin-endoperoxide analog which maintains a stable vasoconstriction, acetylcholine dilated carotid arteries perfused at non-pulsatile flows, but not at pulsatile flows, indicating the endothelium dependent nature of the vasodilation produced by ACh. This was confirmed with the calcium ionophore A-23187, a non-receptor endothelium dependent vasodilator. However, calcium channel blockers (e.g., nimodipine) prostacyclin analogs (e.g., iloprost) or vasodilator nitrates (e.g., sodium nitrite at pH 2.0) produced equivalent dilations in the presence and absence of a functional intact endothelium. This preparation allows for convenient use of single dose application of pharmacologic agents as well as cumulative dose-response relationships.

Acetylcholine↗
PubMed1989

Endothelium-derived vasoactive substances: potential role in hypertension, atherosclerosis, and vascular occlusion.

The endothelium can profoundly affect vascular tone by releasing endothelium-derived relaxing and contracting factor. Nitric oxide (EDRF) is the most important relaxing factor that is released from L-arginine and evokes relaxation by increasing intracellular cyclic GMP in vascular smooth muscle. Endothelin and other endothelium-derived contracting factors (i.e., a cyclooxygenase product and a substance released during hypoxia) may be released as well. In hypertension and atherosclerosis, endothelium-dependent relaxations are impaired and endothelium-dependent contractions may occur, at least in some blood vessels. These changes in endothelium function may promote vasospasm and vascular occlusion and contribute to increased vascular resistance in hypertension. The more effective release of EDRF in arterial coronary bypass grafts-which have a better patency than venous grafts-is in line with the concept that EDRF may play a role in the prevention of vascular occlusion.

Arterial Occlusive Diseases↗
PubMed1989

The influence of endothelium on glyceryl trinitrate induced relaxation in corresponding arteries and veins of the rabbit.

Glyceryl trinitrate (GTN) induced relaxation was investigated in preparations of corresponding femoral arteries and veins from rabbits containing the intact endothelium in comparison to denuded vessels. Either vascular rings (app. 5 mm segments) or helical cut strips were isotonically mounted in organbaths (37 degrees C, Krebs-Henseleit-buffer). Vessels were precontracted with their specific EC-50 of norepinephrine. Cumulative concentration response curves for GTN were evaluated. Arteries and veins were dilated in a concentration dependent manner in the range of 1 nmol/l to 0.1 mmol/l. V.femoralis was the most sensitive vessel with an EC-50 of 10 nmol/l. There was no significant difference in the sensitivity of veins with or without endothelium. In contrast to this, for half-maximal relaxation of A. femoralis 2-3 orders of magnitude higher concentrations were necessary, depending on the presence of endothelium. The concentration ratio artery/vein (A/V) amounted to 800 in normal vessels, 100 in denuded vessels, resp. indicating that for half-maximal relaxation of endothelium containing arteries significant higher concentrations were needed. By preincubation for 60 min with the EC-90 of GTN in arteries, as well as in veins, tolerance could be induced independently of the presence of endothelium. However, veins were more affected than arteries, but tolerant veins were still more sensitive to GTN than tolerant arteries. This was true both for preparations with and without endothelium (A/V = 70 in normal vessels, 20 in denuded vessels, resp.). Moreover, the endothelial dependence of arterial relaxation was attenuated. Treatment of the tolerant vessels with cystein (1 mmol/l) did abolish the GTN-tolerance in veins but not in arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The role of the endothelium on calcium-entry blockade in coronary vasospasm.

Calcium-entry blockers are widely used for the treatment of coronary vasospasm. The mechanisms responsible for coronary vasospasm are still uncertain, but ultimately involve contraction of the vascular smooth muscle of the large coronary artery. The direct constrictor responses of coronary smooth muscle can be reduced by the inhibitory effect of endothelium-derived relaxing factor(s). The absence of endothelium can augment the response of vascular smooth muscle to vasoconstrictor stimuli, but may also modify the potency of calcium-entry blockers. The role of calcium-entry blockers on the endothelial function is not known. Nisoldipine is a new compound from a series of calcium-antagonistic dihydropyridines. The aim of the present experiments was: 1. to determine the effect of nisoldipine on contractions of large coronary arteries evoked by possible mediators of coronary vasospasm and 2. to determine whether or not the presence of endothelial cells affects the response to the calcium-entry blockers. Rings of canine coronary arteries with and without endothelium were studied in organ chambers filled with modified Krebs-Ringer bicarbonate solution. The rings were incubated for 45 min either in control solution or in the presence of increasing concentrations of nisoldipine (10(-10) to 10(-6) M). In the concentration range of 10(-9) to 10(-7) M nisoldipine inhibited the contractile responses evoked by allagents: KCL (10 to 80 mM), 5-hydroxytryptamine (10(-9) to 10(-6) M), ergonovine (10(-9) to 10(-6) M), norepinephrine and phenylephrine (10(-9) to 10(-4) M both in the presence of propranolol 5 X 10(-6) M). Nisoldipine was more potent in inhibiting contractions to potassium chloride in the absence of the endothelium. By contrast, in case of 5-hydroxytryptamine or phenylephrine, nisoldipine was less potent in the absence of the endothelium. Similar results were obtained in the case of ergonovine and norepinephrine. The hypoxic contractions were reduced by nisoldipine in a concentration dependent manner. Nisoldipine inhibited the platelet-induced contractions both in the presence and the absence of endothelium. The present study demonstrates that the dihydropyridine, nisoldipine, is a potent inhibitor of contractions of the smooth muscle of large coronary arteries caused by a number of putative mediators of coronary vasospasm including catecholamines and products released by aggregating platelets. It also prevents hypoxic contractions of coronary vascular smooth muscle.

Animals↗
PubMed1985

Blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation of rabbit aorta by certain ferrous hemoproteins.

We have reported previously that hemoglobin inhibits endothelium-dependent and glyceryl trinitrate-induced relaxation in the rabbit aorta. In this study we have examined the effects of other ferrous and ferric hemoproteins on endothelium-dependent and glyceryl trinitrate-induced relaxation to determine whether they also share the inhibitory properties of hemoglobin. Of the two ferrous hemoproteins tested, myoglobin (1-10 microM) abolished the endothelium-dependent relaxation induced by acetylcholine and produced a concentration-dependent reduction in the endothelium-independent relaxation induced by glyceryl trinitrate, in a manner similar to that reported previously for hemoglobin, but reduced cytochrome C was completely ineffective. The ferric hemoproteins methemoglobin (10 microM) and metmyoglobin (40 microM) produced only a slight inhibition of acetylcholine-induced relaxation. Methemoglobin (10 microM) also blocked only slightly the endothelium-dependent relaxation induced by the ionophore A23187 and had no effect on glyceryl trinitrate-induced relaxation. The inhibitory effects of these hemoproteins were reflected in their respective effects on the stimulation of cyclic GMP levels; thus, myoglobin (10 microM) inhibited the endothelium-dependent rise in cyclic GMP content induced by acetylcholine, as was found previously for hemoglobin, but methemoglobin (10 microM) was much less effective. The effectiveness of hemoglobin and myoglobin and the ineffectiveness of reduced cytochrome C in blocking the relaxations induced by acetylcholine and glyceryl trinitrate might suggest that only ferrous hemoproteins with ligand binding sites are inhibitory.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1988

Effect of 17 beta-estradiol on endothelium-dependent responses in the rabbit.

Experiments were designed to determine the effect of 17 beta-estradiol on endothelium-dependent responses of isolated arteries. Ovariectomized female New Zealand rabbits were treated either with 17 beta-estradiol (100 micrograms i.m.) or with solvent for 4 days. After excision, femoral arteries were cut into rings and suspended for isometric tension recording in organ chambers filled with modified Krebs-Ringer bicarbonate solution. Rings from the 17 beta-estradiol-treated rabbits showed an enhanced endothelium-dependent relaxation to acetylcholine (3 x 10(-9)-3 x 10(-8) M) in the absence or presence of indomethacin. Under the same experimental conditions, the endothelium-dependent responses to the calcium ionophore A23187 were unchanged. In the absence of indomethacin, the response to adenosine diphosphate was depressed in rings with endothelium taken from animals treated with with 17 beta-estradiol; in the presence of the inhibitor of cyclooxygenase, the endothelium-dependent responses were comparable in blood vessels from treated and untreated rabbits. This study suggests that endothelium-dependent responses of arteries can be modulated by steroid hormones.

Acetylcholine↗
PubMed1988

Heterogeneity of endothelium-dependent responses to acetylcholine in canine femoral arteries and veins. Separation of the role played by endothelial and smooth muscle cells.

The purpose of this study was to determine whether heterogeneity in endothelium-dependent responses to acetylcholine between canine blood vessels of different anatomical origin reflects variations in endothelial function or in responsiveness of vascular smooth muscle cells. Experiments were conducted in a bioassay system, where segments of femoral artery or vein with endothelium were perfused intraluminally and the perfusate used to superfuse rings of femoral arteries or veins without endothelium. Indomethacin was present in all experiments to prevent the synthesis of prostanoids. The blood vessels were contracted by phenylephrine. Measurement of wall tension in both the perfused segment and bioassay ring allowed simultaneous detection of endothelium-derived relaxing factor(s) released abluminally (segment) and intraluminally (ring). Intraluminal infusion of acetylcholine (ACh) induced relaxations in the perfused artery but not in vein segments. During arterial superfusion ACh induced relaxation in femoral arterial rings but contraction in venous rings. After treatment with atropine the arterial perfusate evoked relaxations in venous rings. Infusion of ACh through the femoral vein evoked only moderate relaxations in arterial rings. These data demonstrate that depressed endothelium-dependent relaxation to ACh in femoral veins compared to femoral arteries is due to a masking effect of the direct stimulating action of ACh and decreased release of the same mediator or the release of a different relaxing factor from venous endothelium.

Acetylcholine↗
PubMed1986

Inhibitors of acyl-coenzyme A:lysolecithin acyltransferase activate the production of endothelium-derived vascular relaxing factor.

Considerable acyl-CoA:lysolecithin acyltransferase (LAT) activity could be demonstrated in homogenates of cultured bovine endothelial cells. This LAT activity was inhibited by thimerosal and p-hydroxymercuribenzoate in a concentration-dependent manner. Preconstricted strips of rabbit aorta were relaxed by acetylcholine or the LAT inhibitors in a concentration-dependent fashion if the endothelium was intact (maximal effect of both LAT inhibitors at 10(-5) M). In rabbit aortic strips thimerosal also induced a concentration-dependent stimulation of the formation of 6-keto-prostaglandin F1 alpha, the major cyclooxygenase metabolite of this tissue. This effect of thimerosal was more pronounced in endothelium-intact than in endothelium-denuded preparations. Inhibition of prostaglandin synthesis with indomethacin (10(-5) M) did not impair the relaxation. Thimerosal and acetylcholine-induced relaxations were abolished when the endothelium was removed or when endothelium-intact preparations were pretreated with nordihydroguaiaretic acid (3 X 10(-5) M), gossypol (5 X 10(-6) M) or dithiothreitol (3 X 10(-4) M). In contrast, mepacrine (3 X 10(-5) M), that abolished the acetylcholine response, had no effect on the thimerosal relaxation. In other experiments bovine endothelial cells were grown to confluence on microcarrier beads and packed into columns. Adding thimerosal (5 X 10(-6) M) or bradykinin (10(-10) to 10(-8) M) to the medium superfusing the columns induced the release of an unstable nonprostanoid factor (or factors) that relaxed endothelium-denuded rabbit femoral artery segments. Bradykinin induced a transient effect whereas there was a strong and long-lasting release of the factor after administration of thimerosal.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed1986

Role of the vascular endothelium in the contractile response to prostacyclin in the isolated rat aorta.

Prostacyclin (PGI2) relaxes vascular smooth muscle in several species but, in high doses, PGI2 has been reported to contract several isolated arteries. Vascular endothelium is known to be obligatory for the vasodilatory responses to acetylcholine and several other substances. We therefore investigated the contractile effect of various prostanoids on rat abdominal aorta in which the endothelium was left intact or was removed. PGI2 (4-2000 ng/ml), 6-keto-prostaglandin (PG) E1, PGE1 and PGE2 (4-800 ng/ml) contracted both intact and de-endothelialized aortic segments in a dose-dependent manner. PGI2 (8-2000 ng/ml) increased the force generated by aortic rings with intact endothelium from 77.3 +/- 24.6 to 685 +/- 99.2 mg. The response to similar doses of PGI2 in aortic rings with the endothelium removed was reduced significantly (22.7 +/- 14.1 to 260 +/- 116.4 mg). This contractile response to PGI2 in both intact and de-endothelialized aortic rings was abolished by indomethacin pretreatment (20 micrograms/ml for 30 min) and was also blocked completely by the thromboxane receptor antagonist SQ 29548 (100 ng/ml). In contrast, the thromboxane synthase inhibitor OKY 1581 (2.5 micrograms/ml) did not significantly reduce the contractile response to PGI2. Unlike PGI2, the force generated by PGE2 (4-800 ng/ml) in aortic rings with intact endothelium (0-550.0 +/- 107.2 mg) was not significantly different from that generated by aortic rings without endothelium (35.0 +/- 23.6 to 650.0 +/- 193.2 mg).(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗