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PubMedDate not supplied

Barium and 4-aminopyridine inhibit flow-initiated endothelium-independent relaxation.

Although much is known about the underlying mechanism of endothelium-dependent flow-induced vasorelaxation, the cellular processes responsible for the endothelium-independent flow-induced relaxation observed in some vessels is unknown. As there is evidence for the participation of K+ channels in the endothelium-dependent response, the present study was designed to determine whether such channels are involved in the endothelium-independent response and if so, which ones. We examined the effects of various selective K+ channel blockers on endothelium-independent relaxation initiated by intraluminal flow (10-80 microl/min), and by an endothelium-independent vasodilator sodium nitroprusside (SNP, 1 nmol/l to 3 micromol/l) in segments of the rabbit facial vein under isometric conditions. Flow-initiated relaxation was abolished by 25 and 40 mmol/l K+ as well as 10 mmol/l tetraethylammonium (TEA), significantly inhibited by 100 micromol/l Ba2+, 5 mmol/l Cs+ and 7.5 mmol/l 4-aminopyridine (4-AP), but unaffected by 5 micromol/l glibenclamide and 50 nmol/l charybdotoxin. Relaxation induced by SNP was reduced by 7.5 mmol/l 4-AP, but not by any of the above drugs in their listed concentrations. The inhibitory effect of 100 micromol/l Ba2+ on the relaxation caused by low concentrations of K+ (15-20 mmol/l) supports the presence of inward rectifier K+ channels in the vascular smooth muscle cells of this tissue. We speculate that endothelium-independent flow-initiated relaxation of the rabbit facial vein may be associated with activation of inward rectifier and voltage-dependent K+ channels. The latter may also contribute to the vasorelaxation initiated by SNP.

4-Aminopyridine↗
PubMedDate not supplied

Altered dye diffusion and upregulation of connexin37 in mouse aortic endothelium deficient in connexin40.

Connexin40 (Cx40), connexin37 (Cx37) and connexin43 (Cx43) are subunit proteins of gap junction channels in the vascular wall which are presumably involved in the propagation of vasomotor signals. In this study we have investigated in Cx40-deficient versus wild-type aortic endothelium to which extent loss of Cx40 impairs intercellular communication. We show in Cx40-deficient mice that expression of both Cx37 and Cx43 protein was increased approximately 3- and 2-fold over the level in wild-type endothelium, respectively. Furthermore, Cx37 immunosignals were distributed more homogeneously on contacting plasma membranes in Cx40-deficient versus with wild-type endothelium. Cx43 was not detected in endothelium but only in smooth muscle cells of the vessel wall. Iontophoretic injection of Lucifer Yellow or neurobiotin into aortic endothelium of Cx40-deficient mice showed extensive intercellular transfer of neurobiotin but not of Lucifer Yellow. In contrast, intercellular spreading of Lucifer Yellow was observed in endothelium of wild-type aorta. As shown by electron microscopy, gap junctions in Cx40-deficient endothelium were morphologically different from those of wild-type vessels. These results demonstrate that dye diffusibility of endothelial gap junctions is different in Cx40-deficient and wild-type mice, although Cx40-deficient mice retain the capability of intercellular communication. Apparently, Cx40-deficient endothelial cells upregulate and redistribute Cx37 as a molecular adaptation to the lack of Cx40.

Animals↗
PubMed2003

Gonadectomy eliminates endothelium-dependent diethylstilbestrol-induced relaxant effect in rat aorta.

The effects of gender and castration of rats on diethylstilbestrol-induced, endothelium-dependent and endothelium-independent relaxation in rat aorta strips were studied. For this, male and female control and castrated rats were used. Diethylstilbestrol elicited a concentration-dependent (1-30 micromol/l) relaxation of isolated rat aorta. The effect was significantly higher in the presence of endothelium in aorta strips of the control group and also in female as compared with male rats. This effect is NO-dependent, since it is inhibited by N(G)-methyl-L-arginine. Castration of the rats suppressed the endothelium-dependent relaxation, and it was similar to that induced in the absence of endothelium. Acetylcholine-induced relaxation was not suppressed by castration. The acetylcholine-induced relaxation was decreased in aorta strips previously relaxed by diethylstilbestrol. There are no gender differences in the diethylstilbestrol-induced, endothelium-independent component of the relaxation, nor is it modified by the hormonal environment. Therefore, diethylstilbestrol-induced, endothelium-dependent relaxation in rat aorta strips is modulated by the hormonal status of the rats.

Acetylcholine↗
PubMed2003

Cells derived from regenerated endothelium of the porcine coronary artery contain more oxidized forms of apolipoprotein-B-100 without a modification in the uptake of oxidized LDL.

Increased accumulation of lipoproteins and cholesterol within cells from regenerated endothelium may be responsible for their reported dysfunction. This study compared the presence and uptake of oxidized forms of low-density lipoprotein (LDL) in cells derived from native and regenerated endothelium. Four weeks after balloon denudation, primary cultures of native and regenerated endothelial cells were prepared from porcine coronary arteries. Regenerated endothelium stained more strongly using an antibody against oxidized lipoproteins. The increase in oxidized forms of apolipoprotein-B-100 exhibited by cells from regenerated endothelium was not due to an increase in extracellular-induced oxidation of native LDL, measured as the production of thiobarbituric-acid-reactive substances, being identical in both cell types. Intracellular cholesterol and cholesterol ester content were unchanged in regenerated cells. Using flow cytometry, accumulation of oxidized LDL was investigated further by quantifying the uptake of a mildly oxidized preparation of 1,1'-dioctadecyl-3,3,3',3-tetramethyl-indocarbocyanine perchlorate-labelled LDL. The parameters of uptake, EC(50) and E(max), were not different between cells from native and regenerated endothelium suggesting that the number of LOX-1 receptors was identical in the two cell types. Moreover, a negative correlation between the increased uptake of acetylated LDL and decreased cGMP production in response to bradykinin was observed in cells from regenerated endothelium. Thus, the increased incorporation of modified LDL and their intracellular oxidation could be responsible for the alteration in NO production. The presence of oxidized forms of LDL may be a marker of endothelium regeneration and could be involved in the endothelial dysfunction of pig coronary arteries 4 weeks after balloon denudation.

Animals↗
PubMed2006

Role of endothelium sensitivity to shear stress in noradrenaline-induced constriction of feline femoral arterial bed under constant flow and constant pressure perfusions.

The effect of shear stress at the endothelium in the attenuation of the noradrenaline-induced constriction of the femoral vascular bed perfused at a constant blood flow was investigated in 16 anesthetized cats. It is known that the adrenergic vasoconstriction of the femoral vascular bed is considerably greater at a constant pressure perfusion than at a constant blood flow. This difference may depend on the ability of the endothelium to relax smooth muscle in response to an increase in wall shear stress. Since the shear stress is directly related to the blood flow and inversely related to the third power of vessel diameter, vasoconstriction at a constant blood flow increases the wall shear stress that is the stimulus for smooth muscle relaxation opposing constriction. On the other hand, at a constant perfusion pressure, vasoconstriction is accompanied by a decrease in flow rate, which prevents a wall shear stress increase. To reveal the effect of endothelial sensitivity to shear stress, we compared noradrenaline-induced changes in total and proximal arterial resistances during perfusion of the hind limb at a constant blood flow and at a constant pressure in vessels with intact and injured endothelium. We found that in the endothelium-intact bed the same concentration of noradrenaline at a constant flow caused an increase in overall vascular peripheral resistance that was half as large as at a constant perfusion pressure. This difference is mainly confined to the proximal arterial vessels (arteries and large arterioles) whose resistance at a constant flow increased only 0.19 +/- 0.03 times compared to that at a constant pressure. The removal of the endothelium only slightly increased constrictor responses at the perfusion under a constant pressure (noradrenaline-induced increases of both overall and proximal arterial resistance augmented by 12%), while the responses of the proximal vessels at a constant flow became 4.7 +/- 0.4 times greater than in the endothelium-intact bed. A selective blockage of endothelium sensitivity to shear stress using a glutaraldehyde dimer augmented the constrictor responses of the proximal vessels at a constant flow 4.6-fold (+/-0.3), but had no significant effect on the responses at a constant pressure. These results are consistent with the conclusion that the difference in constrictor responses at constant flow and pressure perfusions depends mainly on the smooth muscle relaxation caused by increased wall shear stress.

Animals↗
PubMed1986

Endothelium-dependent responses in isolated blood vessels of lower vertebrates.

Endothelium-dependent relaxations to acetylcholine have been identified in mammalian arteries and veins. To determine the occurrence of such relaxations in other classes of vertebrates, rings of descending aortas of turtles, cayman and bullfrogs and ventral aortas of trout were suspended for isometric force measurements. Acetylcholine and the calcium ionophore A23187 initiated concentration-dependent relaxations in aortas from cayman and bullfrogs contracted with norepinephrine. These relaxations were not affected by meclofenamate, were reversed by methylene blue and abolished by endothelium removal. Acetylcholine caused concentration-dependent contractions in aortas (with and without endothelium) from trout and turtles; these tissues contracted minimally to norepinephrine. In the aortas of the trout contracted with acetylcholine, the calcium ionophore A23187 initiated endothelium-dependent relaxations which were reversed by methylene blue and abolished by meclofenamate. A23187 contracted turtle aortas; an effect reduced by endothelium removal. These data demonstrate endothelium-dependent relaxations and contractions in blood vessels of reptiles, amphibians and teleosts. Thus, endothelium-dependent modulation of the responses of the vascular smooth muscle represents a cardiovascular regulatory mechanism which appears early in vertebrate phylogeny.

Acetylcholine↗
PubMedDate not supplied

Cerebroarterial relaxations mediated by nitric oxide derived from endothelium and vasodilator nerve.

Purposes of this study were to determine whether: (1) nitric oxide is involved in endothelium-dependent relaxation in helical strips of dog cerebral arteries; (2) relaxing factor distinct from NO is also involved, and (3) susceptibility to NG-nitro-L-arginine (L-NA), an NO synthase inhibitor, of the response to mediators liberating NO from the endothelium and nerve differs. Changes in isometric tension were recorded. In the strips contracted with prostaglandin F2 alpha, substance P and arginine vasopressin produced a relaxation which was abolished or reversed to a contraction by endothelium denudation. The relaxations were not influenced by indomethacin but were suppressed dose-dependently by L-NA, as was the response to nicotine that stimulates the non-adrenergic, non-cholinergic vasodilator nerve and liberates NO. The inhibitions were reversed by L- but not D-arginine. NO (acidified NaNO2)-induced relaxations were not reduced by L-NA. The inhibitory effect was greater in the responses to vasopressin than substance P; however, there was no significant difference in the response to nicotine vs. the peptides. Substance P increased the level of cyclic guanosine monophosphate (GMP) in the artery strips with the intact endothelium, the effect being abolished by endothelium denudation, L-NA and oxyhemoglobin. Relaxations caused by adenosine triphosphate (ATP) and adenosine diphosphate (ADP) were dependent partially on the endothelium. Treatment with L-NA attenuated the ATP-induced relaxation in the strips with endothelium but did not alter the response of denuded strips.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗
PubMed2005

Powerful inflammatory properties of large vein endothelium in vivo.

OBJECTIVE: Inflammatory responses of large vein endothelium are of importance in pathological processes such as venous thrombosis, chronic venous congestion, and vein graft atherosclerosis. However, the inflammatory properties of large vein endothelium are unclear. METHODS AND RESULTS: In this study, we used several microscopy techniques to investigate the inflammatory properties of large vein endothelium in vivo. We show that the endothelium in the mouse inferior vena cava (IVC) possesses powerful inflammatory properties that are distinct from the less inflammatory reactive aortic endothelium and virtually identical to endothelial responses in postcapillary venules. Inflammatory stimulation with tumor necrosis factor-alpha induced strong expression of cell adhesion molecules (CAMs) in the IVC. These CAMs promoted recruitment of leukocytes, platelets, and erythrocytes to the vein wall. The inflammatory responses altered endothelial structure and increased endothelial permeability in the IVC. Accumulation of blood cells and endothelial damage were markedly reduced in mice deficient in the endothelial leukocyte recruitment molecules E-selectin and P-selectin, indicating a central role for these molecules in driving structural and functional changes of IVC endothelium. CONCLUSIONS: These findings provide the first comprehensive demonstration of the inflammatory capacity of large vein endothelium and emphasize the actions of endothelial cells as targets in large vein disease.

Animals↗
PubMed1996

Endothelium-dependent and -independent vasodilation of large arteries in normoalbuminuric insulin-dependent diabetes mellitus.

Vascular complications in diabetes mellitus are associated with endothelial dysfunction. Whether endothelium-dependent vasodilation is impaired in normoalbuminuric patients with insulin-dependent diabetes mellitus (IDDM) is controversial. Using a noninvasive echo-Doppler method, we investigated endothelium-dependent and endothelium-independent vasodilation in the brachial artery of IDDM patients. There were 52 normoalbuminuric and normotensive patients with IDDM (aged 31.9 +/- 9.8 years; diabetes duration, 14.9 +/- 7.9 years; glycated hemoglobin, 7.9 +/- 1.2%) and 52 healthy control group (C) subjects comparable for age and sex studied. Brachial artery diameter was measured at baseline, during postocclusion reactive hyperemia (flow-mediated, endothelium-dependent dilation [FMD]), and after 400 micrograms glyceryl trinitrate (GTN) sublingually (endothelium-independent vasodilation). Vasodilation was expressed as the percentage change relative to the baseline diameter. Baseline flow and blood pressure were similar for IDDM patients and C. Baseline vessel diameter was slightly larger in IDDM patients (3.10 +/- 0.52 mm) compared with C (2.89 +/- 0.55 mm, P = 5.0). FMD in IDDM patients was decreased (12.0 +/- 9.1% versus 15.7 +/- 9.5% in C, P = .046), as was GTN-induced vasodilation (14.9 +/- 8.2% versus 18.3 +/- 8.5% in C, P = .045). After correction for the difference in baseline diameter, FMD and GTN-induced dilation were not different between the groups. GTN-induced vasodilation decreased slightly with increasing diabetes duration. There was no relation between the vasodilatory responses and HbA1c. In normoalbuminuric IDDM patients, endothelium-dependent as well as endothelium-independent vasodilation are normal when the difference in baseline diameter is taken into account.

Adult↗
PubMed1998

Adventitial expression of recombinant eNOS gene restores NO production in arteries without endothelium.

The current study was designed to determine the effect of recombinant endothelial nitric oxide synthase (eNOS) gene expression on endothelium-dependent relaxations to bradykinin in isolated canine basilar, coronary, or femoral arteries. Arterial rings were exposed ex vivo (30 minutes at 37 degrees C) to an adenoviral vector encoding either the eNOS gene (AdCMVeNOS) or the beta-galactosidase reporter gene (AdCMVbeta-Gal). Twenty-four hours after transduction, transgene expression was evident mainly in the adventitia. Expression of recombinant proteins was much higher in basilar arteries than in coronary or femoral arteries. Rings of control, AdCMVbeta-Gal, and AdCMVeNOS arteries with and without endothelium were suspended for isometric tension recording. Levels of cGMP were measured by radioimmunoassay. In AdCMVeNOS basilar arteries with endothelium, relaxations to low concentrations of bradykinin (3 x 10(-11) to 10(-9) mol/L) were significantly augmented. In contrast, in coronary and femoral arteries with endothelium, AdCMVeNOS transduction did not affect relaxations to bradykinin. Removal of the endothelium abolished bradykinin-induced relaxations in control and AdCMVbeta-Gal basilar arteries. However, in basilar arteries transduced with AdCMVeNOS even when the endothelium was removed, stimulation with bradykinin (3 x 10(-11) to 10(-9) mol/L) caused relaxations as well as increases in cGMP production. The relaxations to bradykinin were completely blocked by an NOS inhibitor, NG-nitro-L-arginine methyl ester. Electron microscopic analysis revealed that recombinant eNOS protein was expressed in fibroblasts of the basilar artery adventitia. These results suggest that genetically modified adventitial fibroblasts may restore production of NO in cerebral arteries without endothelium. Our findings support a novel concept in vascular biology that fibroblasts in the adventitia may play a role in the regulation of vascular tone after successful transfer and expression of recombinant eNOS gene.

Adenoviridae↗
PubMedDate not supplied

Properties of cultured endothelium from adult human vessels.

Endothelium was isolated from samples of aorta and vena cava obtained from cadaver donors at the time kidneys were harvested for transplantation. Digestion with collagenase and gentle swabbing were used to free the cells from the intimal surface. Low density seeding permitted isolation of individual colonies with typical endothelial morphology. Modified Medium 199 supplemented with 10%-20% human plasma-derived serum and an extract from the bovine hypothalamus (500 micrograms/ml) enabled subcultured colonies to grow to confluency when culture surfaces were coated with fibronectin (1 micrograms/cm2). The presence of Factor VIII antigen was demonstrated using an indirect immunofluorescence technique. A monoclonal antibody to cultured umbilical vein endothelium, specific for endothelium, reacted with the subcultured cells from the aorta and vena cava. Type IV procollagen, fibronectin, and thrombospondin were identified as labeled proteins secreted by cultures of adult endothelium that had been incubated with 3H-proline and 3H-glycine. When the cultured endothelium was used in a sodium-m-periodate stimulated T lymphocyte mitogenic culture system, the endothelium exhibited accessory cell function. Prostacyclin production stimulated by incubation with arachidonic acid and PGH2 was variable from vessel to vessel. However, average values were lower than normally seen with cultured primary umbilical vein endothelium.

Adult↗
PubMed1989

Endothelium-derived relaxing factor and protection against contractions induced by histamine and serotonin in the human internal mammary artery and in the saphenous vein.

We investigated the release of endothelium-derived relaxing factor (EDRF) in response to serotonin and histamine in the human internal mammary artery and saphenous vein. The arteries and veins were obtained intraoperatively and were suspended in organ chambers to record isometric tension. In mammary arteries, histamine (10(-8) to 3 X 10(-6) M) induced relaxations in rings with (70 +/- 5%, IC50, 6.5 +/- 0.2) but not without endothelium (p less than 0.005 for rings with compared with those without endothelium, n = 7-10). The response was inhibited by methylene blue or hemoglobin, but not meclofenamate, and, therefore, EDRF was delineated as the mediator. Because chlorpheniramine but not cimetidine inhibited the response, EDRF was released by the H1-histaminergic receptor (n = 5-8). In contrast, in saphenous veins, histamine caused only weak or absent endothelium-dependent relaxations, but contractions were enhanced in rings with endothelium (p less than 0.05, n = 6). Serotonin did not induce endothelium-dependent relaxations, but contractions were markedly greater in veins compared with arteries (p less than 0.005, n = 6). The endothelium inhibited the maximal contraction to serotonin in arteries (p less than 0.034) but not in veins. Thus, EDRF protects against contractions induced by histamine and serotonin in the mammary artery but not in the saphenous vein. This may be important for improved graft function and patency of the artery compared with that of the vein.

Endothelium, Vascular↗
PubMed1990

Persistent dysfunction of regenerated endothelium after balloon angioplasty of rabbit iliac artery.

This study investigated the vasodilator function of endothelium that regenerated after balloon angioplasty and the relation of this function to the extent of vascular injury and to subsequent intimal proliferation. Balloon angioplasty was performed in the left iliac artery of 47 New Zealand White rabbits. Vascular responses were examined in vitro 2 and 4 weeks after a "severe" injury (3.0-mm balloon) or a "moderate" injury (2.5-mm balloon). Both degrees of balloon injury caused complete endothelial denudation. Endothelial regrowth 2 weeks after either injury was confirmed histologically. Although the regenerated cells had irregular sizes and polygonal shapes and lacked the typical alignment in the direction of blood flow, immunocytochemical staining for factor VIII-related antigen identified these cells as endothelium. To study the vasodilator function of regenerated endothelium, rings of balloon-injured and control (contralateral) iliac arteries were suspended in organ chambers for recording of isometric force. Endothelium-dependent relaxation of balloon-injured vessels to acetylcholine and to the calcium ionophore A23187 were reduced at 2 and at 4 weeks after severe injury. After moderate injury, endothelium-dependent relaxations to these agents were reduced at 2 weeks but had normalized by 4 weeks. Endothelium-independent relaxation to sodium nitroprusside, however, was preserved in all study groups. Morphometric analysis revealed an inverse correlation between the degree of intimal thickening and maximal relaxation to acetylcholine (r = 0.45, p less than 0.01). Thus, there is a persistent attenuation of receptor- and nonreceptor-mediated endothelium-dependent relaxations after arterial injury. The regenerated cells have an altered morphological appearance, but staining for factor VIII-related antigen confirms their endothelial origin. The degree and duration of endothelial dysfunction depends on the severity of the initial injury and is related to the extent of intimal thickness.

Acetylcholine↗
PubMed1993

The role of nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patients.

BACKGROUND: Patients with hypercholesterolemia have a reduced response to endothelium-dependent vasodilators. However, the regulatory function of the endothelium on vascular tone is mediated through the release of several vasoactive substances; therefore, a reduced response to endothelium-dependent agents does not identify which of the factors released by the endothelium is involved in this abnormality. METHODS AND RESULTS: To investigate the role of nitric oxide in the endothelium-dependent vasodilation in hypercholesterolemia, we studied the effect of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of endothelial nitric oxide synthesis, on basal vascular tone and on the responses to acetylcholine, an endothelium-dependent vasodilator, and to sodium nitroprusside, a direct smooth muscle dilator. The study included 33 hypercholesterolemic patients (17 men; 51 +/- 8 years; plasma cholesterol, > or = 240 mg/dL) and 23 normal controls (12 men; 48 +/- 7 years; plasma cholesterol, < 210 mg/dL). Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by strain-gauge plethysmography. Basal blood flow and vascular resistance were similar in hypercholesterolemic patients and normal controls (3.1 +/- 1 versus 2.6 +/- 0.8 mL/min per 100 mL and 32.1 +/- 13 versus 36.1 +/- 12 mm Hg/mL-1.min-1.100 mL-1, respectively). The reduction in basal blood flow and increase in vascular resistance produced by L-NMMA were not significantly different between the two groups. L-NMMA markedly blunted the response to acetylcholine in normals (maximum flow decreased from 16.4 +/- 8 to 7.0 +/- 3; P < .005); however, the arginine analogue did not significantly modify the response to acetylcholine in the hypercholesterolemic patients (maximum flow, 11.1 +/- 8 versus 10.0 +/- 8). L-NMMA did not modify the vasodilator response to sodium nitroprusside in either controls or patients. CONCLUSIONS: These findings indicate that hypercholesterolemic patients have a defect in the bioactivity of nitric oxide that may explain their impaired endothelium-dependent vascular relaxation.

Acetylcholine↗
PubMed1994

Thrombin-induced endothelium-dependent inhibition and direct activation of platelet-vessel wall interaction. Role of prostacyclin, nitric oxide, and thromboxane A2.

BACKGROUND: Platelet-vessel wall interaction plays an important role in acute cardiovascular disorders. Thrombin is a potent platelet activator but also has profound effects on the endothelium. Endothelial cells possess antithrombotic activity by releasing nitric oxide and prostacyclin, both potent vasodilators and platelet inhibitors. We studied the role of thrombin as a regulator of platelet-vessel wall interaction in isolated human arteries suspended in organ chambers for isometric tension recording. METHODS AND RESULTS: In arteries with endothelium, thrombin (0.01 to 1 U/mL) induced endothelium-dependent relaxations, which were reduced by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10(-4) mol/L) and/or indomethacin (10(-5) mol/L). Human platelets (75,000/microL) evoked only marginal contractions in arteries with endothelium (3 +/- 3% of the contraction to KCl 100 mmol/L; NS), which were markedly enhanced by endothelial removal (22 +/- 4%; P < .05). Thrombin (1 U/mL) did not affect the response to platelets in arteries with (6 +/- 5%; NS) but induced a huge contraction in rings without endothelium (53 +/- 6%; P < .01 versus control without endothelium). The potent contraction to thrombin-activated platelets (1000 to 75,000/microL) in arteries without endothelium was markedly inhibited by the thromboxane A2 synthetase/receptor antagonist ridogrel (10(-5) mol/L; P < .005 versus control) and the single-acting thromboxane receptor blocker SQ-30741 (10(-7) mol/L; P < .01 versus control). CONCLUSIONS: Thus, thrombin directly stimulates platelets to release thromboxane A2, inducing potent vasoconstriction, which is prevented by the simultaneous thrombin-induced release of prostacyclin and nitric oxide from endothelial cells. In arteries devoid of functional endothelial cells, as occurs in patients with coronary artery disease, a combined inhibition of thromboxane production and action provides a potent therapeutic tool to interfere with the thrombin-induced activation of platelet-vessel wall interaction.

Coronary Vessels↗
PubMed1997

Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans.

BACKGROUND: Hyperhomocyst(e)inemia is a risk factor for atherosclerosis and is prevalent in the elderly. The objective of this study was to determine whether hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. METHODS AND RESULTS: High-resolution vascular ultrasonography was used to study endothelium-dependent and -independent vasodilation in a nonatherosclerotic peripheral conduit artery of 26 elderly hyperhomocyst(e)inemic subjects and 15 age- and sex-matched subjects with normal homocysteine levels. Flow-mediated, endothelium-dependent (nitric oxide-mediated) vasodilation was assessed by measuring the percent change in brachial artery diameter during reactive hyperemia. Endothelium-independent vasodilation was assessed after the administration of 0.4 mg sublingual nitroglycerin. Endothelium-dependent vasodilation was significantly impaired in the hyperhomocyst(e)inemic subjects compared with control subjects (3.7 +/- 0.6% versus 8.1 +/- 1.2%; P = .004), whereas endothelium-independent vasodilation was not different between the two groups (10.1 +/- 1.6% versus 9.3 +/- 1.5%; P = NS). In a linear regression analysis with serum homocysteine concentration, folic acid, age, sex, cholesterol (serum total, LDL, or HDL cholesterol), mean arterial blood pressure, use of antihypertensive medication, and baseline brachial artery diameter included as covariates, serum homocysteine concentration emerged as the only significant predictor of flow-mediated vasodilation. CONCLUSIONS: These data indicate that hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans and suggest that the bioavailability of nitric oxide is decreased in hyperhomocyst(e)inemic humans.

Aged↗
PubMed1998

Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women.

BACKGROUND: Epidemiological studies indicate that estrogen replacement therapy decreases the risk of cardiovascular events in postmenopausal women. Estrogen may confer cardiovascular protection by improving endothelial function because it increases endothelium-dependent vasodilation. It is not known whether progesterone attenuates the beneficial effects of estrogen on endothelial function. METHODS AND RESULTS: Seventeen postmenopausal women with mild hypercholesterolemia were enrolled in a placebo-controlled, crossover trial to evaluate the effect of transdermal estradiol, with and without vaginal micronized progesterone, on endothelium-dependent vasodilation in a peripheral conduit artery. Brachial artery diameter was measured with high-resolution B-mode ultrasonography. To assess endothelium-dependent vasodilation, brachial artery diameter was determined at baseline and after a flow stimulus induced by reactive hyperemia. To assess endothelium-independent vasodilation, brachial artery diameter was measured after administration of sublingual nitroglycerin. During estradiol therapy, reactive hyperemia caused an 11.1+/-1.0% change in brachial artery diameter compared with 4. 7+/-0.6% during placebo therapy (P<0.001). Progesterone did not significantly attenuate this improvement. During combined estrogen and progesterone therapy, flow-mediated vasodilation of the brachial artery was 9.6+/-0.8% (P=NS versus estradiol alone). Endothelium-independent vasodilation was not altered by estradiol therapy, either with or without progesterone, compared with placebo. There was a modest decrease in total and LDL cholesterol during treatment both with estradiol alone and when estradiol was combined with progesterone (all P<0.001 versus placebo). In a multivariate analysis that included serum estradiol, progesterone, total and LDL cholesterol concentrations, blood pressure, and heart rate, only the estradiol level was a significant predictor of endothelium-dependent vasodilation. CONCLUSIONS: The addition of micronized progesterone does not attenuate the favorable effect of estradiol on endothelium-dependent vasodilation. The vasoprotective effect of hormone replacement therapy may extend beyond its beneficial actions on lipids.

Aged↗
PubMed2007

Arachidonic acid metabolites as endothelium-derived hyperpolarizing factors.

The endothelium regulates vascular tone through the release of a number of soluble mediators, including NO, prostaglandin I2, and endothelium-derived hyperpolarizing factor. Epoxyeicosatrienoic acids are cytochrome P450 epoxygenase metabolites of arachidonic acid. They are synthesized by the vascular endothelium and open calcium-activated potassium channels, hyperpolarize the membrane, and relax vascular smooth muscle. Endothelium-dependent relaxations to acetylcholine, bradykinin, and shear stress that are not inhibited by cyclooxygenase and NO synthase inhibitors are mediated by the endothelium-derived hyperpolarizing factor. In arteries from experimental animals and humans, the non-NO, non-prostaglandin-mediated relaxations and endothelium-dependent hyperpolarizations are blocked by cytochrome P450 inhibitors, calcium-activated potassium channel blockers, and epoxyeicosatrienoic acid antagonists. Acetylcholine and bradykinin stimulate epoxyeicosatrienoic acid release from endothelial cells and arteries. These findings indicate that epoxyeicosatrienoic acids act as endothelium-derived hyperpolarizing factors and regulate arterial tone.

Arachidonic Acids↗