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PubMed1995

Endothelium-derived hyperpolarizing factor does not contribute to the decrease in endothelium-dependent relaxation in the aorta of streptozotocin-induced diabetic rats.

1. We examined the contribution of endothelium-derived hyperpolarizing factor (EDHF) to the impairment of endothelium-dependent relaxation caused by acetylcholine (ACh) in the aorta of streptozotocin-induced diabetic rats, by using N omega-L-nitro-arginine methylester (L-NAME) and tetraethylammonium chloride (TEA) to inhibit nitric oxide (NO) and EDHF, respectively. 2. ACh-induced relaxation of the aorta decreased in diabetic rats. In contrast, sodium nitroprusside-induced relaxation was the same in diabetic rats and control rats. 3. Treatment with 5 x 10(-7) M L-NAME resulted in a right shift of the dose-response curves of ACh-induced relaxation in the aorta. The shift was greater in the control aorta. 4. Treatment with 5 x 10(-4) M TEA resulted in a similar right shift in both the control and diabetic aorta. 5. Therefore, while endothelium-derived NO appears to contribute to the impairment of ACh-induced endothelium-dependent relaxation in the aorta of diabetic rats, EDHF does not.

Acetylcholine↗
PubMed1997

Variations of segmental endothelium-dependent and endothelium-independent vasomotor tone after cardiac transplantation (qualitative changes in endothelial function).

Endothelial dysfunction is a common phenomenon after cardiac transplantation. However, qualitative differences in endothelial vasoregulation at different coronary segments and at different postoperative times have rarely been explored. To uncover the functional variations of endothelium responses we infused the endothelium-dependent vasodilator acetyl-choline (50 micrograms) followed by the endothelium-independent vasodilator 3-morpholinosydnonimine (SIN-1) (1 mg; 16 patients) or nitroglycerin (0.3 mg; 14 patients) sequentially into the left coronary artery. We investigated the responses of 120 nonstenotic coronary segments (proximal and distal left anterior descending and right circumflex coronary arteries) in 30 patients with quantitative angiography (group 1: 13 patients, 12 +/- 1 months after cardiac transplantation; group 2: 17 patients, 55 +/- 3 months after cardiac transplantation). Continuous-flow measurement was performed to exclude significant reduction of microvascular response influencing epicardial dilation. Five responses to acetylcholine administration followed by nitrates were observed. On the one end of the spectrum, segments dilate to acetylcholine administration with no further dilation to exogenous nitric oxide, indicating completely preserved endothelial function. On the other end, segments constrict to acetylcholine with no change after endogenous nitric oxide, reflecting a defective endothelial and defective smooth muscle function. The different patterns of coronary vasomotor lone responses to endogenous nitric oxide followed by exogenous nitric oxide represent different degrees of endothelial function after cardiac transplantation. In addition, the functional assessment of endothelial integrity shows qualitative time-dependent differences between proximal and distal coronary parts. The existence of coronary segments with functioning endothelium indicates that the latter is not diffusely disturbed in all cardiac transplant recipients and that the endothelial damage is perhaps not irreversibly lost.

Acetylcholine↗
PubMed1983

Lung injury mediated by antibodies to endothelium. I. In the rabbit a repeated interaction of heterologous anti-angiotensin-converting enzyme antibodies with alveolar endothelium results in resistance to immune injury through antigenic modulation.

To study the effects of relatively long-term interaction of antibodies with surface antigens of lung endothelium, rabbits were intravenously injected for a maximum of 4 d with goat anti-rabbit lung angiotensin-converting enzyme (Gt anti-RbACE) antibodies. On day 1 69%, on day 2 13%, and on days 3 and 4 of injection none of the rabbits developed lethal pulmonary edema. By immunofluorescence microscopy, deposits of GtIgG, frequently in association with RbC3, were found along the endothelium of alveolar capillary walls in all rabbits studied on day 1, in 57% on day 2, in 33% on day 3, and in none of them on day 4. While in vitro anti-ACE antibodies bound in a linear pattern to the lung endothelium, the binding pattern in vivo was distinctly granular. The in vivo interaction of antibodies with ACE also redistributed ACE in a granular pattern along capillary walls. In contrast to the granular deposition of injected anti-ACE IgG and F(ab')2 fragments of anti-ACE IgG, Fab fragments of anti-ACE IgG localized, without fixing C3, in a linear pattern along the endothelium of lung capillaries and did not modify the normal distribution of ACE. However, when the injection of Fab fragments of Gt anti-RbACE IgG was followed by an injection of Rb anti-GtIgG serum, granular deposits of Gt Fab fragments, RbIgG and RbC3 were seen along alveolar capillary walls. Biochemical measurement of ACE activity in lung homogenates provided data in agreement with those obtained by immunofluorescence microscopy, showing diminished activity to none on day 4, with some return of ACE activity on day 5, 24 h after the last injection of antibody, and normal values on day 21. The results obtained indicate that divalent antibodies to an antigen expressed on the plasma membrane of rabbit lung endothelial cells promotes a rapid redistribution of antigenic receptors, fixation of complement and, in surviving rabbits, disappearance of the antigen from the endothelial cells that are no longer susceptible to immune injury. In vivo "immunologic enzymectomy" induced by a ligand-surface antigen interaction is an example of antigenic modulation. These events may have an important role in the pathogenesis of inflammatory lesions induced by antibodies reacting with antigens expressed on the plasma membrane of cells in the lung and in other organs.

Animals↗
PubMed1993

The role of sarcoplasmic reticulum in endothelium-dependent and endothelium-independent rhythmic contractions in the rabbit mesenteric artery.

Upon stimulation with phenylephrine, the rabbit mesenteric artery displays endothelium-dependent and endothelium-independent rhythmic contractions in the absence and the presence of ryanodine, respectively. For examination of the involvement of the sarcoplasmic reticulum (SR) in these two types of rhythmic contractions, the mesenteric ring was suspended in an organ chamber for isometric tension recordings. Phenylephrine induced endothelium-dependent rhythmic contractions (EDRC), which were converted to endothelium-independent rhythmic contractions (EIRC) by the subsequent addition of ryanodine. Cyclopiazonic acid (CPA) also induced EIRC in the artery contracted with phenylephrine. The nifedipine-treated artery displayed neither EDRC upon phenylephrine stimulation nor EIRC by the addition of ryanodine or CPA: however, these agents relaxed the arteries. Phenylephrine induced EDRC in the artery treated with the K+ channel antagonist sparteine, but these rhythmic contractions were converted to a sustained contraction by ryanodine and CPA without producing relaxation of the artery. Ryanodine and CPA inhibited both phenylephrine-induced Ca2+ release from the SR and Ca2+ sequestration, without affecting Ca2+ influx across the plasmalemma, evaluated by monitoring agonist-induced contractions. These findings indicate that: (1) the EDRC may be attributed to Ca2+ release from the SR, which may be charged by Ca2+ influx via the voltage-dependent Ca2+ channel; and (2) the EIRC may arise from functional impairment of the SR and by the subsequent increase in the K+ efflux, presumably via the Ca(2+)-activated K+ channel.

Animals↗
PubMed1988

Endothelium-dependent and endothelium-independent vasodilation in resistance arteries from hypertensive rats.

The endothelium-dependent and presumed endothelium-independent vasodilators acetylcholine and sodium nitroprusside, respectively, were used to characterize relaxation responses of mesenteric resistance arteries from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY). Vessels were preconstricted using concentrations of norepinephrine or 5-hydroxytryptamine, which reduced their diameters by 50 to 60%. Relaxation responses to acetylcholine (10(-8) - 10(-7) M) were significantly smaller (p less than 0.05) in vessel segments from SHRSP, but the maximal relaxations at higher concentrations were the same in both strains. However, SHRSP vessels relaxed to a greater extent than did those of the WKY at all concentrations of sodium nitroprusside. Endothelium removal significantly enhanced sodium nitroprusside-induced dilations in both rat strains, and the dilations were significantly greater in segments from SHRSP in the concentration range of 3 X 10(-8) to 10(-6) M. The decreased relaxation to acetylcholine in resistance arteries from adult hypertensive rats compared with those from the normotensive strain suggests that functional alterations in the endothelium may play a role in hypertensive disease.

Acetylcholine↗
PubMed1991

Endothelium-derived vasoactive factors: I. Endothelium-dependent relaxation.

Evidence continues to accumulate on the importance of paracrine substances formed in the vascular endothelium in the regulation of the vascular system. Those that relax the underlying smooth muscle include nitric oxide, prostacyclin, and an unidentified hyperpolarizing factor; those causing contraction include angiotensin II, endothelin, oxygen-derived free radicals, prostacyclin H2, and thromboxane A2. Determination of the mechanisms governing the formation and release of these substances in different blood vessels of the same species and in different species as well as the maintenance of the balance between them is important for understanding their role in normal circumstances and in diseases of the blood vessels. In this article, we will summarize the current understanding of the role of endothelium-derived relaxing factors and discuss the possibility that endothelial dysfunction may play a primary as well as a secondary role in the pathogenesis of primary hypertension. As a consequence of this dysfunction, substances formed in the endothelial cells at the sites of the arterial baroreceptors could lead to their resetting, resulting in less inhibition of the vasomotor centers, enhanced neurohumoral activity, and a consequential increase in systemic vascular resistance. This increase could be enhanced by a predominant action of endothelium-derived contracting factors in the resistance vessels. Proliferation of the vascular smooth muscle would follow, because of the mitogenic action of some of these factors and other growth promotors. By these mechanisms, the endothelium may participate in the polygenic dysfunction characteristic of primary hypertension, not only in initiating the increase in arterial blood pressure, but also in sustaining it.

Animals↗
PubMed1991

Endothelium-derived vasoactive factors: II. Endothelium-dependent contraction.

Endothelial cells may produce and release vasoconstrictor substances in response to a number of agents and physical stimuli. In this brief review, current understanding of the mechanisms of endothelium-dependent contractions will be discussed. Cyclooxygenase products of arachidonic acid metabolism including thromboxane A2, prostaglandin H2, superoxide anions, vasoconstrictor peptide endothelin-1, and unidentified factor released from endothelium by hypoxia may mediate these contractions. The physiological role of endothelium-dependent contractions in regulation of the cardiovascular system is unknown. Existing evidence supports the concept that contracting factors may become important regulators of vascular tone under pathological conditions. We speculated about the possible importance of endothelium-dependent contractions for venous graft function, development of vasospasm, increased vascular resistance in hypertension, and vascular complications in diabetes.

Animals↗
PubMedDate not supplied

Ultrastructural studies of pial vascular endothelium following damage resulting in loss of endothelium-dependent relaxation.

The changes in pial arterioles of 7 cats were examined by electron microscopy after injury that eliminates endothelium-dependent relaxation to acetylcholine or bradykinin. The injury was produced by exposing the vessels to mercury light in situ in the presence of intravascular sodium fluorescein dye. Previous studies showed that, at the time of initial injury and loss of endothelium-dependent responses, the endothelial cells displayed minimal ultrastructural evidence of injury. Because these changes might indicate the beginning of a sequence of irreversible alterations representing or leading to cell death, the present study was carried out 31/2-4 hours later, when ultrastructural evidence of progressive cell degeneration should readily be recognized. No such changes were observed. Instead, most vessels showed only the minimal alterations observed initially (endothelial vacuolation, blebs, and lucencies). Four of 19 vessels were completely normal. The findings fail to support the hypothesis that irreversible cell damage or death caused by the light + dye injury has caused the associated loss of endothelium-dependent relaxation. Rather, the findings support the concept that much lesser degrees of trauma are sufficient to impair the dilating responses of cerebral microvessels. This greatly expands the potential spectrum of pathologic states that might result in loss of endothelium-dependent relaxation.

Animals↗
PubMed1993

Endothelium-derived hyperpolarizing factor and endothelium-dependent relaxations.

The endothelial cells inhibit the tone of the underlying vascular smooth muscle by releasing endothelium-derived relaxing factors (EDRF). The existence of at least two such factors, nitric oxide and endothelium-derived hyperpolarizing factor (EDHF), has been demonstrated. EDHF is an as yet unidentified substance that hyperpolarizes vascular smooth muscle cells and causes their relaxation. The contribution of endothelium-dependent hyperpolarization varies along the vascular tree. Particularly in smaller blood vessels, EDHF acts on vascular smooth muscle in cooperation with nitric oxide. Basal release of EDHF is not likely to occur, at least in vitro. The production and/or release of EDHF is regulated by the cytosolic concentration of Ca2+ ions, derived both from the extracellular space and intracellular stores. Calmodulin may be involved in its production and/or release. EDHF hyperpolarizes the vascular smooth muscle by opening K+ channels. The hyperpolarization closes voltage-dependent Ca2+ channels and, as a consequence, EDHF relaxes blood vessels. In the absence of chemical identification of EDHF, it is difficult to assess its contribution to endothelium-dependent relaxations in vivo.

Animals↗
PubMed2004

Construction of human liver cancer vascular endothelium cDNA expression library and screening of the endothelium-associated antigen genes.

AIM: To gain tumor endothelium associated antigen genes from human liver cancer vascular endothelial cells (HLCVECs) cDNA expression library, so as to find some new possible targets for the diagnosis and therapy of liver tumor. METHODS: HLCVECs were isolated and purified from a fresh hepatocellular carcinoma tissue sample, and were cultured and proliferated in vitro. A cDNA expression library was constructed with the mRNA extracted from HLCVECs. Anti-sera were prepared from immunized BALB/c mice through subcutaneous injection with high dose of fixed HLCVECs, and were then tested for their specificity against HLCVECs and angiogenic effects in vitro, such as inhibiting proliferation and inducing apoptosis of tumor endothelial cells, using immunocytochemistry, immunofluorescence, cell cycle analysis and MTT assays, etc. The identified xenogeneic sera from immunized mice were employed to screen the library of HLCVECs by modified serological analyses of recombinant cDNA expression libraries (SEREX). The positive clones were sequenced and analyzed by bio-informatics. RESULTS: The primary cDNA library consisted of 2 x 10(6) recombinants. Thirty-six positive clones were obtained from 6 x 10(5) independent clones by immunoscreening. Bio-informatics analysis of cDNA sequences indicated that 36 positive clones represented 18 different genes. Among them, 3 were new genes previously unreported, 2 of which were hypothetical genes. The other 15 were already known ones. Series analysis of gene expression (SAGE) database showed that ERP70, GRP58, GAPDH, SSB, S100A6, BMP-6, DVS27, HSP70 and NAC alpha in these genes were associated with endothelium and angiogenesis, but their effects on HLCVECs were still unclear. GAPDH, S100A6, BMP-6 and hsp70 were identified by SEREX in other tumor cDNA expression libraries. CONCLUSION: By screening of HLCVECs cDNA expression library using sera from immunized mice with HLCVECs, the functional genes associated with tumor endothelium or angiogenesis were identified. The modified SEREX, xenogeneic functional serum screening, was demonstrated to be effective for isolation and identification of antigen genes of tumor endothelium, and also for other tumor cell antigen genes. These antigen genes obtained in this study could be a valuable resource for basic and clinical studies of tumor angiogenesis, thus facilitating the development of anti- angiogenesis targeting therapy of tumors.

Animals↗
PubMed1999

Hypoxia and alkalinization inhibit endothelium-derived nitric oxide but not endothelium-derived hyperpolarizing factor responses in porcine coronary artery.

We investigated the mechanisms by which hypoxia and alkalinization inhibit the endothelium-dependent relaxation to Substance P (SP) in porcine coronary artery. In a KCl contracture, the major component of the SP response is endothelium-derived nitric oxide (EDNO), whereas with receptor-mediated 9,11-dideoxy-llalpha, 9alpha-epoxymethanoprostaglandin F(2alpha) (U46619) stimulation, the SP response is dependent on both EDNO and endothelium-derived hyperpolarization factor. Intracellular alkalinization by NH(4)Cl reduced the peak of SP responses when arteries were contracted with KCl, whereas with U46619 stimulation, the peak was little effected but the duration was shortened. In endothelial cell-denuded arteries, alkalinization with NH(4)Cl shifted the sodium nitroprusside concentration-relaxation relations rightward. The effects of NH(4)Cl in SP- and sodium nitroprusside-induced relaxations were attenuated by decreasing extracellular pH (pH(o)) from 7.4 to 7.2, which normalized intracellular pH (pH(i)) to control levels. In contrast, in U46619 contractures, the SP response in the presence of a NO synthase inhibitor was unaffected by NH(4)Cl. Moreover, hypoxia blunted but did not abolish the responses to SP for U46619 contractures; addition of KCl, however, abolished the SP response under hypoxia. Endothelial [Ca(2+)](i) was measured with fura-2 differentially loaded only into endothelial cells on intact arteries. Despite the attenuation of the SP response in KCl contractures by NH(4)Cl or hypoxia, endothelial [Ca(2+)](i) responses were unchanged. Our results suggest that hypoxia and alkalinization inhibit EDNO but not endothelium-derived hyperpolarization factor relaxations through a mechanism(s) not involving endothelial cell [Ca(2+)](i). Inhibition of EDNO relaxation by alkalinization with NH(4)Cl is likely to occur at the level of activation of guanylate cyclase and/or at a step downstream in smooth muscle.

Ammonium Chloride↗
PubMed1990

[Vascular endothelium (review). I. General morphology. 2B: phylogenesis of the vascular endothelium].

The phylogenetic descent of vascular endothelium from mesenchyme--derived precursors is described related to the development of a vessel--bound microcirculation. Endothelial precursors in primitive animals may have migrated into tissue clefts gradually forming vascular tubes. True microcirculatory vessels at first appear in the nemertines, a closed vascular system is present in some annelids whereas in arthropods an open lacunar system predominates. The first appearance of true endotheliocytes is under discussion; the author gives some evidence that it is present already in some annelids. Precursor of the endothelial wall of vessels may be the so called "Leydig's membrane", covered with amoebocytes and other mesenchymal cells. The molluscs exhibit many variants of endothelium. In the fishes, the vascular system begins to split into a blood and a lymphatic system. Obviously the specialization of endothelium correlates with the level of evolution. Despite the complicated course, the evolution of endothelium may be regarded as monophyletic.

Animals↗
PubMed1989

[Vascular endothelium--a review. I. General morphology of the vascular endothelium].

The vascular endothelium as a monolayer interposed between blood/lymph and interstitial fluid realizes different functions as continuous circulation of blood/lymph, processes of clotting, fibrinolysis and antithrombotic surface properties, some aspects of defense, inflammation, different synthetic activities, and establishing of exchange pathways and barriers for several substances. This survey will be presented as a sequence of 6 single articles. The 1st one deals with the general morphology of vascular endothelium. Heteromorphism of endothelium means variability of shape and orientation as a result of different functional conditions, mediated by the cytoskeleton. "Contactons" are units of interconnected cells; each cell exhibits 4 zones of different structural and functional specialization: nuclear-, organelle-, peripheric-, and contact zone. Membrane associated structures of the surface are the glycocalix and the subplasmalemmal subcortical layer. Composition and function of these including the plasmalemma itself are explained. Structures formed by the endothelial plasmalemma are vesicles, fenestrations, pores, gaps, and microvilli. Arrangement, function, dynamics, and their relationships to the cytoskeleton are referred including TEM, SEM, and Freeze Etching techniques. Concerning interendothelial contacts, different types of junctions and 4 types of junctional fibrils are described. A short structural description of the basement membrane and of the organelles of endothelium is given. Some new informations of the endothelial cytoskeleton, concerning composition, structure, arrangement, properties, and relationships to other subcellular constituents are presented, completed by impressive SEM-photographs.

Animals↗
PubMed1993

The sydnonimine C87-3754 evokes endothelium-independent relaxations and prevents endothelium-dependent contractions in blood vessels of the dog.

Experiments were designed to compare the relaxing activities of the new sydnonimine C87-3754 with SIN-1 in arteries and veins of the dog, and to determine whether C87-3754 can prevent endothelium-dependent contractions. Rings of coronary and femoral arteries, and saphenous veins were suspended in organ chambers for the measurement of changes in isometric tension. SIN-1 and C87-3754 evoked concentration-dependent relaxations in all rings of blood vessels contracted with a submaximal concentration of either prostaglandin F2 alpha, endothelin-1, phenylephrine, or norepinephrine. In both arteries and veins, the concentration-relaxation curves to C87-3754 were shifted significantly to the right (by two to three logarithmic units) of that to SIN-1. The presence of endothelium significantly inhibited the relaxations to SIN-1 but did not affect those to C87-3754. The treatment of coronary arteries with methylene blue or oxyhemoglobin significantly impaired the relaxation to SIN-1 and C87-3754. Neither C87-3754 nor its prodrug pirsidomine (CAS 936) affected the membrane potential in coronary arteries. The endothelium-dependent contractions evoked by nitro L-arginine, arachidonic acid, and the calcium ionophore A23187 in basilar arteries of the dog were inhibited by C87-3754. These results indicate that the sydnonimine C87-3754 is a dilator of both arterial and venous smooth muscle, and can prevent endothelium-mediated contractions in cerebral arteries of the dog. The inhibition of vascular tone is likely to involve the activation of soluble guanylate cyclase, causing enhanced production of cyclic guanosine monophosphate in the smooth muscle without a change in membrane potential.

Animals↗
PubMed1995

Lysophosphatidylcholine inhibits relaxation of rabbit abdominal aorta mediated by endothelium-derived nitric oxide and endothelium-derived hyperpolarizing factor independent of protein kinase C activation.

Hypercholesterolemia is associated with increased oxidized LDL and impaired endothelium-dependent relaxation (EDR). An inhibitory component of oxidized LDL is lysophosphatidylcholine (LPC). To determine the effect and mechanism(s) of action of LPC on EDR mediated by endothelium-derived nitric oxide (EDNO) and endothelium-derived hyperpolarizing factor (EDHF), rabbit abdominal aortic rings were suspended for measurement of isometric tension and studied under three conditions: control; with 25 mmol/L K+ buffer to isolate relaxation mediated by EDNO; and in rings treated with N omega-nitro-L-arginine methyl ester (L-NAME, 30 mumol/L) to isolate relaxation mediated by EDHF. Incubation with LPC (10 and 30 mumol/L) for 30 minutes inhibited EDR in a concentration-dependent manner. LPC (30 mumol/L) significantly inhibited maximal relaxation to acetylcholine in control, 25 mmol/L K(+)-, and L-NAME-treated rings (77.1 +/- 7.8%, 42.1 +/- 8.9%, and 3.4 +/- 7.7%) compared with untreated rings (99.0 +/- 0.9%, 90.9 +/- 2.2%, and 54.7 +/- 4.7%, P < .05). Inhibition of relaxation was specific to endothelium-dependent responses in that relaxation to direct smooth muscle vasodilators (papaverine, 8-bromo-cGMP, and sodium nitroprusside) were unaltered by LPC. The inhibition by LPC (30 mumol/L) was not due to cytotoxicity, because EDR returned to normal levels after repeated washing with physiological salt solution containing 0.1% albumin. Co-incubation with protein kinase C inhibitors, staurosporine (20 nmol/L) or calphostin C (1 mumol/L), had no effect on the EDR inhibition by LPC (30 mumol/L). Furthermore, LPC continued to inhibit EDR in rings in which protein kinase C was down-regulated by incubation for 18 hours with 1 mumol/L phorbol 12-myristate 13-acetate (PMA).(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1999

Oscillations in the human cutaneous blood perfusion signal modified by endothelium-dependent and endothelium-independent vasodilators.

The purpose of the present study was to compare the effects of endothelium-dependent [acetylcholine (ACh)] and endothelium-independent [sodium nitroprusside (SNP)] vasodilators on the oscillatory components of the cutaneous blood perfusion signals in humans. The unstimulated basal blood perfusion and the blood perfusion during iontophoretically delivered ACh and SNP were measured using laser Doppler flowmetry (LDF). The wavelet transform was calculated before spectral analysis of the measured signals. In the frequency interval from 0.0095 to 1.6 Hz the LDF signal consists of oscillations with five different characteristic frequencies. In addition to the cardiac (1 Hz) and respiratory (0.3 Hz) rhythms, three other oscillations in the regions around 0.1, 0.04, and 0.01 Hz were detected. The oscillations with the different frequencies were observed in unstimulated blood flow and also during stimulation with ACh and SNP. Compared to the unstimulated blood flow, both ACh and SNP increased the mean amplitude of the total spectrum (P < 0. 005 for both substances). The only significant difference between the effects of ACh and SNP was observed in the amplitude of oscillations with the frequency of around 0.01 Hz. ACh increased the absolute amplitude of this frequency to a greater extent than SNP in athletes (P = 0.03), whereas only a trend was observed in controls (P = 0.2). The relative amplitude, defined as the ratio between the absolute amplitude of a particular frequency interval and the mean amplitude of the total spectrum, was also higher for ACh compared to SNP both in controls (P = 0.008) and in athletes (P = 0.004), only for oscillations with the frequency of around 0.01 Hz. We conclude that ACh selectively influences the oscillatory component of around 0.01 Hz in the cutaneous blood perfusion signal to a greater extent than SNP. This finding indicates that endothelium-mediated vasodilatation is manifested as oscillations with a repetition time of approximately 1 min. The mechanisms for the endothelial dependency of this frequency remain to be elucidated. Our data indicate that spectral analysis based on wavelet transform of the cutaneous perfusion signal can be used clinically to investigate endothelial function. The described noninvasive method might be used to evaluate endothelial function for research, for diagnostic purposes, and maybe also to assess effects of therapy in cardiovascular diseases.

Acetylcholine↗
PubMed1991

Effects of native and oxidized low-density lipoproteins on endothelium-dependent and endothelium-independent vasomotion.

Native and oxidized low-density lipoproteins (LDL) were investigated for their direct influence on EDRF-formation, EDRF-activity, and vascular smooth muscle tone. Native (n) LDL, isolated from fresh human plasma, was oxidized by Cu(2+)-incubation. EDRF released from cultured endothelial cells was inactivated by both n-LDL and ox-LDL (1 mg/ml) as detected in a bioassay system. n-LDL reduced the EDRF-mediated vasodilations of the detector segments by 38.5 +/- 5.3%, and ox-LDL by 55.5 +/- 4.6%. The effects of lipoproteins on EDRF-formation were studied on cultured endothelial cells, preincubated with either n-LDL or ox-LDL (1 mg/ml, 1 h) and stimulated for EDRF-release with bradykinin after washout of the lipoproteins. EDRF was assessed by measuring its stimulatory effect on the activity of a purified soluble guanylate cyclase. Preincubation with both n-LDL and ox-LDL did not reduce the bradykinin-induced EDRF-formation. Accordingly, acetylcholine-induced, EDRF-mediated dilations of intact rabbit femoral artery segments were not impaired by luminal exposure to n-LDL or ox-LDL (1 h, 1mg/ml). Effects of n-LDL and ox-LDL on vascular smooth muscle tone were investigated in isolated perfused rabbit femoral arteries. Perfusion of endothelium-intact and -denuded segments with ox-LDL (80-500 micrograms protein/ml) caused no or only weak vasoconstrictions in the absence of contractile agonists. However, in the presence of ox-LDL, vasoconstrictions to threshold concentrations of norepinephrine (NE), serotonin (5-HT), phenylephrine (PE) or potassium were significantly enhanced. Native LDL (80-1000 micrograms/ml) had no effect on vascular tone, neither in presence nor in absence of contractile agonists. Preincubation with verapamil, diltiazem, and nitrendipine inhibited vasoconstrictions evoked by ox-LDL. The contractile responses to ox-LDL were significantly greater in endothelium-denuded segments than in endothelium-intact segments. In conclusion, neither n-LDL nor ox-LDL acutely impair the formation of EDRF, but do inactivate EDRF after its release from endothelial cells. n-LDL has no direct influence on vascular smooth muscle tone, but ox-LDL greatly enhances vasoconstrictions to various contractile agonists by direct interaction with vascular smooth muscle. Thus, in regions of lipoprotein-accumulation in the arterial wall, both n-LDL and ox-LDL may favor inappropriate vasoconstrictions.

Animals↗
PubMed1999

Estradiol increases rat aorta endothelium-derived relaxing factor (EDRF) activity without changes in endothelial NO synthase gene expression: possible role of decreased endothelium-derived superoxide anion production.

OBJECTIVES: Estradiol is known to exert a protective effect against atherosclerosis, but the mechanism(s) whereby this protection is mediated is/are unclear. However, estradiol-treated castrated animals exhibit increased activity of endothelium-derived relaxing factor (EDRF), which could contribute to vasculoprotection. In the present work, we investigated the molecular mechanism(s) of the enhancement of EDRF activity in the thoracic aorta of oophorectomized female rats given 17 beta-estradiol (E2, 2 or 40 micrograms/kg/day) compared to those given a placebo. METHODS AND RESULTS: The abundance in the thoracic aorta of NO synthase I, II and III mRNA (using RT-PCR) and of NO synthase I, II and III immunoreactive protein (using Western blotting) was unaltered by E2. NO synthase activity (based on arginine/citrulline conversion) in thoracic aorta homogenates did not differ significantly among the three groups, suggesting that NO production was not enhanced by E2. In contrast, lucigenin-enhanced chemiluminescence of aorta from the E2 group was decreased compared to that of the placebo group. Desendothelialization and exogenously added superoxide dismutase suggested that this difference was due to a decrease in extracellular endothelium-derived production of superoxide anion (O2-.). Experiments in cultured bovine aortic endothelial cells confirmed a decreased extracellular production of O2-. in response to ethinylestradiol (1 nM) using both lucigenin-enhanced chemiluminescence and ESR spectroscopy. Luminol-enhanced chemiluminescence revealed that ethinylestradioltreated cultured endothelial cells generated less peroxynitrite (the byproduct of NO-. and O2-. interaction) than control cells. CONCLUSION: Estradiol increases rat aorta EDRF activity in the absence of changes in endothelial NO synthase gene expression. The decreased endothelium-derived generation of O2-. in response to estrogens could account for enhanced EDRF-NO bioactivity and decreased peroxynitrite release. All of these effects could contribute to the vascular protective properties of estrogens.

Animals↗