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PubMed1994

Comparison of endothelium-dependent and -independent tension oscillation in aortae of stroke-prone spontaneously hypertensive rats and Wistar Kyoto rats.

Differences in noradrenaline-induced tension oscillations between aortae from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive control Wistar Kyoto rats (WKY) were studied. Endothelium-intact and -removed ring preparations were made from thoracic aorta of SHRSP and WKY, and isometric contraction was observed. Endothelium-intact preparations from WKY showed tension oscillations in response to high concentration of noradrenaline at significantly higher ratio, while only a few endothelium-removed preparation showed tension oscillations in response to low concentration of the drug. Fifteen out of 41 endothelium-removed preparations from SHRSP showed tension oscillations in response to low concentration of noradrenaline but no preparation showed oscillations in response to high concentration of the drug. Seven and 14 out of 42 endothelium-intact preparations from SHRSP showed oscillatory response to low and high concentration of the drug, respectively. Acetylcholine-induced relaxation and tension oscillations, both of which being significantly less in the preparation from SHRSP. Both the endothelium-independent tension oscillations and endothelium-dependent tension oscillations were abolished by removal of extracellular Ca or by verapamil. It is suggested that aortic smooth muscle of SHRSP possesses the property which produced tension oscillations, while the tension oscillations of WKY aorta is endothelium-dependent. The opening of voltage-dependent Ca++ channel of smooth muscle cell membrane which generates rhythmic contraction is increased in the aorta of SHRSP, while the release of endothelium-derived factors which induces rhythmic activities of smooth muscle cell is decreased.

Animals↗

PubMed2006

Impaired coronary endothelium-dependent vasodilation is associated with microalbuminuria in patients with type 2 diabetes and angiographically normal coronary arteries.

OBJECTIVE: Microalbuminuria and impaired endothelium-dependent vasodilation are both predictors for cardiac events in patients with type 2 diabetes. The aim of the study was to evaluate whether microalbuminuria correlated with coronary endothelium-dependent vasodilation. RESEARCH DESIGN AND METHODS: We evaluated 84 patients (47 men, mean age 50.5 +/- 5.9 years) with type 2 diabetes for 9.4 +/- 3.4 years, without angiographic coronary stenosis and without major cardiovascular risk factors or other confounding factors, for endothelium investigation. Quantitative coronary angiography was used to assess coronary artery response to cold pressor testing, used to assess endothelium-dependent vasodilation, and to isosorbide dinitrate (endothelium-independent vasodilation). RESULTS: Endothelium-dependent vasodilation differed in the patients with and without microalbuminuria (changes in coronary artery diameter during cold pressor testing: -15.0 +/- 1.9% vs. -10.2 +/- 1.3%, respectively, P < 0.05) and correlated with urinary albumin excretion rate (r = -0.39, P = 0.003), diastolic blood pressure (r = 0.29, P < 0.01), and left ventricular mass index (r = -0.24, P < 0.05). Independent predictors for endothelium-dependent vasodilation were urinary albumin excretion rate (beta -0.04 [95% CI -0.07 to -0.01], P < 0.005) and left ventricular mass index (-0.26 [-0.49 to -0.05], P < 0.05). Endothelium-independent vasodilation was similar in both groups. CONCLUSIONS: Type 2 diabetic patients with microalbuminuria have a more severely impaired coronary endothelium-dependent vasodilation than those with normoalbuminuria. These data suggest a common pathophysiological process for both coronary vasomotor abnormalities and microalbuminuria.

Albuminuria↗

PubMed1988

Alterations in endothelium-dependent responsiveness of the canine basilar artery subarachnoid hemorrhage.

To investigate the alteration of endothelium-dependent responses in chronic vasospasm after subarachnoid hemorrhage (SAH), experiments were carried out in the double-hemorrhage canine model. After the presence of vasospasm was confirmed by cerebral angiography on Days 0 and 7, pharmacological studies on the basilar artery were conducted in vitro on Day 8. In the SAH group, endothelium-dependent relaxation was abolished in response to arginine vasopressin and was significantly reduced in response to thrombin. Endothelium-independent relaxation in the SAH group was preserved in response to papaverine and was minimally reduced in response to sodium nitroprusside. Endothelium-dependent contraction in response to arachidonic acid, acetylcholine, the calcium ionophore A23187, adenosine diphosphate, mechanical stretching, and hypoxia persisted in the SAH group. The maximal contraction to KCl and uridine triphosphate, which is endothelium-independent, was diminished in the SAH group, but not changes in sensitivity were noted in the concentration-response relationships. A significant correlation was observed between the degree of vasospasm determined angiographically and the loss of endothelium-dependent relaxation. The loss of endothelium-dependent relaxation and the persistence of endothelium-dependent contraction suggest that the deterioration in the endothelium-dependent responses may be an important component in the pathogenesis of cerebral vasospasm.

Animals↗

PubMed1999

Glycyrrhetinic acid-sensitive mechanism does not make a major contribution to non-prostanoid, non-nitric oxide mediated endothelium-dependent relaxation of rat mesenteric artery in response to acetylcholine.

Pharmacological characteristics of non-prostanoid (PGI2), non-NO mediated endothelium-dependent relaxation in response to acetylcholine (ACh) were examined in the isolated rat mesenteric artery, especially focusing on the possible contribution of the gap junctional communication in the response. ACh produced an endothelium-dependent relaxation of the isolated rat mesenteric artery with functional endothelium in the presence of both indomethacin (3 x 10(-6) M) and N(G)-nitro-L-arginine methyl ester (L-NAME) (10(-4) M), an inhibitor of nitric oxide synthase (NOS). ACh-induced relaxation of the rat mesenteric artery in the presence of indomethacin and L-NAME was strongly attenuated in the solution containing high (80 mM) KCl, tetraethylammonium (TEA) (10(-2) M), which suggests the involvement of endothelium-derived relaxing factor(s) (EDHF(s)) in the response. Non-PGI2, non-NO mediated endothelium-dependent relaxation to ACh was not profoundly affected by glibenclamide (10(-6) M), 4-aminopyridine (4-AP) (10(-4) M), iberiotoxin (10(-7) M), agitoxin-2 (10(-8) M), or apamin (10(-7) M), but was abolished by the treatment with apamin (10(-7) M) plus charybdotoxin (10(-7) M). Non-PGI2, non-NO mediated endothelium-dependent relaxation to ACh was not substantially affected by arachidonic acid (AA) (10(-4) M) or ONO-RS-082 (10(-5) M), an inhibitor of phospholipase A2, which rules out the involvement of AA metabolites in the vascular response. Furthermore, a gap junction inhibitor, 18alpha-glycyrrhetinic acid (18alpha-GA) did not show dramatic inhibitory effect on non-PGI2, non-NO mediated endothelium-dependent relaxation induced by ACh. These findings suggest that 1) metabolites of AA are not involved in non-PGI2, non-NO mediated endothelium-dependent relaxation to ACh in the isolated rat mesenteric artery; 2) Heterocellular gap junctional communication does not mainly account for non-PGI2, non-NO mediated endothelium-dependent relaxation evoked by ACh in this artery.

Acetylcholine↗

PubMed1975

[Morphology of the corneal endothelium under normal conditions and during regeneration after mechanical injury].

On a preparation of the corneal endothelium membrane from a rabbit, the morphological structure of the endothelium is examined under normal physiological conditions and during regeneration after abrasion by mechanical means. Thematerial which is submitted here is outlined in two chapters: (1) The morphology of the normal corneal endothelium; (a) in the contest of the literature on the subject, (b) in comparison with different methods of preparation. (2) The morphology of endothelium regeneration; (a) in the literature as physiological regeneration and, after experimental abrasion, as a model for human endothelium pathology, (b)as a systematic examination at different points of time after mechanical abrasion and in single phases of indirect and direct cell multiplication. After a survey of the comprehensive literature on the subject, several histological fixations and methodds of endothelium preparation as a membrane are given. In a comparison of the findings of the presentation of the normal endothelium, these methods are described in virw of a specific presentation of pathological endothelium rocesses. On the basis of the dyeing characteristics of the cells after intraocular pre-fixation; the evidence of the viscous mucopolysaccharoid membrane on the cell surface (the membrane having been dissected from the endothelium) is discussed...

Animals↗

PubMed2002

Mechanisms of mitotic inhibition in corneal endothelium: contact inhibition and TGF-beta2.

PURPOSE: Contact inhibition has been implicated as an important antiproliferative mechanism in developing and mature corneal endothelium. Although exogenous TGF-beta2 and TGF-beta2 in aqueous humor suppress S-phase entry in cultured rat corneal endothelial cells, it is not known whether TGF-beta2 contributes to the mitotic inhibition that occurs during in vivo endothelial development. TGF-beta receptors I, II, and III must be coexpressed for a TGF-beta2-induced intracellular signal to be transmitted. The current study was conducted to determine whether TGF-beta2 contributes to mitotic inhibition during endothelial development, by investigating when these receptors become coexpressed in the endothelium of neonatal rats. Cyclin-dependent kinase inhibitors (CKIs), such as p27kip1 and p15INK4b, help mediate mitotic inhibition in other cell types. The role of CKIs in inhibiting proliferation in corneal endothelium was examined by first determining the kinetics of p27kip1 expression in neonatal rat corneal endothelium. Studies were then extended to cultured cells to more directly compare the effects of TGF-beta2 and cell-cell contact on the relative protein and mRNA expression of the CKIs, p27kip1, and p15INK4b. METHODS: Immunocytochemistry (ICC) detected TGF-beta receptors I, II, and III (RI, RII, RIII, respectively) in the endothelium of rat corneas on postnatal days 1, 10, and 21, and in adult (3-month-old) rats. ICC for p27kip1 was conducted on postnatal days 1, 7, 14, and 21. Samples were taken for p27kip1 RT-PCR on postnatal days 7, 14, and 21 and from adult rats. The effect of TGF-beta2 on p27kip1 and p15INK4b expression was determined in G(0)-phase synchronized subconfluent rat corneal endothelial cells incubated for 24 hours in 10% serum +/- 5 ng/mL TGF-beta2. CKI expression was also examined in fully confluent cultures. RT-PCR and Western blot analysis detected p27kip1 and p15INK4b mRNA and protein expression, respectively. The effect of releasing cells from cell-cell contact on proliferation and p27kip1 protein expression was studied in confluent cultures treated for 1 hour with and without 2.0 mg/mL di-sodium EDTA and then maintained for 24 hours in 10% serum. Cultures were then either fixed for ICC of Ki67, a marker of actively cycling cells, or extracted for Western blot determination of p27kip1 protein. RESULTS: Positive staining for TGF-beta RIII was detected on postnatal day 10, and staining for RI and RII was detected on postnatal day 21. The endothelium stained positively for p27kip1 on postnatal day 1 and thereafter, and p27kip1 PCR product was detectable at the earliest time point tested (postnatal day 7). In cultured cells, TGF-beta2 and cell-cell contact had relatively little effect on expression of p27kip1 or p15INK4b mRNA. TGF-beta2 lowered the levels of both proteins, but p27kip1 remained at a higher level than p15INK4b. In confluent cultures, p15INK4b protein was reduced; however, p27kip1 protein levels increased 20-fold. Positive staining for Ki67 was detected, and p27kip1 protein levels substantially decreased in EDTA-treated confluent cells compared with the untreated control. CONCLUSIONS: Previous studies from this laboratory showed that corneal endothelial cell proliferation ceases in neonatal rat by postnatal day 13. This timing correlated with the formation of stable cell-cell contacts, implicating contact inhibition as an important mechanism of growth arrest during endothelial development. The current studies showed that coexpression of TGF-beta RI, RII, and RIII occurred too late for TGF-beta2 to have a significant role in inhibiting proliferation during endothelial development. Studies in cultured cells suggest that p27kip1 mediates inhibition of proliferation induced by TGF-beta2, although the response to this cytokine was relatively weak. ICC and RT-PCR of p27kip1 in neonatal endothelium and RT-PCR and Western blot studies in cultured cells indicate that contact inhibition is mediated, in large part, through the activity of p27kip1. These results, together with previous data from this laboratory, strongly suggest that contact inhibition is an important mechanism responsible for inducing cell cycle arrest during corneal endothelial development and for maintaining the mature monolayer in a nonproliferative state. In both cases, contact-induced inhibition is mediated, at least in part, by p27kip1. TGF-beta2 appears not to induce mitotic arrest in the developing endothelium, but may function to maintain the mature endothelium in a nonreplicative state should cell-cell contact be lost in the monolayer.

Animals↗

PubMed2003

[Role of nitric oxide and other endothelium-derived factors].

The endothelial cell layer displays the features of a distributed organ and has a variety of biological functions such as keeping the balance between coagulation and fibrinolysis, expression of adhesion molecules for cells in the immune system, metabolism of noradrenaline and 5-hydroxytryptamine, and conversion of angiotensin I and bradykinin. The endothelium also regulates the underlying smooth muscle layer and vascular tone by release of endothelium-derived relaxing factors such as nitric oxide (NO), prostaglandins, and endothelium-derived hyperpolarizing factor (EDHF) as well as vasoconstricting factors such as endothelin, superoxide (O(2)(-)), and thromboxane. We have reviewed the nature, mechanisms of action, and role of these factors in regulation of vascular tone, with special emphasis on NO. By a process catalyzed by NO synthase, NO and citrulline is formed from the substrates molecular O(2) and L-arginine. The main receptor for NO is guanylyl cyclase leading to formation of smooth muscle cyclic guanosinmonophosphate and relaxation. EDHF is an endothelium-derived factor causing vasorelaxation of the underlying smooth muscle layer by hyperpolarization. The nature of EDHF is still unknown, but several candidates for EDHF have been proposed such as potassium ions, hydrogen peroxide, and epoxyeicosatrienoic acids. Prostaglandins such as prostacyclin and prostaglandin E2 binds to specific receptors followed by increases in cyclic adenosinmonophosphate and vasorelaxation, while contractile prostaglandins constrict vessels by activation of thromboxane and endoperoxidase receptors. Superoxide anions induce contraction of vascular smooth muscles cells by scavenging NO. Endothelin is a potent endothelium-derived contractile factor. The synthesis of endothelin-1 is induced by hypoxia, thrombin, interleukin-1, transforming growth factor-beta1, vasopressin, and catecholamines. Cardiovascular risk factors like age, hypertension, and hyperlipidemia are associated with impaired endothelium-dependent vasodilation either as a consequence of increased inactivation of endothelium-derived vasodilators or increased formation of endothelium-derived contracting factors. This imbalance of endothelium-derived factors plays a role for development of atheroslerosis and ischemic vascular diseases.

Age Factors↗

PubMed1991

Role of endothelium on the effects of neuropeptide Y in mesenteric resistance arteries of spontaneously hypertensive and Wistar-Kyoto normotensive rats.

The role of the endothelium in the effects of neuropeptide Y (NPY) and norepinephrine was investigated in mesenteric resistance arteries of the spontaneously hypertensive rat (SHR) and of the normotensive Wistar-Kyoto rat (WKY). Endothelium-dependent relaxation to acetylcholine (1 microM) was reduced in arteries of SHR compared with WKY. In the presence of the endothelium, the vessels of the two strains responded similarly to norepinephrine and NPY (100 nM) produced only a slight contraction. After removal of the endothelium, the response to norepinephrine was greater in WKY than in SHR. Furthermore, endothelium denudation enhanced markedly contraction elicited by NPY in WKY (up to 40% of the maximal effect of norepinephrine), but not in SHR. NPY potentiated the contractile response to low concentrations of norepinephrine (less than 300 nM) in both strains regardless whether the endothelium was intact or not. These results indicate that the contractile responses to NPY and to norepinephrine are inhibited by the endothelium in vessels of WKY, but not in those of the SHR. Furthermore, the potentiating effect of NPY occurs via an endothelium-independent mechanism in mesenteric arteries of both SHR and WKY. It is proposed that the differential responses between the two strains are related to abnormal function of the endothelium and to decreased responsiveness of smooth muscle cells in mesenteric resistance arteries of SHR compared to WKY.

Animals↗

PubMed1987

A possible role for the endothelium in porcine coronary smooth muscle responses to dihydropyridine calcium channel modulators.

The role of the endothelium in contraction and relaxation produced by the dihydropyridine calcium channel modulators was examined in porcine coronary smooth muscle. The optically pure dihydropyridine calcium agonists (+)-S202-791 and (-)-Bay k 8644 both produced greater contractions in tissues without endothelium compared with tissues with intact endothelium. In contrast, histamine produced the same degree of contraction in tissues with and without endothelium. In the presence of KCl-induced active muscle tone, the optically pure calcium antagonists (-)-R202-791 and (+)-Bay k 8644 and the nitrovasodilator isosorbide dinitrate all produced the same degree of relaxation in tissues with and without endothelium. These results suggest that the endothelium plays an inhibitory role in dihydropyridine-induced contraction. When coronary rings with intact endothelium were pretreated for 60 min with 10 or 100 nM (-)-R202-791, the contraction to subsequent addition of (+)-S202-791 was significantly greater than in control tissues pretreated with only solvent. However, in rings with denuded endothelium, pretreatment with (-)-R202-791 resulted in a rightward shift of the dose-response curve to (+)-S202-791, and a depression of the maximal contraction compared with controls. Thus, the interaction between the calcium agonist [(+)-S202-791] and antagonist [(-)-R202-791] is more complex than competitive inhibition. We suggest that the calcium agonists produce two effects, a release of endothelium-derived relaxant factor and a direct contraction of smooth muscle; the calcium antagonists can inhibit both processes.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1989

Endothelium-derived relaxing factor(s) and calcium antagonists.

The presence of endothelium attenuates norepinephrine-induced vasoconstriction in the rat thoracic aorta by the spontaneous release of endothelium-derived relaxing factor. Calcium antagonists also inhibit catecholamine-induced vasoconstriction. Experiments were designed to determine the effect of calcium antagonists in the presence and absence of the endothelium on the responsiveness of the isolated rat aorta to norepinephrine. Rings of the thoracic aorta of Wistar Kyoto rats were suspended in organ chambers (in the presence of indomethacin) for isometric measurement of force. Mechanical removal of the endothelium shifted the concentration response curve to norepinephrine to the left and augmented the maximal response to the catecholamine. Diltiazem and verapamil shifted the concentration response curve to norepinephrine to the right only in rings without endothelium; they abolished the difference in sensitivities to norepinephrine caused by removal of the endothelium. Diltiazem, but not verapamil, also reduced the difference in the maximal response to norepinephrine. In the presence of oxyhemoglobin, diltiazem had similar effects on rings with and without endothelium. Sodium nitroprusside also abolished the hypersensitivity to norepinephrine caused by removal of the endothelium. These data suggest that calcium antagonists can prevent the hypersensitivity to norepinephrine in arteries in which the endothelium has been removed. They may explain some of the beneficial effects of calcium antagonists in conditions with endothelial dysfunction.

Animals↗

PubMed1987

Endothelium, arachidonic acid, and coronary vascular tone.

Vasoactive mediators play an important role in the control of coronary vascular tone. Arachidonic acid (AA) metabolites and endothelium-derived vasoactive factors have been implicated in coronary vasoregulation. AA can be metabolized via three separate routes in blood vessels, mediated by cyclooxygenase, lipoxygenase, and cytochrome P-450-dependent monooxygenase enzymes. AA can evoke endothelium-dependent relaxations that are due in part to the formation of cytochrome P-450-dependent metabolites, inasmuch as drugs that modify cytochrome P-450 activity produce parallel changes in endothelium-dependent relaxations to AA. Moreover, some cytochrome P-450-derived metabolites formed biologically cause relaxations of isolated blood vessels. A cytochrome P-450-dependent pathway does not appear to contribute to endothelium-dependent relaxations induced by acetylcholine, which suggests that there may be a number of endothelium-derived relaxing factors (EDRFs). In addition, two endothelium-derived contractile factors have been described, including an unidentified cyclooxygenase metabolite of AA and a polypeptide isolated from cultured cells. As both prostaglandin I2 and acetylcholine-induced EDRF also inhibit platelet aggregation, endothelial injury and loss of these factors may predispose to vasospasm precipitated by release of platelet-derived mediators such as thromboxane A2 (TXA2) and 5-hydroxytryptamine. Unstable angina may be a clinical syndrome in which these events occur, which can be alleviated by inhibition of platelet activation and TXA2 formation with aspirin. Attenuation of endothelium-dependent relaxations can also occur without loss of endothelial cells. Neutrophil-endothelium interactions, precipitated by an ischemic episode, may initiate endothelial dysfunction and underlie the development of vasospasm in some conditions. Whether increased production of endothelium-derived contractile factors also occurs in vasospastic conditions remains to be determined.

Animals↗

PubMed1993

The heparin target organ--the endothelium. Studies in a rat model.

Plasma levels of the antithrombotic drug heparin, as estimated by coagulation tests, are a poor indicator of antithrombotic effectiveness. The interaction of heparin with endothelium is a poorly studied but important factor in the clinical activity of heparin. This study describes the interaction of heparin with endothelium, following intragastric administration. The concentrations of heparin in endothelium and plasma were determined by gel electrophoresis following administration of heparin to rats by various routes. Heparin concentrations in endothelium versus plasma were approximately 100 times greater following intravenous or ex vivo administration and more than 1000 times greater when administered by intrapulmonary, subcutaneous, intraperitoneal and intragastric routes indicating that the route of administration affects the distribution of the drug. At 2.4 and 6 min after intravenous administration, 88 and 51% respectively of the administered dose was found associated with endothelium. Heparin was rapidly absorbed following intragastric administration and could be detected associated with endothelium at 2.4 min. At 6 min less than 1% of the administered dose was found in plasma, and 45% was associated with endothelium. These results show that endothelium is the main site of heparin distribution. Heparins could also be detected in cellular and pericellular fractions of cultured porcine aortic endothelial cells when 125I-heparin was added to medium. Bound radioactivity was released to medium from both cellular and pericellular fractions suggesting that heparin taken up by endothelium can be released. Intragastric administration of heparin and dextran sulphates significantly prevented thrombus formation in a rat model of thrombosis without significant changes in activated partial thromboplastin times.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Recovery of endothelium-dependent relaxations four weeks after ischemia and progressive reperfusion in canine coronary arteries.

The acute impairment of endothelium-dependent relaxations after ischemia and acute reperfusion injury has been studied extensively. However, less is known about the chronic status of the coronary endothelium following progressive reperfusion. Experiments were designed to characterize, after 60 min of ischemia followed by progressive reperfusion, the coronary endothelial function under acute and chronic conditions. Heartworm-free mongrel dogs were used. A percutaneous balloon catheter was inflated to occlude the left anterior descending coronary artery for 60 min, followed by progressive deflation. After 60 min or 4 weeks of reperfusion, the coronary arteries were dissected free, cut into rings, suspended in organ chambers, and exposed to endothelium-dependent and endothelium-independent agonists, both in the presence and absence of pertussis toxin. Left circumflex coronary arteries (from the same dogs) that had not been subjected to occlusion and reperfusion were studied in parallel as controls. The acute endothelium-dependent relaxations to serotonin, thrombin, and adenosine/diphosphate were impaired significantly following ischemia-reperfusion injury. Four weeks after ischemia-reperfusion injury, the endothelium-dependent relaxations to these substances were normal compared with those of controls. The endothelium-dependent relaxations to acetylcholine, bradykinin, and the calcium ionophore A23187 were unaffected either acutely or chronically. An early impairment of endothelium-dependent relaxations after ischemia-reperfusion injury occurs in response to serotonin, thrombin, and adenosine diphosphate. This early impairment is transient and is not evident 4 weeks after reperfusion. In contrast to the regenerated endothelium following balloon deendothelialization, the chronic endothelial pertussis toxin-sensitive G-protein function is not impaired selectively after ischemia-reperfusion injury, provided the reperfusion occurs gradually.

Acetylcholine↗

PubMed1996

Aortic endothelium in HIV-1 infection: chronic injury, activation, and increased leukocyte adherence.

Clinical and serological studies provide evidence for a pathogenetically relevant vasculopathy in acquired immune deficiency syndrome (AIDS); however, the morphological status of the endothelium under conditions of human immunodeficiency virus (HIV)-1 infection is only sparsely documented. In this study we adapted an en face preparation technique of endothelium for use in immunohistochemistry and investigated the aortic endothelium of pre-AIDS and AIDS patients (n = 32) in comparison with an HIV-negative group (n = 17). The control group showed a regular pattern of evenly distributed aortic endothelial cells, whereas the endothelial cell pattern in the HIV-1-infected patients was clearly disturbed. Simultaneously, the degree of leukocyte adherence on the aortic endothelium increased significantly. These changes were accompanied by an up-regulation of the vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (ELAM-1). The endothelium turnover increased, and one-half of the HIV-1-infected patients exhibited HLA-DR (major histocompatibility complex class II) antigen in the aortic endothelium. Our results provide evidence for a profound and repeated injury with regeneration and activation of the endothelium in HIV-1 infection. Injury as well as activation of the endothelium impairs its normal regulatory properties. This could have consequences for the maintenance of the blood-brain barrier; it might influence the immunologically important interaction of the endothelium with T cells; and it might trigger Kaposi's sarcoma.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Defective endothelium-dependent relaxation in fructose-hypertensive rats.

The present study examined the endothelium-dependent and -independent responses of isolated mesenteric arteries to acetylcholine and the endothelium-independent vasodilator sodium nitroprusside in mesenteric arteries from fructose-induced hypertensive rats. Fructose feeding resulted in hyperinsulinemia and elevated blood pressure when compared to controls (plasma insulin, 5.9 +/- 0.4 v control 3.6 +/- 0.4 ng/mL, P < .05; systolic blood pressure, 154 +/- 5 v control 127 +/- 7 mm Hg, P < .05). The maximum contractile response of mesenteric arteries to norepinephrine did not differ between the control and fructose groups, either with or without the endothelium. In arteries with intact endothelia, precontracted with the approximate ED50 of norepinephrine, the percent maximum relaxation produced by acetylcholine in hypertensive rats was lower than the control arteries (62 +/- 7 v control 95 +/- 5, P < .05) without any change in sensitivity. In arteries precontracted with norepinephrine, the endothelium-independent vasodilator sodium nitroprusside produced a dose-dependent relaxation in arteries obtained from control and fructose groups, both with and without the endothelium. The maximum relaxation produced by sodium nitroprusside did not differ between control and fructose arteries, either with or without the endothelium; however, removal of the endothelium caused an increase in sensitivity of this agonist. These data suggest that in the insulin resistant and hyperinsulinemic fructose-hypertensive rats, there is a defective endothelium-dependent yet preserved endothelium-independent relaxation.

Acetylcholine↗

PubMed1989

Increases in flow reduce the release of endothelium-derived relaxing factor in the aorta of normotensive and spontaneously hypertensive rats.

Experiments were designed to compare basal and acetylcholine-induced release of endothelium-derived relaxing factor at different flow rates in the aorta of the normotensive (Wistar-Kyoto; WKY) and spontaneously hypertensive (SHR) rat. Aortic segments (with endothelium) of either WKY or SHR were perfused at different flow rates (1 or 4 mL/min) with modified Krebs-Ringer solution; the relaxing activity of the perfusate from the two types of segments was bioassayed by measuring the isometric force in rings (without endothelium, and contracted with norepinephrine) of aortas of both WKY and SHR. All studies were performed in the presence of indomethacin to prevent endothelial production of prostacyclin and other vasodilator prostanoids. The basal release of endothelium-derived relaxing factor was not significantly affected by the flow rate in either the WKY or the SHR aortas. At the two flow rates, and with both types of bioassay rings, the basal release of endothelium-derived relaxing factor was smaller with SHR than with WKY aortas, but this reached significance only at 4 mL/min using the SHR-aorta as bioassay tissue. Both with WKY and SHR aortas the release of endothelium-derived relaxing factor evoked by acetylcholine was significantly larger at 1 than at 4 mL/min; no significant differences in responsiveness to acetylcholine were noted between WKY and SHR segments. There was also no difference in responsiveness of WKY and SHR bioassay rings to acetylcholine and acetylcholine-induced release of endothelium-derived relaxing factor. These experiments suggest that prolonged exposure to increases in shear stress reduces the ability of the endothelium to release endothelium-derived relaxing factor in responses to muscarinic activation.

Acetylcholine↗

PubMed2004

Endothelium-derived reactive oxygen species and endothelin-1 attenuate NO-dependent pulmonary vasodilation following chronic hypoxia.

Vasodilatory responses to exogenous nitric oxide (NO) are diminished following exposure to chronic hypoxia (CH) in isolated, perfused rat lungs. We hypothesized that both endothelium-derived reactive oxygen species (ROS) and endothelin-1 (ET-1) mediate this attenuated NO-dependent pulmonary vasodilation following CH. To test this hypothesis, we examined vasodilatory and vascular smooth muscle (VSM) Ca2+ responses to the NO donor spermine NONOate in UTP-constricted, isolated pressurized small pulmonary arteries from control and CH rats. Consistent with our previous findings in perfused lungs, we observed attenuated NO-dependent vasodilation following CH in endothelium-intact vessels. However, in endothelium-denuded vessels, responses to spermine NONOate were augmented in CH rats compared with controls, thus demonstrating an inhibitory influence of the endothelium on NO-dependent reactivity following CH. Whereas both the ROS scavenger tiron and the ETA receptor antagonist BQ-123 augmented NO-dependent reactivity in endothelium-intact vessels from CH rats, neither fully restored vasodilatory responses to those observed following endothelium denudation in vessels from CH rats. In contrast, the combination of tiron and BQ-123 or the nonselective ET receptor antagonist PD-145065 enhanced NO responsiveness in endothelium-intact vessels from CH rats similar to that observed following endothelium denudation. We conclude that both endothelium-derived ROS and ET-1 attenuate NO-dependent pulmonary vasodilation following CH. Furthermore, CH augments pulmonary VSM reactivity to NO.

Animals↗

PubMed1997

N-acetylcysteine does not influence the activity of endothelium-derived relaxing factor in vivo.

Nitric oxide forms complexes with an array of biomolecular carriers that retain biological activity. This reactivity of nitric oxide in physiological systems has led to some dispute as to whether endothelium-derived relaxing factors nitric oxide or a closely related adduct thereof, such as a nitrosothiol. In vitro bioassays used to address this question are limited by the exclusion of biological thiols that are requisite for nitrosothiol formation. Thus, the purpose of this study was to obtain insight into the identity of endothelium-derived relaxing factor in vivo. We reasoned that if endothelium-derived relaxing factor in nitric oxide, infusion of physiological concentrations of thiol would potentiate its bioactivity by analogy with effects seen in vitro, whereas nitrosothiol would be resistant to such modulation. We used venous-occlusion plethysmography to study forearm blood flow in normal subjects. Methacholine (0.3 to 10 micrograms/min) and nitroglycerin (1 to 30 micrograms/min) were infused via the brachial artery to elicit endothelium-dependent and endothelium-independent vasodilation, respectively. Dose-response determinations were made for each drug before and after an intra-arterial infusion of the reduced thiol, N-acetylcysteine, at rates estimated to achieve a physiological concentration of 1 mmol/L. Methacholine increased forearm blood flow in a dose-dependent manner. Infusion of N-acetylcysteine did not change the sensitivity (ED50, 1.7 versus 1.7 micrograms/min, P = NS) or maximal response to methacholine. In contrast, thiol increased the sensitivity to nitroglycerin (ED50, 4.7 versus 2.8 micrograms/min, P < .01). Thus, conflicting with reports in vitro, thiol does not modulate endothelium-derived relaxing factor responses in vivo. These data indicate that sulfhydryl groups are not a limiting factor for endothelium-derived relaxing factor responses in forearm resistance vessels in normal humans and are in keeping with reports that nitrosothiol contributes to endothelium-derived relaxing factor bioactivity in plasma and vascular smooth muscle. Potentiation of the effects of nitroglycerin by N-acetylcysteine can be attributed to its enhanced biotransformation to an endothelium-derived relaxing factor equivalent, such as nitrosothiol. These observations support the notion of an equilibrium between nitric oxide and nitrosothiol in biological systems that may be influenced by redox state.

Acetylcysteine↗