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PubMed2006

Role of probucol on endothelial dysfunction of epicardial coronary arteries associated with left ventricular hypertrophy.

The lipid-lowering agent probucol may be efficacious, through its antioxidant properties, to limit and reverse the vascular endothelial dysfunction associated with left ventricular hypertrophy (LVH). LVH was induced by performing an aortic banding (AB) on swine, except for controls (group 1). The untreated AB group received a placebo (group 2) whereas the treated groups received probucol (1000 mg/d orally); the third group began its treatment on the day of the banding (for 60 d), the fourth began on day 30 and the fifth on day 60 after AB (both for 30 d). Hypertrophy was assessed by echocardiography and histology. Coronary vascular reactivity was evaluated in organ chambers and endothelial function by quantification of NO2/NO3 and cyclic guanosine-3',5'-monophosphate. To assess oxidative stress, hydroperoxides and angiotensin II levels as well as superoxide dismutase activity were evaluated. After treatment with probucol, a significant decrease in left ventricle/body weight ratio was observed compared with the untreated group. Dose-response curves of the probucol groups showed an improvement in endothelium-dependent relaxations, associated with increased nitric oxide bioavailability and decreased angiotensin II and hydroperoxide levels. In conclusion, the antioxidant probucol limited the development and induced the regression of LVH and the associated coronary endothelial dysfunction.

Angiotensin II↗

PubMed2000

Additive effect of coexistent type 2 diabetes and arterial hypertension on endothelial dysfunction in resistance arteries of human forearm vasculature.

Population studies suggest that vascular complications accumulate when arterial hypertension supervenes on diabetes mellitus. Although it has been demonstrated that endothelial function is impaired in patients with either diabetes mellitus or arterial hypertension it is unknown whether or not both diseases exert additive effects on endothelial dysfunction. The authors therefore investigated endothelium-dependent and endothelium-independent vasodilation in the forearm vasculature of 44 individuals: in 10 type 2 diabetic patients (DM), in 12 patients with arterial hypertension (HT), in 10 patients with both DM and HT (DM+HT), and in 12 healthy control subjects (C). Forearm blood flow (FBF) was measured by venous occlusion plethysmography at rest and following intraarterial infusion of acetylcholine (ACh) and the NO-donor sodium nitroprusside (SNP) at increasing doses. FBF at rest was significantly lower in diabetic patients: 2.2 +/- 0.1 (DM) and 2.6 +/- 0.2 (DM+HT) versus 3.1 +/- 0.1 (HT) and 3.4 +/- 0.2 (C) mL/min per 100 mL of tissue. ACh and SNP both increased FBF dose-dependently in each group. The maximum response to ACh was progressively decreased in DM and HT: 13.7 (C) > 8.1 (DM) > 7.6 (HT) > and 5.7 (DM+HT) mL/min per 100 mL of tissue. Reduction of the endothelium-dependent flow reserve assessed as percent increase in maximum FBF was also impaired following the same rank order: 349 (C) > 268 (DM) > 160 (HT) > 126 (DM+HT)%. The flow response to the NO-donor SNP amounted to: 327 (C), 306 (DM), 200 (HT), and 194% (DM+HT). In DM+HT the reduction of endothelium-dependent flow response was more pronounced compared with the endothelium-independent flow response. The present data provide evidence that type 2 diabetes and arterial hypertension impair endothelium-dependent dilation of resistance arteries in an additive manner suggesting that this progressive endothelial dysfunction might contribute to the increased incidence of cardiovascular complications when both diseases are coexistent.

Acetylcholine↗

PubMed1999

Effect of 17beta-estradiol in hypercholesterolemic rabbits with severe endothelial dysfunction.

17beta-Estradiol prevents early vascular lesion development and may also affect advanced atherosclerosis. To test the antiatherosclerotic effect of estrogen under conditions that resemble more advanced human atherosclerosis with severe endothelial dysfunction, we have investigated the effect of 17beta-estradiol in hypercholesterolemic rabbits treated with the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME). Chronic L-NAME administration attenuated endothelial nitric oxide (EDNO)-mediated vascular responses leading to significantly accelerated atherosclerotic plaque development. 17beta-Estradiol treatment alone inhibited aortic lesion formation with concurrent increase in EDNO-mediated responses. The beneficial effect of estrogen persisted in the L-NAME-treated rabbits, suggesting that the antiatherogenic action of 17beta-estradiol involves NO-independent mechanisms as well. Serum cholesterol levels were not altered by any of the treatments. 17beta-Estradiol treatment significantly increased EDNO production under these conditions as well. The reduction in plaque size by 17beta-estradiol was always accompanied by increased EDNO production, suggesting a strong association between these two events. The results demonstrate that estrogen treatment may exert protection against atherosclerosis even in patients with severe endothelial dysfunction.

Acetylcholine↗

PubMedDate not supplied

[Coronary endothelial dysfunction after ischemia-reperfusion: mechanisms and possibilities for protection].

Although cardiac ischaemia-reperfusion is well known as a disease of the myocytes, it is now clear that its consequences also extend to the vascular wall and especially to the endothelial cells. Using a rat model of ischaemia-reperfusion in vivo, we evidenced an impairment of the NO-dependent relaxation to acetylcholine of coronary artery segments. Moreover, we showed that cultured endothelial cells submitted to anoxia/reoxygenation displayed an increased neutrophil adhesion, associated with an increased expression of adhesion molecules, probably responsible for the endothelial injury. In this context, we focused on the concept of endogenous protection against ischaemia, i.e. preconditioning, and demonstrated that endothelial dysfunction could be reversed by both the early and the delayed phase of preconditioning. The delayed endothelial preconditioning mechanism appears to involve complex interactions between NO and free radicals, leading to delayed improvement of NO production and decreased neutrophil adhesion to the endothelium. Identification of these mechanisms may lead to the development of new endothelial protective agents in pathophysiological situations associated with endothelial dysfunction.

Animals↗

PubMed2006

Dimethylarginine dimethylaminohydrolase inhibition and asymmetric dimethylarginine accumulation contribute to endothelial dysfunction in rats exposed to glycosylated protein: effects of aminoguanidine.

OBJECTIVES: To determine whether alterations of endogenous asymmetric dimethylarginine (ADMA) concentration and dimethylarginine dimethylaminohydrolase (DDAH) activity are involved in endothelial dysfunction induced by glycosylated bovine serum albumin (GBSA) in rats and effects of aminoguanidine on them. METHODS: Endothelium-dependent relaxation of aortic rings from Sprague-Dawley rats after treatment with GBSA in vitro and in vivo was tested. Serum concentrations of ADMA, nitrite/nitrate, and activities of aortic DDAH, nitric oxide synthase (NOS) and superoxide dismutase were measured in GBSA-treated rats. Moreover, serum contents of glycosylated serum protein, and malondialdehyde were also assayed. RESULTS: Endothelium-dependent relaxation was significantly impaired either by incubation of aortic rings with GBSA (1.70mmol/l) in vitro for 60min or by injection of GBSA (35mg/kg/d, i.v.) to normal rats for 4 weeks, and serum ADMA levels were remarkably elevated in GBSA-treated rats, which was accompanied by decreases of nitrite/nitrate concentrations, NOS and DDAH activities. Furthermore, elevated glycosylated serum protein, malondialdehyde levels, and reduced superoxide dismutase activity were also observed in GBSA-treated rats. Treatment with aminoguanidine not only improved impairment of endothelium-dependent relaxation but also prevented elevation of endogenous ADMA, which were concomitant with increases of nitrite/nitrate concentration, NOS and DDAH activity. Serum levels of glycosylated serum protein, malondialdehyde, and vascular superoxide dismutase activity were also normalized after aminoguanidine treatment. CONCLUSIONS: Decreased DDAH activity and elevated endogenous ADMA is implicated in endothelial dysfunction of rats exposed to GBSA. Aminoguanidine can protect endothelium of rat aorta against injury induced by GBSA both in vitro and in vivo.

Amidohydrolases↗

PubMedDate not supplied

Treatment of essential arterial hypertension with enalapril does not result in normalization of endothelial dysfunction of the conduit arteries.

It is assumed that endothelial dysfunction due to arterial hypertension could be improved or even normalized by antihypertensive treatment. The present study was designed to explore that assumption in patients with essential hypertension treated with an angiotensin-converting enzyme (ACE) inhibitor-enalapril. Twenty-eight patients (mean age: 55.1 years) who fulfilled the following criteria were included: essential arterial hypertension present for more than 2 years, monotherapy with enalapril for at least 1 year, adequate treatment (blood pressure in the last year <140/90 mm Hg) and absence of other factors (smoking, hypercholesterolemia, diabetes, obesity), which could importantly influence endothelial function. The flow-mediated (endothelium-dependent) dilation (FMD) of the brachial artery was assessed by high-resolution ultrasound and compared with that of 22 age-matched healthy normotensive controls. The patients and controls did not differ in regard to body mass index, lipids, and plasma glucose and insulin; there were no smokers. FMD of the brachial artery was significantly decreased in patients in comparison to controls (7.9% vs 13.5%, p<0.01). FMD in patients was inversely correlated with the duration of hypertension (r = -0.52, p<0.01) and with both systolic (r = -0.72, p<0.01) and diastolic (r = -0.43, p<0.05) blood pressure (measured after temporary withdrawal of treatment). This study showed that the adequate control of blood pressure achieved with enalapril is not followed by normalization of endothelial function, measured by FMD of the brachial artery.

Adult↗

PubMed1999

Endothelial dysfunction, atherosclerosis and diabetes.

The prevalence of early and accelerated development of atherosclerosis associated with high morbidity and mortality is markedly increased among individuals with diabetes and hypertension. Although the link between diabetes and vascular disease is not fully understood, loss of the modulatory role of the endothelium could be implicated in the pathogenesis of diabetic vascular complications. Diabetes-associated pathophysiologic conditions in the endothelium are modifications of lipoproteins, formation of advanced glycation end-products and circulating lipoprotein immune complexes, alteration of the nitric oxide pathway, and elevated levels of homocysteine. The main goals in restoration of endothelial function are optimal glycemic control, lipid lowering, cessation of smoking, normalization of elevated blood pressure, improvement of the NO-status, antioxidants for scavenging free oxygen radicals, normalization of homocysteine levels, antagonizing the hyperinsulinaemia, and regulation of rheology, respectively haemostasis to physiological levels. There is abundant evidence that some pharmacological agents exert direct beneficial effects on endothelium, suggesting that at least part of their therapeutic action is associated with improvement in endothelial dysfunction. A number of new findings about endothelial dysfunction may have potential clinical relevance.

Arteriosclerosis↗

PubMed1997

von Willebrand factor: a marker of endothelial dysfunction in vascular disorders?

The vascular endothelium is involved in the production of many important substances which are involved in a cardiovascular pathophysiology. One such substance which is synthesised by, and stored in, endothelial cells is von Willebrand factor (vWf). When released, vWf appears to mediate platelet aggregation and adhesion. Numerous clinical and experimental reports suggest that high vWf levels reflect damage to the endothelium or endothelial dysfunction. The close association between vWf and the processes of thrombus formation (thrombogenesis) or atherogenesis also suggests that high vWf levels may be a useful indirect indicator of atherosclerosis and/or thrombosis. The availability of a useful marker of endothelial dysfunction may have potential clinical value. The measurement of such a marker can perhaps be a non-invasive way of assisting in clinical diagnosis or as an indicator of disease progression. High vWf levels have also been shown to have prognostic value in patients with ischaemic heart disease, peripheral vascular disease and inflammatory vascular disease. However, there is limited information that increased vWf is actually casual in the progression of vascular disease and that measures aimed at reducing vWf levels will be beneficial. In addition, interpretation of raised plasma vWf levels is complicated by the fact that vWf may be an acute phase reactant. Further research is indicated to explore the predictive value of this marker in population studies and, perhaps, therapeutic approaches in (and the value of) modifying vWf levels or function.

Arteriosclerosis↗

PubMed2002

Family history of cardiovascular events and endothelial dysfunction in children with familial hypercholesterolemia.

OBJECTIVES: in patients with familial hypercholesterolemia (FH), the propensity towards atherosclerosis may vary considerably. In the general population, a positive family history is associated with an increased risk for cardiovascular events. Since endothelial dysfunction is predictive for future cardiovascular events, we evaluated whether FH-children with a positive family history of premature cardiovascular disease have more pronounced endothelial dysfunction compared to children with a negative family history. STUDY DESIGN: 50 FH children, 10-18 years, participated in this study. Thirty-one children had a positive family history for cardiovascular events (fh(+)) and 19 children had no events in the family (fh(-)). Nineteen matched siblings participated as controls. Endothelial function was assessed by testing the flow mediated dilatation (FMD) of the brachial artery. RESULTS: baseline characteristics were comparable for fh(+), fh(-) and controls. Lipid levels were significantly higher in FH children. In FH, FMD was impaired compared to controls (11.7+/-4.4 vs. 15.6+/-6.8%, P<0.03). In addition, FMD was significantly lower in fh(+) compared to fh(-) (10.7+/-9.9 vs. 13.3+/-4.6%, P<0.05). CONCLUSION: In FH-children, endothelial function is impaired compared to matched controls. This impairment is most pronounced in FH children with a positive family history of premature cardiovascular disease.

Adolescent↗

PubMed1994

Vitamin E reverses cholesterol-induced endothelial dysfunction in the rabbit coronary circulation.

Hypercholesterolaemia and atherosclerosis are associated with impaired endothelium-dependent vasodilation. In this study we have examined the effects of vitamin E on cholesterol-induced endothelial dysfunction in the rabbit coronary circulation. Rabbits were maintained for 4 or 8 weeks on one of three experimental diets: (a) control chow, (b) 1% cholesterol or (c) 1% cholesterol for the first half of the treatment period followed by 1% cholesterol + 0.2% vitamin E during the last half of the treatment. After sacrifice, vasodilator responses to acetylcholine and sodium nitroprusside in the isolated perfused heart were studied. Responses to sodium nitroprusside were similar between the groups whereas responses to acetylcholine were significantly impaired in cholesterol-fed rabbits after both 4 and 8 weeks when compared to controls. In the cholesterol + vitamin E group, responses to acetylcholine were similar to controls and significantly greater than in the group receiving cholesterol alone. These results show that both 4 and 8 weeks of cholesterol-feeding induces an endothelial dysfunction in the coronary circulation of the rabbit, and that vitamin E protects against this dysfunction. By comparing responses to acetylcholine in the 4 week cholesterol group with the 8 week cholesterol + vitamin E group it was shown that vitamin E may not only prevent further deterioration of the endothelial function in the rabbit heart, but may also reverse the adverse effects of hypercholesterolaemia.

Acetylcholine↗

PubMed2003

Endothelial dysfunction in acute and chronic coronary syndromes: evidence for a pathogenetic role of oxidative stress.

The past two decades have highlighted the pivotal role of the endothelium in preserving vascular homeostasis. Among others, nitric oxide (NO) is currently believed to be the main component responsible for endothelium dependent vasorelaxation and therefore for endothelial function integrity. Reduced NO bioavailability causes the so-called "endothelial dysfunction," which seems to be the common molecular disorder comprising stable atherosclerotic narrowing lesions or acute plaque rupture causing unstable angina or myocardial infarction. Compelling evidence is accumulating, stressing the role of oxidative stress in causing reduced NO bioavailability and subsequently endothelial dysfunction (ED). More recently, the role of endothelial cell (EC) apoptosis as a possible final stage of ED and plaque activation has been suggested. In vitro and in vivo evidence suggests a role of oxidative stress also as a putative mechanism finally leading to plaque denudation and activation through increased EC apoptosis. Thus, oxidative stress, irrespective of atherosclerotic disease stages, seems to represent a key phenomenon in vascular disease progression and possible prevention.

Acute Disease↗

PubMed1997

[Endothelial dysfunction in cardial failure: potential mechanisms].

From the vascular point of view, cardiac failure is characterised by increased systemic resistances secondary to an increased concentration of a number of vasoconstrictor substances and also to decreased endothelium dependent vasodilatation. Endothelial dysfunction has been described both in man and in animal models, but its causes are not well understood. Such dysfunction could be due to a decrease in the production of nitric oxide, a decrease in its vasodilator effect due to an increased degradation or an increased vasoconstrictor tone. Recent data suggests an improvement or prevention of this endothelial dysfunction observed in cardiac failure by physical training and by chronic treatment with an angiotensin converting enzyme inhibitor. The improvement or preservation of endothelial function induced by exercise or ACE inhibitor could explain some of the benefits of these treatments in terms of tissue perfusion and haemodynamic conditions.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1994

Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis.

OBJECTIVES: The purpose of this study was to test the hypothesis that endothelial dysfunction occurs in humans before the development of structural coronary atherosclerosis when risk factors for this disease are present. BACKGROUND: Animal studies have demonstrated that known risk factors for coronary atherosclerosis (hyperlipidemia, hypertension, diabetes) result in impaired endothelium-dependent vascular reactivity before the development of structural atherosclerosis. Previous studies in patients have been unable to distinguish early structural atherosclerotic disease from dysfunctional endothelium. METHODS: Twenty-six patients with angiographically normal coronary arteries were studied at cardiac catheterization. The epicardial arteries were imaged using high resolution intravascular ultrasound to detect early structural changes and to determine changes in lumen size during pharmacologic provocation. A selective intracoronary Doppler velocity catheter was subsequently used to determine coronary blood flow velocity changes in response to the same pharmacologic provocation. Group I (9 patients) had no risk factors for atherosclerosis. Group II (17 patients) had one or more risk factors present. RESULTS: Although both Groups I and II had a normal microvascular vasodilator response to adenosine or papaverine infusion (estimated coronary flow increase 396 +/- 200% vs. 326 +/- 161% [mean +/- SD], respectively, p = 0.103), only Group I patients had an intact response to acetylcholine infusion (378 +/- 203% vs. 75 +/- 93% in Group II, p = 0.001). Group II patients had an abnormal epicardial artery cross-sectional area vasoconstriction response to acetylcholine infusion (-16.6 +/- 12.4% [13 patients] vs. 1.3 +/- 11.5% in Group I, p = 0.0007). An additional four Group II patients had severe spasm during acetylcholine infusion. Epicardial vasodilator response to nitroglycerin infusion, however, was preserved in Group II (14.6 +/- 4.3% vs. 9.6 +/- 3.5% in Group I, p = 0.212). All Group I patients had normal vessels by intravascular ultrasound. Of the 17 patients in Group II, 7 had minimal disease on ultrasound (intimal thickening or small eccentric plaque) in the study vessel. These patients did not respond differently from the 10 Group II patients without demonstrable disease on ultrasound. CONCLUSIONS: Patients with risk factors for coronary artery disease, normal coronary angiograms and no measurable disease by intracoronary ultrasound exhibit selective endothelial dysfunction at both the epicardial and microvascular levels. These findings may have implications for the treatment of "preclinical" coronary atherosclerosis.

Acetylcholine↗

PubMed1992

Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus.

Raised urinary albumin excretion (UAE) is associated with an increased risk of cardiovascular disease in non-insulin-dependent diabetes mellitus (NIDDM). We have examined the role of endothelial dysfunction as a possible explanation for this association in 94 NIDDM patients by investigating UAE, new cardiovascular events, and plasma concentration of von Willebrand factor (vWF), an indicator of endothelial dysfunction. At baseline, 66 patients had normal UAE (less than 15 micrograms/min), which remained normal in 33 (group 1) and increased in 33 (to median 31.5 micrograms/min, group 2). In 28 patients, baseline UAE was abnormal (67.1 micrograms/min, group 3). Follow-up ranged between 9 and 53 months. vWF did not change in group 1 (median 128% at baseline and 123% at follow-up), but increased in group 2 (from 116 to 219%, p less than 0.0001) and group 3 (from 157 to 207%, p = 0.0005). Baseline level of and change in vWF were strongly related to the development of microalbuminuria (R2 = 0.60, p less than 0.0001), but cardiovascular risk factors were not (R2 = 0.14). Raised baseline UAE was associated with an increased risk of new cardiovascular events only in patients with vWF concentrations above the median (relative risk 3.66, 95% CI 1.3-11.9) and not in patients with lower vWF (0.19, 0.01-1.33). In addition, the cardiovascular risk associated with increased UAE was modified by low compared with high concentrations of serum high density lipoprotein cholesterol (2.86 [1.03-8.48] vs 0.15 [0.01-1.43]). Dysfunction of vascular endothelium may be a link between albuminuria and atherosclerotic cardiovascular disease in NIDDM.

Adult↗

PubMed1995

Abnormalities in intramyocardial arteries detected in cardiac transplant biopsy specimens and lack of correlation with abnormal intracoronary ultrasound or endothelial dysfunction in large epicardial coronary arteries.

OBJECTIVES: We sought to determine whether abnormalities in small intramyocardial vessels could be detected on routine cardiac transplant biopsy specimens and whether these features correlate with intimal thickening by intracoronary ultrasound and endothelial dysfunction in large epicardial vessels. BACKGROUND: Variability in clinical presentation of allograft vasculopathy suggests differential involvement of large and small vessels. Intracoronary ultrasound and endothelial function studies detect large-vessel abnormalities but may not reflect changes in small intramyocardial arteries. The latter could be detected in routine cardiac biopsy specimens by histologic and immunohistochemical studies. METHODS: Thirty-nine cardiac transplant recipients underwent intracoronary ultrasound and acetylcholine studies 5 to 7 days after endomyocardial biopsy. Biopsy tissue was evaluated for coronary artery endothelial plumping and intimal thickening and increased immunostaining for fibronectin, tumor necrosis factor-alpha and receptor for hyaluronan-mediated motility. Large-vessel disease was assessed by calculating an average intimal index from intracoronary ultrasound of the left anterior descending coronary artery. Endothelial function was determined by quantitative coronary analysis after acetylcholine challenge. RESULTS: Coronary arteries were found in the biopsy tissue of 30 (76%) of the 39 patients who formed the study group. Fourteen of 30 patients had abnormal histologic findings. Immunohistochemical analysis for fibronectin, possible in 20 of 30 patients, was positive in 14 (70%) of 20 and correlated with abnormal histologic findings (p = 0.01). Immunostaining was positive for tumor necrosis factor-alpha and receptor for hyaluronan-mediated motility in 12 (40%) and 13 (43%) of 30 patients, respectively. All patients had intimal thickening by intracoronary ultrasound, but intimal index did not correlate significantly with small-artery disease by histologic or immunohistochemical analysis. Large-vessel endothelial dysfunction in 13 patients (43%) did not correlate with either abnormal ultrasound findings or small-vessel disease. CONCLUSIONS: Intramyocardial arteries are readily observed in biopsy specimens from cardiac transplant recipients and provide useful information about allograft vasculopathy. Lack of correlation between intramyocardial and epicardial vessel disease suggests discordant progression of allograft vasculopathy.

Adult↗

PubMed2003

Red wine prevents homocysteine-induced endothelial dysfunction in porcine coronary arteries.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor of coronary artery disease. Clinical studies have indicated that moderate red wine consumption is associated with a reduction of incidence of coronary artery disease. In this study, we determined the effect of red wine on homocysteine- induced endothelial dysfunction in porcine coronary arteries. MATERIALS AND METHODS: Porcine coronary arteries were dissected from 6 pig hearts and cut into 5-mm ring segments, which were assigned into 4 groups (9 rings/group): blank control, homocysteine treated (50 muM), red wine treated (0.08% alcohol), and homocysteine plus red wine treated. The rings were cultured in cell culture medium with or without treatment for 24 h. Myograph analysis was performed with U46619 (10(-7) M) for contraction and cumulative bradykinin (10(-9) to 10(-5) M) for endothelium-dependent relaxation. The endothelial nitric oxide synthase (eNOS) levels were analyzed by RT-PCR, Western blot, and immunohistochemistry. RESULTS: In response to 10(-5) M bradykinin, porcine coronary artery rings treated with homocysteine (50 muM) showed a significant reduction of endothelium-dependent vasorelaxation by 43% as compared to controls (P < 0.05). However, rings treated with red wine (0.08% alcohol) plus homocysteine showed no significant difference as compared to controls. Endothelium-dependent vasorelaxation was not different between control and red wine treated groups. Furthermore, eNOS mRNA density levels were significantly reduced by 36% in homocysteine treated group as compared to controls (P < 0.05). eNOS protein levels were also substantially reduced in the homocysteine-treated group. However, red wine treatment reversed the effect of homocysteine-induced eNOS downregulation. CONCLUSIONS: Homocysteine significantly impaired endothelial functions including endothelium-dependent vasorelaxation and eNOS mRNA and protein levels in porcine coronary arteries; and red wine effectively prevented homocysteine-induced endothelial dysfunction. This study suggests that protecting coronary endothelial cells from homocysteine damage may be an important mechanism of red wine for preventing coronary artery disease.

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

PubMed1997

Low-density lipoprotein size, high-density lipoprotein concentration, and endothelial dysfunction in non-insulin-dependent diabetes.

We examined endothelial function (nitric-oxide mediated) in 29 men with diet-treated non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and 18 male age-matched controls. Forearm blood flow was measured by venous occlusive plethysmography during intra-arterial administration of acetylcholine (ACh, 7.5 and 15 microg min(-1)) and sodium nitroprusside (SNP, 3 and 10 microg min(-1)). LDL particle size was estimated by non-denaturing gel electrophoresis. Serum lipids, blood pressure, and glycated haemoglobin were also measured. LDL particle size was smaller (p = 0.048) in the diabetic patients than controls. In the diabetic patients, LDL particle size was a significant positive predictor (p = 0.01) of the area under the dose-response curve for ACh, after adjusting for age, HbA1c, systolic BP, and cholesterol (R2 0.20). In stepwise regression including serum lipid and lipoprotein concentrations and LDL particle size, decreased HDL cholesterol was the best predictor of an impaired vasodilatory response to ACh. Vasodilatory responses to sodium nitroprusside were not significantly correlated with LDL particle size or serum lipid and lipoprotein concentrations. We conclude that in men with NIDDM, small, dense LDL particle size is associated with abnormal endogenous release of nitric oxide. The contribution of small, dense LDL particles to the development of endothelial dysfunction and early diabetic vasculopathy may not, however, be as great as decreased HDL cholesterol.

Acetylcholine↗

PubMed1994

Angiotensin blockade or calcium antagonists improve endothelial dysfunction in hypertension: studies in perfused mesenteric resistance arteries.

Endothelial regulation of peripheral vascular resistance is impaired in hypertension. We studied the effects of different antihypertensive therapies on endothelial function in perfused mesenteric resistance arteries. Spontaneously hypertensive rats (SHR) aged 7 weeks were treated with either the nonpeptidic angiotensin II (AII) receptor antagonist CGP 48369, the angiotensin-converting enzyme (ACE) inhibitor benazepril HCl, or the calcium antagonist nifedipine (each 10 mg/kg/day orally, p.o.) for 8 weeks. All forms of therapy inhibited the increase in systolic blood pressure (SBP) to a comparable degree (18-23 mm Hg) and reduced but did not normalize medial hypertrophy in SHR. Changes in intraluminal vascular diameter to acetylcholine (ACh), norepinephrine (NE), and endothelin-1 (ET-1) were measured. Impaired endothelium-dependent relaxations to intraluminal ACh improved or normalized with all therapies, whereas the response to extraluminal ACh (which was unimpaired in SHR) remained unaffected. The endothelium-dependent inhibition of contractions to NE was lost in untreated SHR and improved or restored by antihypertensive therapy. In SHR, the sensitivity but not the maximal response of vascular smooth muscle (VSM) to ET-1 was paradoxically decreased. Antihypertensive therapy with CGP 48369, nifedipine, or benazepril HCl restored or increased the sensitivity to ET-1. Thus, chronic blockade of the renin-angiotensin system or voltage-operated calcium channels reduces BP and improves endothelial dysfunction in the resistance circulation of SHR. This may contribute to normalization of peripheral vascular resistance during antihypertensive treatment and improve local blood flow to vital organs.

Acetylcholine↗