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PubMed1995

[Endothelial dysfunction of the infarct-related coronary artery after reperfusion therapy].

The response of the infarct-related coronary artery to acetylcholine (20, 30, 50 micrograms) was investigated in 30 patients without restenosis during a 4-month follow-up period after direct percutaneous transluminal coronary angioplasty (PTCA) of the left proximal anterior descending coronary artery. The patients were divided into two groups according to wall motion as obtained by the centerline method from a left ventricular angiogram: moderate group (n = 10) with reduced wall motion with less than 20 abnormal contraction segments (moderate reduction at the infarcted site), severe group (n = 20) with reduced wall motion with 20 or more abnormal contraction segments (severe reduction). The acetylcholine-induced percentage changes in luminal diameter were assessed at the PTCA site and the distal portion of the coronary artery and the effect of acetylcholine was compared at the two sites. Coronary artery diameter in the moderate and severe groups displayed 8.1 +/- 24.9% and 7.4 +/- 30.8% contraction at the PTCA site and 38.3 +/- 46.3% and 72.5 +/- 28.2% contraction at the distal portion, respectively. Severe group had greater contraction at the distal portion than at the PTCA site. Vasoconstriction of the patent infarct-related coronary artery tended to occur in the infarcted area where wall motion was severely affected. In addition, endothelial dysfunction appears to be induced by a lengthy interruption of epicardial coronary blood flow and is present in the patent infarcted coronary artery without restenosis.

Acetylcholine↗

PubMed1997

Diabetes-induced endothelial dysfunction is prevented by long-term treatment with the modified iron chelator, hydroxyethyl starch conjugated-deferoxamine.

Oxygen radicals are believed to play a role in vascular complications of diabetes mellitus. In this study, we evaluated whether long-term treatment with an iron chelator and inhibitor of metal-catalyzed hydroxyl radicals (.OH) could prevent diabetes-induced defects in endothelium-dependent relaxation. Diabetes was induced in Sprague-Dawley rats by injection of streptozotocin. At 48 h after streptozotocin, a subgroup of diabetic rats received daily injections of 50 mg/kg hydroxyethyl starch conjugated-deferoxamine (HES-DFO) for a total of 8 weeks. Long-term treatment with HES-DFO did not modify serum insulin or blood glucose taken at the end of the study; however, a modest reduction in glycosylated hemoglobin was present. In precontracted aortic rings suspended in tissue baths, endothelium-dependent relaxation to acetylcholine was impaired in diabetic rings compared with control rings in the presence or absence of indomethacin. Endothelium-independent relaxation to nitroglycerin was unaltered. Long-term treatment with HES-DFO had no effect on relaxation to nitroglycerin but completely prevented the impaired relaxation to acetylcholine in diabetic rings in either the presence or absence of indomethacin. These data suggest that iron-catalyzed .OH formation contributes to the development of diabetes-associated endothelial dysfunction.

Animals↗

PubMed2005

Role of endothelial dysfunction and insulin resistance in angina pectoris and normal coronary angiogram.

Angina pectoris and a normal coronary angiogram or cardiac syndrome X is a heterogeneous syndrome that probably encompasses different pathophysiological entities. Patients affected by cardiac syndrome X are often women presenting with severe, invalidating chest pain. However, there is a significant discrepancy among the severity of symptoms, the lack of hemodynamic evidence of myocardial ischemia and the relatively benign long-term prognosis. The vascular endothelium has numerous important functions, including the regulation of vascular tone, blood flow and permeability, secreting both vasorelaxing and vasoconstricting factors. It has been found that both endothelium and non-endothelium-mediated coronary blood flow are impaired in patients with cardiac syndrome X. Interestingly, it has been shown that impaired nitric oxide-dependent vasodilation could increase coronary microvessel tone and produce spasm. It has also been reported that circulating endothelin-1 levels are elevated with a direct relationship between endothelin-1 levels and impaired coronary flow reserve in these patients. In addition, patients with high endothelin-1 levels showed a time onset of chest pain during exercise significantly lower compared to patients with low endothelin-1 concentrations. Moreover, the nitric oxide/endothelin-1 ratio was found decreased in patients with cardiac syndrome X and endothelin-1 levels were also positively correlated with fasting asymmetric dimethylarginine levels. All in all, these data suggest a role of endothelial dysfunction as a cause of regional myocardial and peripheral blood flow abnormalities. Further studies are necessary to characterize the prevailing mechanisms determining alterations in nitric oxide/endothelin-1 pathway in these patients, in order to find new therapies able to improve both quality of life and prognosis.

Animals↗

PubMed2004

Plasma asymmetric dimethylarginine and coronary and peripheral endothelial dysfunction in hypertensive patients.

BACKGROUND: The attenuation of coronary flow reserve (CFR) and endothelium-mediated vasodilation of the brachial artery (EMV-BA) have been frequently reported in hypertensive patients. The present study investigated the link between CFR and EMV-BA in hypertensive patients. We hypothesized that changes in serum asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, and concomitant insulin resistance may be underlying factors connecting the two pathologic alterations. METHODS: A total of 75 patients (30 men and 45 women, 61.5 +/- 10.1 years of age) with essential hypertension and without coronary artery disease and diabetes mellitus were included in the study. Measurements of CFR were made using adenosine-triphosphate stress transthoracic Doppler echocardiography, and forearm EMV-BA was measured by venous occlusion strain gauge plethysmography. A plasma ADMA assay and a 75-g oral glucose tolerance test were also performed. RESULTS: Average CFR and EMV-BA values were 2.54 +/- 0.63 and 86.0 +/- 54.7%, respectively. A significant correlation was found between CFR and EMV-BA (r = 0.493, P <.001). Both CFR and EMV-BA were also significantly correlated with age and plasma ADMA concentration, but were not correlated with insulin resistance, plasma insulin, or left ventricular mass. Multiple regression analysis revealed that ADMA was the only statistically independent parameter associated with CFR and EMV-BA. CONCLUSIONS: The similar deterioration in endothelial function in coronary and peripheral vascular territories may be mainly due to increased plasma ADMA concentration. Plasma ADMA appears to play a major role in endothelial dysfunction in hypertensive patients, independent of insulin resistance or left ventricular hypertrophy.

Aged↗

PubMed1998

Protective effects of nicaraven, a new hydroxyl radical scavenger, on the endothelial dysfunction after exposure of pig coronary artery to hydroxyl radicals.

Recently, we have reported that a new synthetic compound, 1,2bis(nicotinamido)-propane (nicaraven), improved cardiac function following preservation and reperfusion. In this study, we investigated the efficacy of nicaraven as a radical scavenger by using an in vitro model of oxidative stress, to clarify mechanisms of the protective effect of this new compound on reperfusion injury in rat heart. Ring segments of epicardial right coronary arteries (RCA) of pig were suspended in organ chambers and exposed to hydroxyl radicals (.OH), generated (by two different systems) by 0.28 mM FeSO4/0.28 mM H2O2 and DHF/Fe3+-ADP (2.4 mM, 43 nM, and 1.56 uM, respectively) to the bathing solution for 60 min. Prior exposure of the coronary arteries to .OH significantly produced right-ward shift of the dose-response curves of the bradykinin-induced endothelium-dependent relaxations (an increase in the ED50 value for bradykinin by 4.37 and 1.98 times than control in two different .OH generating systems, respectively), but did not affect the maximum relaxation responses. The presence of nicaraven (10(-4) and 10(-5) M) in the .OH generating system, shifted the dose-response curves to bradykinin to the control level, suggesting a significant hydroxyl radical scavenging effect of the drug. These results indicate that nicaraven, a new hydroxyl radical scavenger, exhibits a protective effect on hydroxyl radical-induced endothelial dysfunctions of pig coronary artery.

Animals↗

PubMed2002

Serum basic fibroblast growth factor levels in exercise-induced myocardial ischemia more likely a marker of endothelial dysfunction than a marker of ischemia?

Increased levels and activity of fibroblast growth factor (FGF) have been documented in a variety of diseases, including ischemia. Both acute coronary syndromes and exercise are situations that stimulate FGF release. Since experimental studies have demonstrated that FGFs are involved in myocardial preconditioning, it has been suggested that cardiac and circulating FGFs may play a cardioprotective role in ischemic diseases. However, the profile of basic FGF (bFGF) release during transient myocardial ischemia remains uncertain. We sought to determine whether circulating bFGF might be changed in patients with demonstrated coronary artery disease and evidence of ischemia in exercise scintigraphy (Isch +; n = 21). Serum from 22 age-matched patients with no coronary artery disease and no isotopic ischemia (Isch-) were used as controls. Three blood samples were obtained to determine bFGF at different times: baseline (bFGF-A); maximal exercise (bFGF-B), and isotopic redistribution (bFGF-C). An enzyme-linked immunoassay specific for bFGF was used (limit of detection, 1.0 pg/ml). Circulating bFGF was increased at maximal exercise in both Isch + and control patients. However, serum levels of bFGF were elevated up to more than two-fold in Isch-patients compared to Isch+ patients (8.67 +/- 2.10 pg/ml in Isch+ vs 17.83 +/- 2.97 pg/ml in Isch- patients; p<0.01). According to previous data, these findings suggest that bFGF serum levels could be considered more likely a marker of endothelial dysfunction occurring in patients with coronary artery disease, rather than a marker of acute ischemia. This situation could be different in the clinical setting of chronic myocardial ischemia.

Biomarkers↗

PubMed2004

Endothelial dysfunction in aortic rings and mesenteric beds isolated from deoxycorticosterone acetate hypertensive rats: possible involvement of protein kinase C.

The main objectives of this study were to investigate the effects of deoxycorticosterone acetate (DOCA)-induced hypertension on the aortic and mesenteric vascular responses to vasodilator and vasoconstrictor agents and also to elucidate whether protein kinase C (PKC) was involved in these responses, by using chelerythrine and calphostin C, the inhibitors of protein kinase C. Hypertension was induced in male Sprague-Dawley rats (200-250 g) by DOCA-salt injection [20 mg/kg, twice weekly for 5 weeks, subcutaneously (s.c.)] and NaCl (1%) was added to their drinking water. Control rats received a saline injection (0.5 ml/kg, twice weekly for 5 weeks, s.c.), then the animals were anaesthetised [thiopental, 30 mg/kg, intraperitoneally (i.p.)] and the arterial blood pressure was measured. Mean arterial blood pressure in control and hypertensive rats were 98+/-7.5 and 163+/-3.5 mmHg, respectively (P<0.0001). In the in vitro studies, rings of descending aorta and mesenteric beds were precontracted with phenylephrine and then concentration-response curves to acetylcholine and sodium nitroprusside were constructed. In the tissue removed from hypertensive rats, the responses to acetylcholine, but not to sodium nitroprusside, were significantly reduced. However, addition of chelerythrine (10 microM) or calphostin C (100 nM) to the organ bath significantly restored these impaired responses. Our data suggest that protein kinase C plays a crucial role in the endothelial dysfunction induced by hypertension.

Acetylcholine↗

PubMed2003

Glomerular endothelial dysfunction and hemodynamic maladjustment in vesicoureteric reflux.

A structural defect of the non-vascular component of a nephron namely vesicoureteric reflex (VUR) can induce injury to the vascular component, which is reflected by the alteration in intrarenal hemodynamics. A mild alteration in intrarenal hemodynamics was observed in grades I-II VUR which revealed (a) mild reductions in renal plasma flow (RPF) 543 +/- 104 mL/min/1.73 m2; in peritubular capillary flow (PTCF) 438 +/- 103mL/min/1.73 m2; in glomerular filtration rate (GFR) 105 +/- 19 mL/min/1.73 m2 and in ultrafiltration coefficient (KFG) 0.04 +/- 0.01 mL/s/mmHg; (b) normal values of filtration fraction (FF) 0.2 +/- 0.04, of intraglomerular hydrostatic pressure (PG) 50 +/- 0.3 mmHg, and of afferent arteriolar resistance (RA) 2261 +/- 718 dyne s cm(-5); and (c) a slight elevation of efferent arteriolar resistance (RE) 3914 +/- 962 dyne s cm(-5). In contrast, a moderately severe alteration in intrarenal hemodynamics was observed in severe VUR (grades III up) which revealed greater reductions in RPF 267 +/- 114 mL/min/1.73 m2, in PTCF 195 +/- 90 mL/min/1.73 m2, in GFR 72 +/- 34 mL/min/1.73 m2 and in KFG 0.03 +/- 0.01 mL/s/mmHg; and elevation of PG 53 +/- 2 mmHg, of filtration fraction 0.27 +/- 0.07, of RA 4557 +/- 2340 dyne s cm(-5) and of RE 9417 +/- 4163 dyne s cm(-5). Such an alteration in intrarenal hemodynamics observed in severe VUR induces both intraglomerular hypertension (elevated PG) and an exaggeratedly reduced PTCF. This intrarenal hemodynamic defect is due to the glomerular endothelial dysfunction and its hemodynamic maladjustment. In accordance with the preceding information, treatment to correct the hemodynamic maladjustment is likely to improve renal function and prevent renal disease progression.

Capillaries↗

PubMed2000

Endothelial dysfunction in patients with heart failure: relationship to disease severity.

BACKGROUND: Heart failure is associated with abnormal endothelium-dependent vasodilation. However, the relationship of this abnormality to heart failure severity has not been well defined. METHODS AND RESULTS: We used strain-gauge plethysmography to assess forearm blood flow (FBF) responses to endothelium-dependent, endothelium-independent, and reactive hyperemic stimuli in normal subjects (n = 29) and in patients with mild (n = 26) and severe (n = 41) heart failure. FBF responses to intra-arterial methacholine (0.3, 1.5, 3.0 microg/min) were significantly (P < .005) and similarly reduced in patients with mild (2.8 +/- 0.4, 5.9 +/- 0.7, and 7.7 +/- 1.1 mL/min/dL) and severe (2.7 +/- 0.4, 5.4 +/- 0.7, and 6.9 +/- 0.9) heart failure compared with normal subjects (4.5 +/- 0.4, 9.4 +/- 1.0, and 12.0 +/- 1.1). FBF responses to nitroprusside (1, 5, 10 microg/min) were significantly reduced in mild (2.4 +/- 0.3, 6.7 +/- 1.1, and 11.9 +/- 2.0, P < .05) and severe (1.9 +/- 0.2, 5.1 +/- 0.5, and 7.3 +/- 0.9, P < .001) heart failure groups compared with normal subjects (3.8 +/- 0.5, 10.8 +/- 1.2, and 14.9 +/- 1.2). However, FBF responses were reduced to a greater extent (P < .001) in mild heart failure compared with severe heart failure. Peak reactive hyperemia was significantly impaired only in severe heart failure. There was no correlation between methacholine responses and ejection fraction, maximum oxygen consumption, wedge pressure, or serum norepinephrine. CONCLUSION: Impaired endothelium-dependent vasodilation is present and near maximum in mild heart failure. Endothelial dysfunction may be an early finding in human heart failure.

Blood Pressure↗

PubMed1996

Variable coronary vasomotor responses to acetylcholine in patients with normal coronary arteriograms: evidence for localised endothelial dysfunction.

OBJECTIVE: The vasomotor responses of the epicardial coronary arteries to acetylcholine were examined in patients with normal coronary arteries and chest pain. DESIGN: Quantitative angiography was used to measure minimum lumen diameter of proximal and distal coronary artery segments at baseline, during intracoronary infusion of acetylcholine (10(-7) - 10(-3) mol/l), and following an intracoronary bolus (2 mg) of isosorbide dinitrate. PATIENTS: Coronary arteriograms were obtained in 15 patients (mean (SEM) age 48 (10) years) with normal coronary arteries and chest pain. MAIN RESULTS: In response to the low concentrations of acetylcholine (10(-7) - 10(-6) mol/1) 20 (61%) distal and 11 (41%) proximal segments showed dilatation (group 1), whereas 13 (39%) distal segments and 14 (52%) proximal segments showed constriction (group 2) (P < 0.05 v group 1). In group 1, the maximum dilatation induced by acetylcholine in the proximal and distal segments was 7.83 (1.19)% and 11.6 (2.2)% respectively. In group 2, the maximum constriction at higher concentration was 16.55 (3.3)% and 33.11 (11.63)% in the proximal and distal segments respectively. The two different patterns of the vasomotor response coexisted in eight (53%) of the 15 patients. Intracoronary isosorbide dinitrate caused a greater increase in the coronary luminal diameter of distal segments than in proximal segments in group 1 (25.63 (5.16)% v 12.43 (3.48)%, P < 0.01) but not in group 2 (12.65 (2.53)% v 10.82 (3.33)%. CONCLUSIONS: Constriction and dilatation may occur in proximal and distal coronary artery segments, suggesting local areas of endothelial dysfunction, in response to acetylcholine in patients with chest pain and angiographically normal coronary arteries.

Acetylcholine↗

PubMed2001

Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis.

BACKGROUND: The aim of the study was to establish the influence of proximal coronary artery atheroma and smoking habit on the stimulated release of tissue plasminogen activator (tPA) from the heart. METHODS AND RESULTS: After diagnostic coronary angiography in 25 patients, the left anterior descending coronary artery (LAD) was instrumented, and the proximal LAD plaque volume was determined by use of intravascular ultrasound (IVUS). Blood flow and fibrinolytic responses to selective LAD infusion of saline, substance P (10 to 40 pmol/min; endothelium-dependent), and sodium nitroprusside (5 to 20 microgram/min; endothelium-independent) were measured by intracoronary IVUS and Doppler, combined with arterial and coronary sinus blood sampling. Mean plaque burden was 5.5+/-0.8 mm(3)/mm vessel (range 0.6 to 13.7 mm(3)/mm vessel). LAD blood flow increased with both substance P and sodium nitroprusside (P<0.001), although coronary sinus plasma tPA antigen and activity concentrations increased only during substance P infusion (P<0.006 for both). There was a strong inverse correlation between the LAD plaque burden and release of active tPA (r=-0.61, P=0.003). Cigarette smoking was associated with impaired coronary release of active tPA (current smokers, 31+/-23 IU/min; ex-smokers, 50+/-33 IU/min; nonsmokers 202+/-73 IU/min; P<0.05). CONCLUSIONS: We found that both the coronary atheromatous plaque burden and smoking habit are associated with a reduced acute local fibrinolytic capacity of the heart. These important findings provide evidence of a direct link between endogenous fibrinolysis, endothelial dysfunction, and atherothrombosis in the coronary circulation and may explain the greater efficacy of thrombolytic therapy for myocardial infarction in cigarette smokers.

Area Under Curve↗

PubMed1999

Effects of the superoxide dismutase-mimic compound TEMPOL on oxidant stress-mediated endothelial dysfunction.

The aim of this study was to investigate the effects of oxidant stress on endothelium-dependent and endothelium-independent arterial relaxation. For this, oxidant stress was generated by preincubation of rat aortic rings (RARs) in either 25 mM glucose (mimicking hyperglycemic stress) or 0.5 mM pyrogallol (a superoxide generator) and the effects of the superoxide dismutase (SOD)-mimetic compound 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy free radical (TEMPOL) on the vasorelaxant and cGMP-producing effects of acetylcholine (ACh) and glyceryl trinitrate (GTN) in control RARs and RARs exposed to oxidant stress were examined. Pyrogallol, and to a lesser extent high glucose concentration, enhanced the contractile response of RARs to phenylephrine and markedly inhibited the vasorelaxant response to ACh. Although they existed, the inhibitory effects of high glucose and pyrogallol on the vasorelaxant response to GTN were less profound, especially with pyrogallol. Moreover, both pyrogallol and high glucose concentration inhibited the basal and the ACh-induced vascular cyclic guanosine monophosphate (cGMP) production. Treatment with TEMPOL (1-5 mM) slightly increased the ACh and GTN-induced cGMP levels in control RARs but had a significant effect in high glucose and pyrogallol-pretreated RARs. Additionally, concomitant treatment of RARs with TEMPOL (5 mM) abolished the difference in the relaxation response between control RARs and RARs exposed to either pyrogallol or high glucose concentration. These results further support the theory that reactive oxygen species (ROS), especially superoxide, play a key role in mediation of endothelial dysfunction accompanying diabetes, probably through their effects on the ability of the endothelium to synthesize, release or respond to endogenous nitric oxide (NO) or NO donated by nitrovasodilators.

Acetylcholine↗

PubMed1994

Endothelial dysfunction in cerebral vessels following carotid artery infusion of phorbol ester in rabbits: the role of polymorphonuclear leukocytes.

The effect of 4 beta-phorbol-12 beta-myristate-13 alpha-acetate (PMA) on endothelium-dependent and endothelium-independent vasoconstriction and vasodilation was studied in isolated segments of rabbit middle cerebral artery (MCA). Concentration-dependent responses of the left and right MCA to the constrictors KCl, noradrenaline, uridine 5'-triphosphate, serotonin, and histamine, as well as to the dilators acetylcholine, bradykinin, sodium nitroprusside, and calcium ionophore (A23187), were compared in control animals and after PMA injection into the left common carotid artery. In the control animals there was no significant difference in the responses of the left and right MCA to either the constrictors or the dilators studied. After PMA injection the endothelium-dependent relaxation in response to acetylcholine, bradykinin, and A23187 was reduced in the left MCA (PMA-injected side), whereas the effect of the endothelium-independent dilator sodium nitroprusside remained unchanged. Simultaneously greater contractile responses of the left MCA to serotonin and histamine were obtained. Neither infusion of L-arginine in vivo before the PMA injection nor incubation of the isolated MCA segments with L-arginine affected this difference in MCA reactivity. Platelet depletion did not change the PMA-induced reduction in the endothelium-dependent relaxation, whereas after leukocyte depletion this reduction practically disappeared. These results suggest that the PMA-induced brain microembolia causes acute endothelial dysfunction, which is possibly mediated by intravascular activation of leukocytes and is independent of nitric oxide synthesis from L-arginine. This phenomenon might play an important role in cerebral angiospastic disorders after intravascular activation of leukocytes in cerebral ischemia and reperfusion.

Animals↗

PubMed1997

Endothelial dysfunction is associated with cholesterol levels in the high normal range in humans.

BACKGROUND: The purpose of this study was to test the hypothesis that cholesterol levels in the high normal range are associated with impaired endothelium-dependent vasodilation. METHODS AND RESULTS: We studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (MCh) or the endothelium-independent vasodilator sodium nitroprusside (SNP) in normal volunteers exhibiting a wide range of total cholesterol levels within the normal range (<75th percentile). LBF increased in a dose-dependent fashion in response to the femoral artery infusions of MCh and SNP (P<.001). LBF responses to MCh were significantly blunted (P<.001) in subjects with high normal cholesterol (195+/-6 mg/dL, n=13) compared with subjects with low normal cholesterol (146+/-5 mg/dL, n=20). Maximal endothelium-dependent vasodilation in the high normal group was decreased by nearly 50% compared with the low normal group (146+/-13% versus 268+/-34%, P<.01). There was a negative correlation between total cholesterol levels and maximal endothelium-dependent vasodilation (total cholesterol, r=-.41, P<.02; LDL cholesterol, r=-.42, P<.02). On the other hand, LBF responses to the endothelium-independent vasodilator SNP did not differ between groups. CONCLUSIONS: These data suggest that an inverse and continuous relationship exists between the prevailing cholesterol level and endothelium-dependent vasodilation. Moreover, cholesterol levels even in the normal range may be associated with endothelial dysfunction, thus potentially contributing to the increased risk of macrovascular disease conferred by cholesterol elevations.

Adult↗

PubMed1997

Role of endothelial dysfunction in coronary artery disease and implications for therapy.

Atherosclerosis is a complex process that is characterized by the accumulation of modified low-density lipoprotein (LDL), local inflammatory and immune responses, and reduced nitric oxide bioavailability within the arterial wall. These cellular changes lead to endothelial vasomotor dysfunction, plaque instability, and the development of clinical events such as stable angina and the acute coronary syndromes. The vascular endothelium plays a critical role in modulating both the inflammatory response and vasomotor abnormalities that occur in those with coronary artery disease or risk factors for disease. In these conditions, endothelial cells are activated by cytokines to express cellular adhesion molecules that facilitate the adhesion of leukocytes to the endothelium, and their migration into the subintimal space. Cytokines stimulate inflammatory and smooth muscle cells in the intima to produce degradative enzymes, including metalloproteinases that can weaken the fibrous cap of atherosclerotic lesions and make them vulnerable to rupture. Endothelial cells also regulate vascular tone by the synthesis of nitric oxide. Atherosclerosis and other conventional risk factors for coronary artery disease are associated with endothelial vasodilator dysfunction in the coronary epicardial and resistance vessels, which likely contributes to myocardial ischemia. Several studies have demonstrated that lowering serum total and LDL cholesterol reverses endothelial vasomotor dysfunction, reduces myocardial ischemia, and lowers the risk of the acute coronary syndromes or need for revascularization. Improving endothelial function, for example, by lowering blood cholesterol should now be regarded as a goal of therapy in the treatment of coronary artery disease.

Anticholesteremic Agents↗

PubMed2006

Endothelial dysfunction and decreased vascular responsiveness in the anterior cruciate ligament-deficient model of osteoarthritis.

Chronic inflammation associated with osteoarthritis (OA) may alter normal vascular responses and contribute to joint degradation. Vascular responses to vasoactive mediators were evaluated in the medial collateral ligament (MCL) of the anterior cruciate ligament (ACL)-deficient knee. Chronic joint instability and progressive OA were induced in rabbit knees by surgical transection of the ACL. Under halothane anesthesia, laser speckle perfusion imaging (LSPI) was used to measure MCL blood flow in unoperated control (n = 12) and 6-wk ACL-transected knees (n = 12). ACh, bradykinin, histamine, substance P (SP), and prostaglandin E(2) (PGE(2)) were applied to the MCL vasculature in topical boluses of 100 microl (dose range 10(-14) to 10(-8) mol). In normal joints, ACh, bradykinin, histamine, and PGE(2) evoked a dilatory response. Substance P caused a biphasic response that was dilatory from 10(-14) to 10(-11) mol and constricting at higher doses. In ACL-deficient knees, ACh, bradykinin, histamine, and SP decreased perfusion, whereas PGE(2) had a biphasic response that decreased perfusion at 10(-14) to 10(-11) mol and was dilatory at higher concentrations. Sodium nitroprusside increased perfusion in resting and phenylephrine-precontracted vessels with no significant differences between ACL-transected and control knees. Femoral artery occlusion and release increased perfusion by 74.3 +/- 11.1% in control knees but only by 25.8 +/- 4.4% in ACL-deficient knees. The altered responsiveness of the MCL vasculature to these inflammatory mediators may indicate endothelial dysfunction in the MCL, which may contribute to the progression and severity of OA and to the adaptation of the joint in an altered mechanical environment.

Animals↗

PubMed1998

Effects of enalapril and amlodipine on small-artery structure and composition, and on endothelial dysfunction in spontaneously hypertensive rats.

OBJECTIVES: To determine whether an angiotensin converting enzyme inhibitor, enalapril, and a dihydropyridine calcium channel antagonist, amlodipine, regress the altered structure, media composition, and vascular relaxation of small arteries of spontaneously hypertensive rats. METHODS: Spontaneously hypertensive rats aged 10 weeks were treated for 12 weeks with 10 mg/kg per day enalapril or 10-20 mg/kg per day amlodipine and compared with age-matched untreated spontaneously hypertensive rats. Small coronary, renal, mesenteric, and femoral arteries (lumen diameter 200-250 microm) were studied isometrically on a wire myograph, and mesenteric arteries isobarically as pressurized vessels. The composition of the vascular media of the latter was studied by electron microscopy. RESULTS: Blood pressure, and cardiac and aortic hypertrophy were reduced in treated spontaneously hypertensive rats. Treatment significantly decreased media thickness and media: lumen ratio of coronary, renal, mesenteric, and femoral small arteries studied isometrically and of pressurized mesenteric small arteries. Media cross-sectional area was smaller for coronary arteries studied isometrically and mesenteric arteries studied isobarically. Electron microscopic analysis revealed an increase in collagen: elastin ratio in the media of spontaneously hypertensive rat vessels, and a decrease under treatment to levels found in Wistar-Kyoto rats, with no significant changes detected in smooth muscle cells. The amplitude of contractions induced by acetylcholine on wire-myograph-mounted mesenteric arteries from spontaneously hypertensive rats were decreased by treatment, and relaxation of pressurized arteries induced by acetylcholine was normalized. CONCLUSION: Treatment of spontaneously hypertensive rats with enalapril or with amlodipine resulted in regression of cardiovascular hypertrophy and amelioration of endothelial dysfunction. Morphometric results obtained using an isometric myograph and a pressurized preparation to study rat small arteries were closely correlated. Regression of structural remodeling in small arteries was outward hypotrophic, with a reduction in the collagen: elastin ratio, and without net change in the absolute and relative volumes of smooth muscle and number of smooth muscle layers.

Amlodipine↗

PubMed2003

Effects of sesamin on aortic oxidative stress and endothelial dysfunction in deoxycorticosterone acetate-salt hypertensive rats.

In the present study, we evaluated the relationship between the antihypertensive effect of sesamin, a lignan from sesame oil, and its antioxidative activity in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. After a 5-week treatment period, systolic blood pressure was significantly elevated in normal diet-fed DOCA-salt animals compared with cases in sham-operated animals. Sesamin feeding, tempol (a superoxide dismutase mimetic) treatment or antihypertensive drugs combination (triple therapy; reserpine, hydralazine, hydrochlorothiazide) significantly suppressed the development of DOCA-salt-induced hypertension. Compared with sham-operated rats, the normal diet-fed DOCA-salt rats revealed marked increases in aortic superoxide (O(2)(-)) production. These increases in O(2)(-) production were significantly suppressed by sesamin feeding or tempol treatment, but not by triple therapy. Acetylcholine (Ach)-induced endothelium-dependent relaxation was markedly decreased in normal diet-fed DOCA-salt rats, compared with cases in sham-operated rats. Sesamin feeding and triple therapy significantly improved the DOCA-salt-induced impairment of endothelium-dependent relaxation. However, tempol treatment had no effect on the impaired vasodilator responses induced by DOCA-salt treatment. In DOCA-salt rats with or without sesamin feeding, systolic blood pressure significantly correlated with both aortic O(2)(-) production and endothelium-dependent vascular relaxation. These findings suggest that sesamin feeding inhibits the enhancement of aortic O(2)(-) production in DOCA-salt hypertensive rats, and this effect may contribute to the antihypertensive effect of sesamin. Sesamin feeding-induced improvement of endothelial dysfunction seems to result from the above antioxidative and antihypertensive effects.

Acetylcholine↗