ABSTRACT
Atherosclerotic plaques develop at particular sites in the arterial tree, and this regional localisation depends largely on haemodynamic parameters (such as wall shear stress; WSS) as described in the literature. Plaque rupture can result in heart attack or stroke and hence understanding the development and vulnerability of atherosclerotic plaques is critically important. The purpose of this study is to characterise the haemodynamics of blood flow in the mouse aortic arch using numerical modelling. The geometries are digitalised from synchrotron imaging and realistic pulsatile blood flow is considered under rigid wall assumptions. Two cases are considered; arteries with and without plaque. Mice that are fed under fat diet present plaques in the aortic arch whose size is dependent on the number of weeks under the diet. The plaque distribution in the region is however relatively constant through the different samples. This result underlines the influence of the geometry and consequently of the wall shear stresses for plaque formation with plaques growing in region of relative low shear stresses. A discussion of the flow field in real geometry in the presence and absence of plaques is conducted. The presence of plaques was shown to alter the blood flow and hence WSS distribution, with regions of localised high WSS, mainly on the wall of the brachiocephalic artery where luminal narrowing is most pronounced. In addition, arch plaques are shown to induce recirculation in the blood flow, a phenomenon with potential influence on the progression of the plaques. The oscillatory shear index and the relative residence time have been calculated on the geometry with plaques to show the presence of this recirculation in the arch, an approach that may be useful for future studies on plaque progression.
ABSTRACT
BACKGROUND AND PURPOSE: Nitrate tolerance, the loss of vascular responsiveness with continued use of nitrates, remains incompletely understood and is a limitation of these therapeutic agents. Vascular superoxide, generated by uncoupled endothelial NOS (eNOS), may play a role. As arginase competes with eNOS for L-arginine and may exacerbate the production of reactive oxygen species (ROS), we hypothesized that arginase inhibition might reduce nitrate tolerance. EXPERIMENTAL APPROACH: Vasodilator responses were measured in aorta from C57Bl/6 and arginase II knockout (argII -/-) mice using myography. Uncoupling of eNOS, determined as eNOS monomer : dimer ratio, was assessed using low-temperature SDS-PAGE and ROS levels were measured using L-012 and lucigenin-enhanced chemiluminescence. KEY RESULTS: Repeated application of glyceryl trinitrate (GTN) on aorta isolated from C57Bl/6 mice produced a 32-fold rightward shift of the concentration-response curve. However this rightward shift (or resultant tolerance) was not observed in the presence of the arginase inhibitor (s)-(2-boronethyl)-L-cysteine HCl (BEC; 100 µM) nor in aorta isolated from argII -/- mice. Similar findings were obtained after inducing nitrate tolerance in vivo. Repeated administration of GTN in human umbilical vein endothelial cells induced uncoupling of eNOS from its dimeric state and increased ROS levels, which were reduced with arginase inhibition and exogenous L-arginine. Aortae from GTN tolerant C57Bl/6 mice exhibited increased arginase activity and ROS production, whereas vessels from argII -/- mice did not. CONCLUSION AND IMPLICATIONS: Arginase II removal prevents nitrate tolerance. This may be due to decreased uncoupling of eNOS and consequent ROS production.
Subject(s)
Arginase/antagonists & inhibitors , Drug Tolerance , Nitroglycerin/pharmacology , Vasodilator Agents/pharmacology , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/physiology , Arginase/genetics , Arginase/metabolism , Arginine/metabolism , Boronic Acids/pharmacology , Drug Tolerance/physiology , Human Umbilical Vein Endothelial Cells , Humans , In Vitro Techniques , Mice , Mice, Inbred C57BL , Mice, Knockout , Nitric Oxide Synthase Type III/metabolism , Reactive Oxygen Species/metabolismABSTRACT
It is well recognised that increased levels of high density lipoprotein (HDL) protect against atherosclerosis and correlate with improved prognosis for vascular disease associated events. While many of the atheroprotective effects of HDL are ascribed to the ability to remove cholesterol from the vasculature through the reverse cholesterol transport system, recent work has shown that HDL may be atheroprotective through its other functions, such as regulation of endothelial adhesion molecule expression, stimulation of endothelial nitric oxide synthase and inhibition of the damaging effects of oxidised low density lipoproteins. Recently, HDL has also been described to interact with circulating cells inhibiting both leukocyte and platelet activation, therefore having further systemic anti-inflammatory functions. This review summarises the studies and models used to examine the anti-inflammatory effects of HDL and details data describing the ability to inhibit leukocyte activation, contributing to the hypothesis that raised HDL is beneficial in the context of inflammation in atherosclerosis. Further, HDL modification in disease and current therapeutic strategies such as reconstituted HDL particles and apoA I mimetic peptides is discussed to provide insights to the potential applicability of raising HDL to regress cardiovascular disease.
Subject(s)
Inflammation/metabolism , Lipoproteins, HDL/metabolism , Animals , Humans , Mice , RatsABSTRACT
BACKGROUND AND PURPOSE: Arginase and nitric oxide (NO) synthase share the common substrate L-arginine, and arginase inhibition is proposed to increase NO production by increasing intracellular levels of L-arginine. Many different inhibitors are used, and here we have examined the effects of these inhibitors on vascular tissue. EXPERIMENTAL APPROACH: Each arginase inhibitor was assessed by its effects on isolated rings of aorta and mesenteric arteries from rats by: (i) their ability to preserve the tolerance to repeated applications of the endothelium-dependent agonist acetylcholine (ACh); and (ii) their direct vasorelaxant effect. KEY RESULTS: In both vessel types, tolerance (defined as a reduced response upon second application) to ACh was reversed with addition of L-arginine, (S)-(2-boronethyl)-L-cysteine HCl (BEC) or N(G)-Hydroxy-L-arginine (L-NOHA). On the other hand, N(omega)-hydroxy-nor-L-arginine (nor-NOHA) significantly augmented the response to ACh, an effect that was partially reversed with L-arginine. No effect on tolerance to ACh was observed with L-valine, nor-valine or D,L, alpha-difluoromethylornithine (DFMO). BEC, L-NOHA and nor-NOHA elicited endothelium-independent vasorelaxation in both endothelium intact and denuded aorta while L-valine, DFMO and nor-valine did not. CONCLUSIONS AND IMPLICATIONS: BEC and L-NOHA, but not nor-NOHA, L-valine, DFMO or nor-valine, significantly reversed tolerance to ACh possibly conserving L-arginine levels and therefore increasing NO bioavailability. However, both BEC and L-NOHA caused endothelium-independent vasorelaxation in rat aorta, suggesting that these inhibitors have a role beyond arginase inhibition alone. Our data thus questions the interpretation of many studies using these antagonists as specific arginase inhibitors in the vasculature, without verification with other methods.
Subject(s)
Aorta, Thoracic/drug effects , Arginase/antagonists & inhibitors , Endothelium, Vascular/drug effects , Mesenteric Arteries/drug effects , Nitric Oxide/physiology , Vasodilator Agents/pharmacology , Acetylcholine/pharmacology , Animals , Aorta, Thoracic/physiology , Arginine/analogs & derivatives , Arginine/pharmacology , Boronic Acids/pharmacology , Eflornithine/pharmacology , Endothelium, Vascular/physiology , In Vitro Techniques , Male , Mesenteric Arteries/physiology , Nitric Oxide Synthase/metabolism , Rats , Rats, Sprague-Dawley , Tachyphylaxis , Valine/pharmacologyABSTRACT
BACKGROUND AND PURPOSE: The association of polymorphisms in the nitric oxide synthase 3 (NOS3) gene (T-786C, variable number tandem repeats 4A/B/C, and G894T) and in the methylenetetrahydrofolate reductase (MTHFR) gene (C677T) with acute ischemic stroke have been reported. METHODS: First-time onset acute ischemic stroke patients (n = 120) and controls (n = 207) with no past history of stroke were compared. Allele specific gene amplification and restriction fragment length polymorphism (RFLP) analysis were used to determine the genotype and allelic frequencies in both groups. Plasma homocysteine (Hcy) and nitrite levels were measured. RESULTS: No significant association of NOS3 polymorphisms with ischemic stroke was noted. The TT genotype of the MTHFR C677T polymorphism was significantly associated with ischemic stroke (P = 0.004). Elevated plasma Hcy levels were also significantly associated with ischemic stroke (P = 0.001). CONCLUSIONS: The TT genotype of C677T polymorphism in the MTHFR gene contributes to genetic susceptibility of acute ischemic stroke in a Singapore population.
Subject(s)
Brain Ischemia/genetics , Genetic Predisposition to Disease/genetics , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Polymorphism, Genetic/genetics , Stroke/genetics , Acute Disease , Asian People , Brain Ischemia/enzymology , Brain Ischemia/physiopathology , DNA Mutational Analysis , Female , Gene Frequency/genetics , Genetic Markers/genetics , Genetic Testing , Genotype , Homocysteine/blood , Humans , Hyperhomocysteinemia/blood , Hyperhomocysteinemia/complications , Hyperhomocysteinemia/genetics , Male , Middle Aged , Nitric Oxide Synthase Type III/genetics , Nitrites/blood , Singapore , Stroke/enzymology , Stroke/physiopathologyABSTRACT
Adhesion molecules have been implicated in the development and progression of cardiovascular disease, which is highly prevalent in people with diabetes. Adhesion molecules can mediate adhesion of leukocytes to the endothelium. Furthermore, P-selectin expressed on platelets is able to mediate the adhesion of leukocytes to platelets. In this study, we examine the in-vivo and in-vitro effects of rosiglitazone with particular emphasis on three important adhesion molecules (VCAM-1, ICAM-1 and P-selectin). In the aorta of STZ-diabetic apolipoprotein E-deficient (apoE KO) mice, rosiglitazone significantly reduced both total and arch plaque area. The mechanism for this appeared to be reduced macrophage infiltration into the atherosclerotic plaque which was also associated with reduced mRNA levels for VCAM-1, ICAM-1, MCP-1 and P-selectin in the aorta. In-vitro studies revealed reduced cell adhesion of monocytic cells (THP-1) to fibrinogen and endothelial cells (HUVEC) after incubation with rosiglitazone. Furthermore, the reduction in leukocyte adhesion also correlated with significant reductions in mRNA levels for VCAM-1, ICAM-1 and P-selectin indicating that reduced macrophage infiltration in atherosclerotic plaques may occur as a result of a direct effect of rosiglitazone on adhesion molecules in both monocytes and endothelial cells. Thus, we have shown that rosiglitazone appears to have direct anti-atherosclerotic effects in an animal model of diabetes-associated atherosclerosis which are at least partly due to effects on VCAM-1, ICAM-1, MCP-1 and P-selectin expression which leads to decreased leukocyte adhesion and macrophage infiltration.
Subject(s)
Atherosclerosis/drug therapy , Cell Adhesion Molecules/genetics , Diabetes Mellitus, Experimental/drug therapy , Diabetic Angiopathies/drug therapy , Hypoglycemic Agents/pharmacology , Thiazolidinediones/pharmacology , Animals , Aortic Diseases/drug therapy , Aortic Diseases/immunology , Apolipoproteins E/genetics , Atherosclerosis/immunology , Cells, Cultured , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Diabetes Mellitus, Experimental/immunology , Diabetic Angiopathies/immunology , Disease Models, Animal , Down-Regulation , Endothelial Cells/drug effects , Endothelial Cells/immunology , Humans , Intercellular Adhesion Molecule-1/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , P-Selectin/genetics , P-Selectin/metabolism , RNA, Messenger/metabolism , Rosiglitazone , Umbilical Veins/cytology , Vascular Cell Adhesion Molecule-1/genetics , Vasculitis/drug therapy , Vasculitis/immunologyABSTRACT
The amino acid l-arginine participates in a variety of key biochemical and physiological activities, including its well-recognized role as the key substrate for nitric oxide (NO) biosynthesis. The current review describes the cellular influences on arginine metabolism with particular focus on the transport of l-arginine in the endothelium. It details the processes by which intracellular and extracellular levels of l-arginine may influence nitric oxide production and further documents the imbalance that is evident in various cardiovascular disease states. In man, impairment of l-arginine transport has been observed in hypertension, heart failure, and renal disease, and it may thus be a relevant therapeutic target for rectification of nitric oxide pathogenesis in these conditions.
Subject(s)
Amino Acid Transport Systems, Basic/antagonists & inhibitors , Arginine/metabolism , Cardiovascular Diseases/metabolism , Animals , Biological Transport , Cardiovascular Diseases/drug therapy , Humans , Kinetics , Nitric Oxide/biosynthesisABSTRACT
AIMS/HYPOTHESIS: AGE contribute to the pathogenesis of diabetic complications, including dyslipidaemia and atherosclerosis. However, the precise mechanisms remain to be established. In the present study, we examined whether AGE modification of apolipoprotein A-I (apoA-I) affects its functionality, thus altering its cardioprotective profile. MATERIALS AND METHODS: The ability of AGE-modified apoA-I to facilitate cholesterol and phospholipid efflux, stabilise ATP-binding cassette transporter A1 (ABCA1) and inhibit expression of adhesion molecules in human macrophages and monocytes was studied. RESULTS: The ability of AGE-modified apoA-I to promote cholesterol efflux from THP-1 macrophages, isolated human monocytes and from ABCA1-transfected HeLa cells was significantly reduced (>70%) compared with unmodified apoA-I. This effect was reversed by preventing AGE formation with aminoguanidine or reversing AGE modification using the cross-link breaker alagebrium chloride. AGE-modification of HDL also reduced its capacity to promote cholesterol efflux. AGE-apoA-I was also less effective than apoA-I in stabilising ABCA1 in THP-1 cells as well as in inhibiting expression of CD11b in human monocytes. CONCLUSIONS/INTERPRETATION: AGE modification of apoA-I considerably impairs its cardioprotective, antiatherogenic properties, including the ability to promote cholesterol efflux, stabilise ABCA1 and inhibit the expression of adhesion molecules. These findings provide a rationale for targeting AGE in the management of diabetic dyslipidaemia.
Subject(s)
Apolipoprotein A-I/metabolism , Atherosclerosis/metabolism , Glycation End Products, Advanced/metabolism , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , ATP-Binding Cassette Transporters/physiology , Biological Transport/drug effects , Biological Transport/physiology , CD11b Antigen/metabolism , Cell Line , Cells, Cultured , Cholesterol/metabolism , Electrophoresis, Polyacrylamide Gel , Glycosylation/drug effects , Guanidines/pharmacology , HeLa Cells , Humans , Lipid Metabolism/drug effects , Lipoproteins, HDL/metabolism , Phospholipids/metabolism , Ribose/metabolism , Thiazoles/pharmacology , TransfectionABSTRACT
Vascular endothelial cells produce nitric oxide (NO), which contributes to the regulation of blood pressure and regional blood flow. Endothelial nitric oxide synthase (eNOS) gene polymorphisms are associated with coronary artery disease, but their linkage with primary hypertension is controversial. A total of 103 individuals with primary hypertension and 104 normotensive control subjects were studied in Singapore. The specific genotypes for G894T missense variant in exon 7, variable number tandem repeats (VNTR) in intron 4 (eNOS 4A/B/C) and T-786C in the promoter were isolated using allele-specific gene amplification and restriction fragment length polymorphism to examine the association of genotype and allelic frequency in both groups. Logistic regression analysis was also used to detect the association between genotypes and hypertension. Five genotypes of intron 4 VNTR (AA, AB, BB, AC and BC) were observed. Intron 4 B/B genotype was significantly associated with the hypertension group (P = 0.035), but disequilibrium of G894T and T-786C was absent between the two groups (P = 0.419 and P = 0.227), respectively. The overall distribution of allelic frequency differed significantly between the two groups, with four-repeat allele (4A) of intron 4 more frequent in the normotensive group than the hypertensive group (P = 0.019). Logistic regression analysis showed that intron 4 B/B genotype was significantly associated with systolic blood pressure of individuals with body mass index greater than 25 kg/m2 (P = 0.04). In conclusion, the eNOS 4 B/B genotype is a genetic susceptibility factor for primary hypertension in a Singapore population.
Subject(s)
Hypertension/genetics , Nitric Oxide Synthase Type III/genetics , Polymorphism, Genetic , Blood Pressure , Body Mass Index , Diabetes Mellitus/genetics , Dyslipidemias/genetics , Female , Genotype , Humans , Male , Middle Aged , SingaporeABSTRACT
Raised levels of soluble P-selectin (sP-selectin) have been reported in the plasma of patients with vascular diseases; however, the functional importance of this ligand remains unclear. In this study we have examined a potential role for plasma sP-selectin in regulating neutrophil adhesion in patients with peripheral arterial occlusive disease (PAOD). Patients with PAOD had significantly higher levels of sP-selectin (mean+/-SD: 73.3+/-13.0 versus 16.7+/-6.4 ng/mL) and enhanced whole blood leukocyte adhesion to platelets under shear. To examine whether the raised sP-selectin levels can directly influence leukocyte adhesion, isolated neutrophils were incubated with plasma from PAOD patients before and after immunodepletion of sP-selectin. Neutrophil adhesion to fibrinogen increased 2-fold following incubation with PAOD plasma, which was abrogated on sP-selectin immunodepletion. We subsequently demonstrated that recombinant sP-selectin dose-dependently (75 to 250 ng/mL) increased leukocyte adhesion to fibrinogen and platelet monolayers. This increase was PSGL-1 and Src kinase-dependent and correlated with an increase in sP-selectin-mediated Mac-1 activation. sP-selectin-stimulated neutrophil adhesion to platelet monolayers was inversely correlated with shear, such that at low shear (50 s(-1)) a 92.7%+/-15.7 increase in adhesion was observed decreasing to 38.5%+/-11.9 at 150 s(-1) and 10.1%+/-7.4 at 300 s(-1). These studies suggest a potentially important role for sP-selectin in modulating neutrophil adhesion in patients with PAOD, particularly at sites of low shear, where it raises the possibility that raised plasma sP-selectin levels may enhance leukocyte recruitment to vascular injury and promote disease progression.
Subject(s)
Arterial Occlusive Diseases/blood , Cell Adhesion , Leukocytes/physiology , P-Selectin/blood , Peripheral Vascular Diseases/blood , Aged , Female , Fibrinogen/physiology , Humans , Male , Middle Aged , Neutrophils/physiologyABSTRACT
There is increasing evidence that dietary supplementation, such as L-arginine, anti-oxidant vitamins, soy phytoestrogens, flavonoids and omega-3 fatty acids exert vascular protective benefits particularly in terms of restoring endothelial function in cardiovascular disease states. The endothelium has been a major focus over the past 20 years as being a primary site at which dysfunction occurs in association with, and contributing to, vascular pathologies. Such states include mild compromise of the cardiovascular system as observed in smokers, hypercholesterolemics and hypertensives, through to end-point heart failure. This review will focus on the experimental and clinical evidence examining the effect of nutriceuticals on vascular function, in particular endothelium-derived factors, and argues that there is a role for nutriceuticals in the clinical management of the cardiovascular compromised individual.
Subject(s)
Cardiovascular Diseases , Dietary Supplements , Endothelium, Vascular , Hypercholesterolemia/drug therapy , Animals , Antioxidants/administration & dosage , Antioxidants/therapeutic use , Arginine/administration & dosage , Arginine/therapeutic use , Arteriosclerosis/complications , Arteriosclerosis/physiopathology , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiology , Fatty Acids, Omega-3/administration & dosage , Fatty Acids, Omega-3/therapeutic use , Flavonoids/administration & dosage , Flavonoids/therapeutic use , Humans , Isoflavones/administration & dosage , Isoflavones/therapeutic use , Phytoestrogens , Plant Preparations/administration & dosage , Plant Preparations/therapeutic use , Vitamins/administration & dosage , Vitamins/therapeutic useABSTRACT
BACKGROUND: Isoflavones (phytoestrogens) offer potential cardioprotective benefits. We recently reported on the vasodilatory activity of the isoflavone metabolite, dehydroequol, in rat isolated aortic ring preparations. In the current study, we examine the effect of this metabolite on the vascular haemodynamic profile in human forearm resistance arteries. METHODS AND RESULTS: Responses to brachial artery infusion of dehydroequol (0.1, 0.3, 1 and 3 micromol/min) in forearm resistance arteries were obtained in six healthy males. These were done, on two separate occasions, in the absence and presence of endogenous nitric oxide synthase inhibition using NG-monomethyl-L-arginine, with sufficient sodium nitroprusside to maintain vascular tone. Dehydroequol produced a dose-dependent increase in forearm blood flow from 2.44 +/- 0.37 (basal) to 5.25 +/- 1.07 mL/100 mL/min (P < 0.05) at dehydroequol 3 micromol/min. Responses to dehydroequol were significantly dampened with inhibition of endogenous nitric oxide synthase (at 3 micromol/min: % increase in forearm blood flow fell from 114.3 +/- 22.81 to 19.45 +/- 9.19; P < 0.01). CONCLUSION: This is the first report of dehydroequol, a metabolite derived from the isoflavone diadzein, demonstrating potent vasodilatory properties in human resistance arteries via a nitric oxide-dependent mechanism.
Subject(s)
Brachial Artery/drug effects , Isoflavones/administration & dosage , Nitric Oxide/metabolism , Vasodilation/drug effects , Adult , Brachial Artery/physiology , Enzyme Inhibitors/administration & dosage , Forearm/blood supply , Humans , Isoflavones/metabolism , Lipids/blood , Male , Regional Blood Flow/drug effects , Vascular Resistance/drug effects , omega-N-Methylarginine/administration & dosageABSTRACT
BACKGROUND AND AIMS: There is evidence that dampened responses to endogenous vasoconstrictors contribute to the hyperdynamic circulation that is characteristic of advanced cirrhosis. The aim of this study was to determine whether there is an altered vascular responsiveness to the endothelium derived constricting factor endothelin-1 (ET-1) in patients with decompensated chronic liver disease which might contribute to this abnormal circulatory state, and whether normal endothelin responses are restored following liver transplantation. METHODS: Using forearm plethysmography, we studied the vascular response to an intra-arterial ET-1 infusion in six patients with end stage cirrhosis, before and after liver transplantation, compared with six normal control subjects. Responses to the selective endothelin A (ET(A)) receptor subtype antagonist, BQ123, were also examined. RESULTS: The forearm vessels of patients with cirrhosis vasodilated in response to ET-1 infusion while in healthy controls a marked vasoconstriction response was observed (p<0.0001, area under the curve time-blood flow was normal compared with the cirrhosis groups, ANOVA). Prior to commencement of liver transplant surgery, cirrhotic patients were confirmed to have a hyperdynamic circulation with a high cardiac index (4.07 (0.23) l/min/m(2) (normal range 2.8-3.6 l/min/m(2))) and low systemic vascular resistance index (1284 (115) dynxs/cm(5)/m(2) (normal range 1760-2600 dynxs/cm(5)/m(2))). Following transplantation, normal vasoconstrictor responses to ET-1 were restored. Responses to BQ123 were not different in patients with advanced cirrhosis compared with controls. CONCLUSION: In patients with end stage cirrhosis, ET-1 produces vasodilatation at a dose that causes marked vasoconstriction in normal control subjects. This effect is not attributable to impairment of ET(A) receptor responses. Our findings suggest that altered endothelin responses may contribute to the generalised dilatation of the circulation that occurs in patients with advanced liver disease.
Subject(s)
Endothelin-1/pharmacology , Endothelium, Vascular/drug effects , Liver Cirrhosis/metabolism , Liver Cirrhosis/surgery , Liver Transplantation/physiology , Vasodilation , Analysis of Variance , Case-Control Studies , Chronic Disease , Endothelin A Receptor Antagonists , Female , Forearm/blood supply , Humans , Infusions, Intravenous , Male , Middle Aged , Peptides, Cyclic/pharmacology , Plethysmography , Postoperative Period , Vasodilator Agents/pharmacologyABSTRACT
Legume-derived isoflavones such as genistein, diadzein and equol have been associated with a reduction in risk of cardiovascular disease. In the current study, we explore the vascular activity of several isoflavone metabolites namely dihydrodaidzein, cis and trans-tetrahydrodaidzein and dehydroequol for potential cardioprotective properties. Rat isolated aortic rings were used. 17beta-oestradiol, equol, and all four of the metabolites studied significantly antagonized contractile responses to noradrenaline. The direct vasodilatory action of these compounds were examined and in contrast to 17beta-oestradiol, the vasodilatory effect of which was demonstrated to be endothelium independent, the dilatory action of all four compounds could be inhibited by endothelium denudation. Further, the dilatory action of both dihydrodaidzein and cis-tetrahydrodaidzein were inhibited by the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine (NOLA), by the soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and by 40 mM KCl. Dilatory responses to dehydroequol and trans-tetrahydrodaidzein, on the other hand, were inhibited by 40 mM KCL but not by NOLA nor ODQ. Finally, we examined the protective potential of these compounds in inhibiting endothelium damage by oxidized low density lipoprotein (ox-LDL). Trans-tetrahydrodaidzein was at least 10 fold more potent than 17beta-oestradiol in protecting against ox-LDL induced damage. We conclude that the isoflavone metabolites, dihydrodaidzein, cis- and trans-tetrahydrodaidzein and dehydroequol, may potentially represent a novel series of cardioprotective therapeutics.
Subject(s)
Aorta/drug effects , Endothelium, Vascular/drug effects , Isoflavones/pharmacology , Protective Agents/pharmacology , Animals , Aorta/physiology , Endothelium, Vascular/physiology , Estradiol/pharmacology , In Vitro Techniques , Isoflavones/metabolism , Lipoproteins, LDL/antagonists & inhibitors , Male , Norepinephrine/pharmacology , Protective Agents/metabolism , Rats , Rats, Sprague-Dawley , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects , Vasodilator Agents/pharmacologyABSTRACT
OBJECTIVES: We sought to examine the effects of plasma lipids, especially in remnants after a fat meal, on systemic arterial compliance (SAC), a newly recognized cardiovascular risk factor. BACKGROUND: Post-prandial remnants correlate with coronary heart disease events through mechanisms that may include vascular dysfunction, although the effect on SAC has not been studied. METHODS: Systemic arterial compliance was measured non-invasively over 6 h after a fat meal in 16 subjects with varying plasma triglyceride levels. Changes were related to rises in plasma lipids and remnant lipids. Systemic arterial compliance was measured in 20 subjects after a control low-fat meal. RESULTS: The fat meal induced increments in plasma triglyceride and remnant cholesterol and triglyceride (respectively +54%, 50% and 290% at 3 h, analysis of variance <0.001). Systemic arterial compliance fell at 3 h and 6 h by 25% and 27% (analysis of variance <0.001). Baseline SAC correlated significantly with all lipid concentrations at 0, 3 h and 6 h, but only with triglyceride on stepwise regression analysis. The SAC response to the low-fat meal was very small and not significant. CONCLUSIONS: This is the first demonstration of SAC becoming impaired after a fat meal. Remnant lipids and plasma total triglyceride appeared to contribute to the fall in SAC.
Subject(s)
Arteries/drug effects , Arteries/physiology , Cholesterol/blood , Compliance/drug effects , Dietary Fats/pharmacology , Postprandial Period , Triglycerides/blood , Female , Humans , Male , Middle Aged , Time FactorsABSTRACT
Hypercholesterolaemia is a major risk factor for the development of atherosclerosis which, in turn, underlies most ischaemic heart disease (IHD). This review deals briefly with the pathophysiology of lipids in humans and follows with a discussion of current lipid-lowering therapies. In those patients with a history of myocardial infarction (MI) or unstable angina, appropriate lipid-lowering therapy has been convincingly shown to reduce not only cardiac events but also overall mortality. The advent of the HMG CoA reductase inhibitors in the late 1980s has had a revolutionary impact in the clinical management of hypercholesterolaemia, not only because of their efficacy but especially because they are well-tolerated. The use of other treatments such as the fibrates and bile acid resins are also discussed. Given the successful use of the statins, it is felt that an emergence of a different class of LDL-cholesterol lowering compound is unlikely in the near future and rather that compounds which can increase HDL-cholesterol while lowering LDL will be of greater impact. There may also be a shifting trend towards such naturally occurring compounds as plant stanols and phytoestrogens.
Subject(s)
Arteriosclerosis/etiology , Hypercholesterolemia/drug therapy , Lipid Metabolism , Cholestyramine Resin/therapeutic use , Clinical Trials as Topic , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/complications , Niacin/therapeutic use , Nutritional Physiological Phenomena , Probucol/therapeutic useABSTRACT
BACKGROUND: Acute coronary syndromes present with an increased incidence from 6:00 AM to 12:00 noon. Whether endothelial function follows a diurnal rhythm and whether this rhythm is impaired in coronary artery disease (CAD) has not previously been studied. METHODS AND RESULTS: Diurnal variation in endothelium-dependent vasodilatation was examined in 10 CAD patients and 10 control subjects. Forearm blood flow responses to acetylcholine, sodium nitroprusside, and N(G)-monomethyl-L-arginine were determined by plethysmography at 8:00 AM, 2:00 PM, and 8:00 PM. Heart rate, blood pressure, plasma cortisol, and inflammatory markers were also determined. Heart rate and the low-frequency component of heart rate variability were greatest in the morning in control subjects, suggesting a diurnal variation in sympathetic activity. Basal forearm blood flows were significantly reduced in control subjects at 8:00 PM compared with 8:00 AM and 2:00 PM (1.2+/-0.2 versus 2.1+/-0.2 [8:00 AM] and 2.1+/-0.3 [2:00 PM] mL. 100 mL(-1). min(-1); P<0.05) but unchanged in the CAD group. Acetylcholine (37 microgram/min) responses were greater at 8:00 AM than at 8:00 PM in control subjects (12.5+/-3.7 versus 19.6+/-2.9 mL. 100 mL(-1). min(-1), respectively; P<0.05), but these responses were not time dependent in the CAD group. Responses to sodium nitroprusside were similar at all time points and between those with and without CAD. CONCLUSIONS: Thus, normal volunteers have a diurnal variation in their endothelium-dependent vasodilatation that may counteract other, potentially adverse, diurnal variations in hemodynamic and other parameters. In contrast, CAD patients who had presented with acute coronary syndromes showed a loss of this protective mechanism.
Subject(s)
Circadian Rhythm , Coronary Disease/physiopathology , Endothelium, Vascular/physiopathology , Hemodynamics , Acetylcholine , Acute Disease , Analysis of Variance , Blood Glucose/analysis , Blood Pressure , Carrier Proteins , Cholesterol/blood , Coronary Disease/blood , Cyclic AMP Receptor Protein/blood , Forearm/blood supply , Heart Rate , Humans , Hydrocortisone/blood , Interleukin-6/blood , Male , Middle Aged , Nitroprusside , Plethysmography , Triglycerides/blood , Vasodilation , omega-N-MethylarginineABSTRACT
BACKGROUND: The clinical features of congestive heart failure (CHF) result from a complex interaction between reduced ventricular function, neurohormonal activation, and impaired endothelial function. Although endothelial dysfunction has been well documented, the mechanisms that contribute to this abnormality remain unknown. Recent studies, however, indicate a potential therapeutic role for supplemental L-arginine, suggesting the presence of an underlying disorder of L-arginine metabolism. METHODS AND RESULTS: We used 2 complementary approaches to assess L-arginine transport in control subjects and patients with CHF. During a steady-state intra-arterial infusion of [(3)H]L-arginine (100 nCi/min), forearm clearance of [(3)H]L-arginine was significantly reduced in CHF patients compared with forearm kinetics in control subjects (64+/-2 versus 133+/-14 mL/min, P=0.002). In conjunction with this, [(3)H]L-arginine uptake by peripheral blood mononuclear cells (PBMCs) was also substantially reduced in heart failure patients compared with controls (V(max) 10. 1+/-1.3 versus 49.8+/-7.1 pmol/10(5) cells per 5 minutes, P<0.001). In association with this finding, we observed a 76% (P<0.01) reduction in mRNA expression for the cationic amino acid transporter CAT-1, as assessed by ribonuclease protection assay. CONCLUSIONS: These data document both in vivo and in vitro evidence for a marked depression of L-arginine transport in human CHF and therefore provide an explanation for the restorative actions of supplemental L-arginine on vascular function in CHF.
Subject(s)
Arginine/pharmacokinetics , Heart Failure/drug therapy , Adult , Amino Acid Transport Systems, Basic , Arginine/blood , Biological Transport , Carrier Proteins/genetics , Forearm/blood supply , Gene Expression Regulation/drug effects , Heart Failure/physiopathology , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Membrane Proteins/genetics , Middle Aged , RNA, Messenger/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Regional Blood Flow/drug effects , Time Factors , TritiumABSTRACT
Patients with heart failure exhibit impaired endothelium-dependent vasodilation. Although brief intraarterial administration of L-arginine improves endothelium-dependent vasodilatation in these patients, long-term oral supplementation is ineffective. To resolve these conflicting findings, we examined the effect of a single, short-term oral dose of L-arginine on serial, hourly forearm vascular responses to acetylcholine, sodium nitroprusside, and norepinephrine. Eighteen patients with heart failure were randomly allocated in a double-blinded, crossover study to receive either a single 20-g oral dose of L-arginine or placebo. Vascular responses were measured by forearm venous occlusion plethysmography before and at 60, 120, and 180 min after dosage. Blood was obtained for measurement of L-arginine and nitric oxide metabolite levels. Oral L-arginine increased plasma levels by fourfold at 60, 120, and 180 min. Vasodilatation to acetylcholine, 37 microg/min, was significantly enhanced at 60 min (percentage increase in forearm blood flow: placebo, 413 +/- 64%; L-arginine, 587 +/- 94%; p < 0.05), discernible at 120 min (p = 0.058) but no longer apparent at 180 min. Neither basal forearm blood flow, sodium nitroprusside, nor norepinephrine responses nor plasma levels of nitrite and nitrate were altered. We conclude that although short-term oral supplementation with L-arginine produced marked sustained elevation of plasma levels of L-arginine in patients with heart failure, responses to acetylcholine were only transiently improved.