Emerging thrombotic effects of drug eluting stents.
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Animals↗
Biomedical subjects
David E Newby
Publications and source records attributed to David E Newby.
Connexin 43 mediates endothelium-derived hyperpolarizing factor-induced vasodilatation in subcutaneous resistance arteries from healthy pregnant women.
The role of gap junctions in endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation of human arteries was assessed using connexin mimetic peptides (CMPs) designated (37,43)Gap27, (40)Gap27, and (43)Gap26 according to homology with the major vascular connexins (Cx37, Cx40, and Cx43). Resistance arteries were obtained from subcutaneous fat biopsies of healthy pregnant women undergoing elective cesarean section. Endothelium-dependent vasodilatation to bradykinin (BK) was assessed using wire myography. N(omega)-nitro-l-arginine methyl ester (l-NAME) and indomethacin (nitric oxide synthase and cyclooxygenase inhibitors, respectively) attenuated maximal relaxation to BK (R(max)) by approximately 50%. Coincubation with l-NAME, indomethacin, and the combined CMPs ((37,43)Gap27, (40)Gap27, and (43)Gap26) almost abolished relaxation to BK (R(max) = 12.2 +/- 3.7%). In arteries incubated with l-NAME and indomethacin, the addition of either (37,43)Gap27 or (40)Gap27 had no significant effect on R(max), whereas (43)Gap26 caused marked inhibition (R(max) = 21 +/- 6.4%, P = 0.005 vs. l-NAME plus indomethacin alone) that was similar to that of the triple combination. Endothelium-independent vasorelaxation was unaffected by CMPs, l-NAME, or indomethacin. Immunohistochemistry demonstrated Cx37, Cx40, and Cx43 expression in the endothelium and vascular smooth muscle. In pregnant women, EDHF-mediated vasorelaxation of subcutaneous resistance arteries is dependent on Cx43 and gap junctions.
Adult↗
Direct vascular effects of protease-activated receptor type 1 agonism in vivo in humans.
BACKGROUND: Protease-activated receptor type 1 (PAR-1) has been proposed as the principal thrombin receptor in humans, although its actions in vivo have not been defined. The aim of the present study was to determine the direct vascular actions of PAR-1 agonism in humans. METHODS AND RESULTS: Dorsal hand vein diameter was measured by the Aellig technique in 14 healthy volunteers during local intravenous SFLLRN (PAR-1 agonist; 0.05 to 15 nmol/min) and SLIGKV (PAR-2 agonist; 1.6 to 160 nmol/min) infusions. The venous effects of SFLLRN were further assessed in the presence or absence of norepinephrine or the glycoprotein IIb/IIIa antagonist tirofiban. Forearm blood flow was measured by venous occlusion plethysmography in 16 volunteers during infusion of SFLLRN (1 to 50 nmol/min), SLIGKV (160 to 800 nmol/min), and the endothelium-dependent vasodilator bradykinin (100 to 1000 pmol/min). Platelet-monocyte binding (a sensitive measure of platelet activation) and plasma tissue plasminogen activator (tPA), plasminogen-activator inhibitor 1, and von Willebrand factor concentrations were measured at intervals throughout the study. SFLLRN caused dose-dependent venoconstriction (P<0.001) that was unaffected by norepinephrine or tirofiban co-infusion. In forearm resistance vessels, SFLLRN increased forearm blood flow (P<0.001), tPA release (P<0.001), and platelet-monocyte binding (P<0.0001) without affecting plasma plasminogen-activator inhibitor 1 or von Willebrand factor concentrations. SLIGKV caused venous (P<0.001) and arterial (P<0.01) dilatation without tPA release. CONCLUSIONS: We have demonstrated that PAR-1 agonism causes platelet activation, venous constriction, arterial dilatation, and tPA release in vivo in humans. These unique and contrasting effects provide important insights into the physiological and pathophysiological role of thrombin in the human venous and arterial circulations.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Intravascular glucocorticoid metabolism during inflammation and injury in mice.
11beta-hydroxysteroid dehydrogenases (11betaHSDs) catalyze interconversion of 11-hydroxy-glucocorticoids with inactive 11-keto metabolites. In blood vessel walls, loss of 11betaHSD1 is thought to reduce local glucocorticoid concentrations, reducing the progression of atheroma and enhancing angiogenesis. Conversely, on the basis that 11betaHSD1 is up-regulated approximately 5-fold by inflammatory cytokines in cultured human vascular smooth muscle cells, it has been proposed that increased 11betaHSD1 during vascular inflammation provides negative feedback suppression of inflammation. We aimed to determine whether inflammation and injury selectively up-regulate 11betaHSD1 reductase activity in vitro and in vivo in intact vascular tissue in mice. In isolated mouse aortae and femoral arteries, reductase activity (converting 11-dehydrocorticosterone to corticosterone) was approximately 10-fold higher than dehydrogenase activity and was entirely accounted for by 11betaHSD1 because it was abolished in vessels from 11betaHSD1(-/-) mice. Although 11betaHSD1 activity was up-regulated by proinflammatory cytokines in cultured murine aortic smooth muscle cells, no such effect was evident in intact aortic rings in vitro. Moreover, after systemic inflammation induced by ip lipopolysaccharide injection, there was only a modest (18%) increase in 11beta-reductase activity in the aorta and no increase in the perfused hindlimb. Furthermore, in femoral arteries in which neointimal proliferation was induced by intraluminal injury, there was no change in basal 11betaHSD1 activity or the sensitivity of 11betaHSD1 to cytokine up-regulation. We conclude that increased generation of glucocorticoids by 11betaHSD1 in the murine vessel wall is unlikely to contribute to feedback regulation of inflammation.
11-beta-Hydroxysteroid Dehydrogenase Type 1↗
Endothelial function is associated with pulse pressure, pulse wave velocity, and augmentation index in healthy humans.
Arterial stiffness is an independent predictor of mortality and is regulated by a number of factors, including vascular smooth muscle tone. However, the relationship between endothelial function and definitive measures of arterial stiffness and wave reflections has not been described in healthy individuals. Therefore, we tested the hypothesis that endothelial function is inversely correlated with aortic pulse wave velocity (PWV), central pulse pressure, and augmentation index in healthy individuals. Peripheral and central pulse pressure and augmentation index were determined at rest, and global endothelial function was measured using pulse wave analysis and administration of sublingual nitroglycerin and inhaled albuterol. Aortic PWV was also determined at baseline in a subset of 89 subjects. In a separate group of subjects (n=89), aortic PWV was measured and brachial artery flow-mediated dilatation assessed as a measure of conduit artery endothelial function. Global endothelial function was significantly and inversely correlated with aortic PWV (r=-0.69; P<0.001), augmentation index (r=-0.59; P<0.001), and central (r=-0.34; P<0.001) and peripheral pulse pressure (r=-0.15; P=0.03). Moreover, there was a stronger correlation between central rather than peripheral pulse pressure. After adjusting for potential confounders, global endothelial function remained independently and inversely associated with aortic PWV and augmentation index. There was also a significant, inverse relationship between conduit artery endothelial function and aortic PWV (r=0.39, P<0.001), which remained independent after adjusting for confounding factors. In healthy individuals, a decline in endothelial function is associated with increased large artery stiffness, wave reflections, and central pulse pressure.
Administration, Inhalation↗
A single-particle characterization of a mobile Versatile Aerosol Concentration Enrichment System for exposure studies.
BACKGROUND: An Aerosol Time-of-Flight Mass Spectrometer (ATOFMS) was used to investigate the size and chemical composition of fine concentrated ambient particles (CAPs) in the size range 0.2-2.6 microm produced by a Versatile Aerosol Concentration Enrichment System (VACES) contained within the Mobile Ambient Particle Concentrator Exposure Laboratory (MAPCEL). The data were collected during a study of human exposure to CAPs, in Edinburgh (UK), in February-March 2004. The air flow prior to, and post, concentration in the VACES was sampled in turn into the ATOFMS, which provides simultaneous size and positive and negative mass spectral data on individual fine particles. RESULTS: The particle size distribution was unaltered by the concentrator over the size range 0.2-2.6 microm, with an average enrichment factor during this study of approximately 5 (after dilution of the final air stream). The mass spectra from single particles were objectively grouped into 20 clusters using the multivariate K-means algorithm and then further grouped manually, according to similarity in composition and time sequence, into 8 main clusters. The particle ensemble was dominated by pure and reacted sea salt and other coarse inorganic dusts (as a consequence of the prevailing maritime-source climatology during the study), with relatively minor contributions from carbonaceous and secondary material. Very minor variations in particle composition were noted pre- and post-particle concentration, but overall there was no evidence of any significant change in particle composition. CONCLUSION: These results confirm, via single particle analysis, the preservation of the size distribution and chemical composition of fine ambient PM in the size range 0.2-2.6 microm after passage through the VACES concentration instrumentation.
Journal Article↗
Can intensive statin therapy cause regression of coronary atherosclerosis?
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Comment↗
Vascular and fibrinolytic effects of intra-arterial tumour necrosis factor-alpha in patients with coronary heart disease.
Elevated plasma t-PA (tissue plasminogen activator) and serum CRP (C-reactive protein) concentrations are associated with an adverse cardiovascular risk. In the present study, we investigated whether acute local inflammation causes vascular dysfunction and influences t-PA release in patients with stable coronary heart disease. Serum CRP, plasma t-PA and PAI-1 (plasminogen activator inhibitor type 1) concentrations were determined in 95 patients with stable coronary heart disease. A representative subpopulation of 12 male patients received an intra-brachial infusion of TNF-alpha (tumour necrosis factor-alpha) and saline placebo using a randomized double-blind cross-over study design. Forearm blood flow and plasma fibrinolytic and inflammatory variables were measured. Serum CRP concentrations correlated with plasma t-PA concentrations (r=0.37, P<0.001) and t-PA/PAI-1 ratio (r=-0.21, P<0.05). Intra-arterial TNF-alpha caused a rise in t-PA concentrations (P<0.001) without affecting blood flow or PAI-1 concentrations. TNF-alpha pretreatment impaired acetylcholine- and sodium nitroprusside-induced vasodilatation (P<0.001 for both) whilst doubling bradykinin-induced t-PA release (P=0.006). In patients with stable coronary heart disease, plasma fibrinolytic factors correlate with a systemic inflammatory marker and local vascular inflammation directly impairs vasomotor function whilst enhancing endothelial t-PA release. We suggest that the adverse prognosis associated with elevated plasma t-PA concentrations relates to the underlying causative association with vascular inflammation and injury.
Acute Disease↗
Inducible nitric oxide synthase activity does not contribute to the maintenance of peripheral vascular tone in patients with heart failure.
Enhanced iNOS (inducible nitric oxide synthase) activity may contribute to vascular dysfunction in patients with heart failure. In the present study, we aimed to determine whether iNOS activity contributes to the maintenance of vascular tone in patients with symptomatic heart failure with the use of the highly selective iNOS inhibitor 1400W {N-[3-(aminomethyl)benzyl] acetamidine}. Bilateral forearm blood flow was measured using venous occlusion plethysmography in 12 patients with New York Heart Association class II-IV heart failure and eight matched healthy control subjects during intra-brachial infusion of 1400W (0.1-1 micromol/min), L-NMMA (N(G)-monomethyl-L-arginine; a non-selective NOS inhibitor; 2-8 micromol/min) and noradrenaline (control vasoconstrictor; 60-480 pmol/min). In both patients and controls, intra-brachial infusion of L-NMMA and noradrenaline caused a dose-dependent reduction in infused forearm blood flow (P<0.05 for both): peak reduction of 32+/-6% and 37+/-4% during L-NMMA and 52+/-6% and 49+/-5% during noradrenaline respectively (P values were not significant when patients were compared with controls). In contrast, 1400W had no effect on blood flow at 1 micromol/min [-3+/-4% in patients (95% confidence intervals, -11 to 5%) and 3+/-8% in controls; P value was not significant]. In conclusion, we have demonstrated that intrabrachial selective iNOS inhibition does not influence forearm blood flow in patients with heart failure. We conclude that iNOS activity does not contribute to peripheral vascular tone in patients with symptomatic heart failure.
Aged↗
Bradykinin does not contribute to peripheral vascular tone in patients with cirrhosis and ascites.
Bradykinin is an endothelium-dependent vasodilator and inflammatory mediator. The aim of the present study was to examine the effects of bradykinin on peripheral vascular tone in patients with cirrhosis and ascites. Forearm blood flow was measured using venous occlusion plethysmography in 8 patients with biopsy-proven alcohol-induced cirrhosis, ascites, and portal hypertension, and 8 age- and sex-matched healthy controls. On 1 occasion, subjects received an intrabrachial infusion of the selective bradykinin antagonist B9340 (1.5-13.5 nmol/min) followed by a control vasoconstrictor norepinephrine (60-540 pmol/min), and on another occasion bradykinin (100-900 pmol/min) followed by the endothelium-independent vasodilator, sodium nitroprusside (SNP, 2-8 microg/min). Bradykinin and SNP caused a dose-dependent vasodilatation (P < 0.001 for both) that did not differ between the 2 groups. Although norepinephrine caused a similar dose-dependent vasoconstriction in both groups (P < 0.001), B9340 had no effect on forearm blood flow in either group (at 13.5 nmol/min in patients; -5%, 95% CI -13-3). Bradykinin does not provide a major contribution to the maintenance of peripheral vascular tone in patients with cirrhosis and ascites. Our findings also suggest that, in contrast to cardiovascular disease, patients with liver cirrhosis do not have marked endothelial dysfunction.
Bradykinin↗
Altered endothelin-1 vasoreactivity in patients with untreated normal-pressure glaucoma.
PURPOSE: Vasospasm, resulting from a generalized dysfunction in the vascular endothelium, is implicated in the development of normal-pressure glaucoma (NPG). Impaired endothelium-derived nitric oxide activity and abnormalities of the endothelin system suggest systemic endothelial cell dysfunction in patients with NPG. Endothelin (ET)-1 vasoreactivity was assessed in the peripheral circulation of patients with NPG. METHODS: Forearm blood flow was measured using venous occlusion plethysmography in eight patients with untreated NPG and eight age- and sex-matched healthy volunteers during intra-arterial infusion of ET-1 (5 pmol/min) and, on a separate occasion, to BQ123, a selective endothelin-A receptor antagonist, (100 nmol/min). Blood pressure and heart rate were measured in the noninfused arm, and plasma ET-1 concentrations were measured using a radioimmunoassay. RESULTS: Forearm blood flow fell during infusion of ET-1 (P<0.001 for both) to a similar extent in both groups (P=0.7; patients versus control subjects). In contrast, BQ123 increased forearm blood flow in both groups (P<0.001 for both), although the vasodilatation was lower in patients than in control subjects (P<0.001; patients versus control subjects). There was no difference in basal plasma ET-1 concentrations between the two groups (P=0.81; patients versus control subjects). CONCLUSIONS: Despite normal responses to ET-1, patients with NPG have reduced vasodilatation in response to ETA-receptor antagonism. This could be due to attenuated ETA-receptor-mediated tone, increased ETB-receptor-mediated contraction or impaired ETB-receptor-mediated release of endothelial nitric oxide. These results are consistent with the authors' previous demonstration of systemic vascular dysfunction in patients with NPG.
Blood Flow Velocity↗
Management of acute coronary syndromes.
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Acute Disease↗
Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis.
BACKGROUND: Although the mechanisms are unknown, it has been suggested that transient exposure to traffic-derived air pollution may be a trigger for acute myocardial infarction. The study aim was to investigate the effects of diesel exhaust inhalation on vascular and endothelial function in humans. METHODS AND RESULTS: In a double-blind, randomized, cross-over study, 30 healthy men were exposed to diluted diesel exhaust (300 microg/m3 particulate concentration) or air for 1 hour during intermittent exercise. Bilateral forearm blood flow and inflammatory factors were measured before and during unilateral intrabrachial bradykinin (100 to 1000 pmol/min), acetylcholine (5 to 20 microg/min), sodium nitroprusside (2 to 8 microg/min), and verapamil (10 to 100 microg/min) infusions 2 and 6 hours after exposure. There were no differences in resting forearm blood flow or inflammatory markers after exposure to diesel exhaust or air. Although there was a dose-dependent increase in blood flow with each vasodilator (P<0.0001 for all), this response was attenuated with bradykinin (P<0.05), acetylcholine (P<0.05), and sodium nitroprusside (P<0.001) infusions 2 hours after exposure to diesel exhaust, which persisted at 6 hours. Bradykinin caused a dose-dependent increase in plasma tissue plasminogen activator (P<0.0001) that was suppressed 6 hours after exposure to diesel (P<0.001; area under the curve decreased by 34%). CONCLUSIONS: At levels encountered in an urban environment, inhalation of dilute diesel exhaust impairs 2 important and complementary aspects of vascular function in humans: the regulation of vascular tone and endogenous fibrinolysis. These important findings provide a potential mechanism that links air pollution to the pathogenesis of atherothrombosis and acute myocardial infarction.
Adult↗
Do inhaled carbon nanoparticles translocate directly into the circulation in humans?
RATIONALE: Increased exposure to particulate air pollution (PM(10)) is a risk factor for death and hospitalization with cardiovascular disease. It has been suggested that the nanoparticulate component of PM(10) is capable of translocating into the circulation with the potential for direct effects on the vasculature. OBJECTIVE: The study's aim was to determine the extent to which inhaled technetium-99m ((99m)Tc)-labeled carbon nanoparticles (Technegas) were able to access the systemic circulation. METHODS AND MAIN RESULTS: Ten healthy volunteers inhaled Technegas and blood samples were taken sequentially over the following 6 h. Technegas particles were 4-20 nm in diameter and aggregated to a median particle diameter of approximately 100 nm. Radioactivity was immediately detected in blood, with levels increasing over 60 min. Thin-layer chromatography of whole blood identified a species that moved with the solvent front, corresponding to unbound (99m)Tc-pertechnetate, which was excreted in urine. There was no evidence of particle-bound (99m)Tc at the origin. gamma Camera images demonstrated high levels of Technegas retention (95.6 +/- 1.7% at 6 h) in the lungs, with no accumulation of radioactivity detected over the liver or spleen. CONCLUSIONS: The majority of (99m)Tc-labeled carbon nanoparticles remain within the lung up to 6 h after inhalation. In contrast to previous published studies, thin-layer chromatography did not support the hypothesis that inhaled Technegas carbon nanoparticles pass directly from the lungs into the systemic circulation.
Adult↗
Sildenafil potentiates nitric oxide mediated inhibition of human platelet aggregation.
Nitric oxide (NO) inhibits platelet aggregation primarily via a cyclic 3'5'-guanosine monophosphate (cGMP)-dependent process. Sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor that potentiates NO action by reducing cGMP breakdown. We hypothesised that sildenafil would augment the inhibitory effects of NO on in vitro platelet aggregation. After incubation with sildenafil or the soluble guanylate cyclase inhibitor H-(1,2,4)oxadiazolo(4,3-a)quinoxallin-1-one (ODQ), collagen-mediated human platelet aggregation was assessed in the presence of two NO donors, the cGMP-dependent sodium nitroprusside (SNP) and the cGMP-independent diethylamine diazeniumdiolate (DEA/NO). SNP and DEA/NO caused a concentration-dependent inhibition of platelet aggregation. ODQ inhibited and sildenafil augmented the effect of SNP, and to a lesser extent the effect of DEA/NO. We conclude that sildenafil potentiates NO-mediated inhibition of platelet aggregation through blockade of cGMP metabolism and that PDE5 inhibitors may have important antiplatelet actions relevant to the prevention of cardiovascular disease.
3',5'-Cyclic-GMP Phosphodiesterases↗
Depressed glutathione synthesis precedes oxidative stress and atherogenesis in Apo-E(-/-) mice.
Glutathione is a vital intracellular antioxidant. The enzymes involved in its synthesis and utilisation are tightly regulated, but the importance of glutathione regulation in atherogenesis is poorly understood. Here, we establish that glutathione is severely (approximately 80%) depleted very early (10 weeks) in the atheroma-prone aortic arch of male apoprotein E-deficient (Apo-E(-/-)) mice compared to age-matched wild-type controls. Importantly, this event pre-empts lipid peroxidation and detectable atheroma by several months. Depletion of glutathione was associated with excessive oxidant burden and reduced transcription and activity of the rate-limiting enzyme for glutathione synthesis, gamma-glutamylcysteine ligase, together with the glutathione-dependent antioxidant enzyme, glutathione peroxidase. Depletion via reduced synthesis of glutathione precedes lipid peroxidation and atherogenesis in Apo-E(-/-) mice. We suggest that glutathione deficiency is central to the failure of the intracellular antioxidant defences and is causally implicated in the pathogenesis of atherosclerosis. Modification of the glutathione pathway may present a novel and important therapeutic target in the prevention and treatment of atherosclerosis.
Animals↗
Combustion-derived nanoparticles: a review of their toxicology following inhalation exposure.
This review considers the molecular toxicology of combustion-derived nanoparticles (CDNP) following inhalation exposure. CDNP originate from a number of sources and in this review we consider diesel soot, welding fume, carbon black and coal fly ash. A substantial literature demonstrates that these pose a hazard to the lungs through their potential to cause oxidative stress, inflammation and cancer; they also have the potential to redistribute to other organs following pulmonary deposition. These different CDNP show considerable heterogeneity in composition and solubility, meaning that oxidative stress may originate from different components depending on the particle under consideration. Key CDNP-associated properties of large surface area and the presence of metals and organics all have the potential to produce oxidative stress. CDNP may also exert genotoxic effects, depending on their composition. CDNP and their components also have the potential to translocate to the brain and also the blood, and thereby reach other targets such as the cardiovascular system, spleen and liver. CDNP therefore can be seen as a group of particulate toxins unified by a common mechanism of injury and properties of translocation which have the potential to mediate a range of adverse effects in the lungs and other organs and warrant further research.
Journal Article↗
Stimulated tissue plasminogen activator release as a marker of endothelial function in humans.
The initiation, modulation, and resolution of thrombus associated with eroded or unstable coronary plaques are critically dependent on the efficacy of endogenous fibrinolysis. This is dependent on the cellular function of the surrounding endothelium and vascular wall. In particular, the acute release of tissue plasminogen activator from the endothelium makes an important contribution to the defense against intravascular thrombosis. Here, we describe the rationale and methodology for, and clinical relevance of, assessing acute endothelial tissue plasminogen activator release in humans. The investigation of endothelial fibrinolytic function has the potential to provide major new insights into the pathophysiology of cardiovascular disease, and to shape future therapeutic interventions.
Atherosclerosis↗