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Biomedical subjects

Stephen J Duffy

Publications and source records attributed to Stephen J Duffy.

7 recordsLinked to original sources
PubMed2004

Coronary endothelial dysfunction is not rapidly reversible with ascorbic acid.

In humans with cardiovascular risk factors, increased vascular production of superoxide anion may contribute to endothelial dysfunction by its reacting with nitric oxide and reducing its biological activity. High concentrations of ascorbic acid scavenge superoxide anion and restore normal endothelium-dependent vasodilation in humans with cardiovascular risk factors. To investigate the contribution of increased superoxide anion to endothelial dysfunction in atherosclerotic coronary arteries, we examined the effect of sequential infusions of ascorbic acid (final concentration 0.1, 1.0, and 10 mmol/L) or placebo on coronary endothelial function in 26 subjects referred for cardiac catheterization to evaluate coronary artery disease. Coronary vasomotor function was evaluated using intracoronary agonist infusion, quantitative angiography, and intracoronary Doppler measurements. At baseline, endothelium-dependent vasodilation of epicardial arteries and coronary microvessels was impaired to an equivalent extent in the ascorbic acid and placebo groups. Sequential ascorbic acid infusions had no effect on the acetylcholine-induced change in coronary artery diameter (-11+/-8, -12+/-10, and -9+/-9%) compared with the effect of placebo (-14+/-13, -16+/-10, and -13+/-9%) infusions (p=0.98). Similarly, the changes in coronary blood flow during acetylcholine infusions were equivalent during ascorbic acid (51+/-44, 67+/-66, and 62+/-52%) and placebo (61+/-104, 55+/-93, and 50+/-69%) infusions (p=0.63). Ascorbic acid also had no effect on the dilator response to intracoronary nitroglycerin (p=0.19). These data argue against an important role for superoxide-mediated "inactivation" of nitric oxide or another rapidly reversible form of oxidative stress as a mechanism of coronary endothelial dysfunction in patients with coronary atherosclerosis.

Acetylcholine↗
PubMed2003

Short- and long-term COX-2 inhibition reverses endothelial dysfunction in patients with hypertension.

Hypertension is associated with endothelial dysfunction that is attributable to oxidative stress and a proinflammatory state. Under these conditions, enhanced expression of cyclooxygenase-2 might lead to increased production of vasoconstrictor prostanoids and reactive oxygen species that reduce the bioavailability of endothelium-derived nitric oxide. To investigate the contribution of cyclooxygenase-2 activity to endothelial dysfunction in human hypertension, we evaluated brachial artery vasodilator function by ultrasound in 29 hypertensive patients before and after treatment with the selective cyclooxygenase-2 inhibitor celecoxib or placebo in a randomized, double-blind study. Brachial artery flow-mediated dilation improved from a baseline of 7.9+/-4.5% to 9.9+/-5.1% (P=0.005) 3 hours after the first dose and to 10.1+/-6.1% (P=0.006) after 1 week of treatment with celecoxib. In contrast, placebo treatment had no significant effect on flow-mediated dilation (8.1+/-4.4%, 8.3+/-3.5%, and 8.0+/-3.2%, respectively). Neither treatment altered nitroglycerin-mediated dilation, extent of reactive hyperemia, or baseline arterial diameter. Celecoxib treatment had no significant effect on the urinary concentrations of F2 isoprostane or thromboxane metabolites. However, urinary concentrations of the prostacyclin metabolite 2,3-dinor-6-ketoprostglandin F1alpha were significantly lower after 1 week of celecoxib treatment. Thus, cyclooxygenase-2 products contribute to endothelial dysfunction in hypertension, and treatment with a cyclooxygenase-2 inhibitor could have a beneficial effect in this setting. However, cyclooxygenase-2 inhibition also has an adverse effect on prostacyclin production that could promote thrombosis, and the net clinical consequences of improved endothelial function versus loss of prostacyclin merits further investigation.

Adult↗
PubMed2003

Sickle cell anemia is associated with reduced nitric oxide bioactivity in peripheral conduit and resistance vessels.

The purpose of the study was to examine endothelium-dependent and -independent vasodilation of conduit and resistance vessels in sickle cell anemia (HbSS). We measured the effects of intra-arterial infusion of methacholine, sodium nitroprusside, and NG-monomethyl-L-arginine (L-NMMA) on forearm blood flow using venous occlusion plethysmography in eight patients with HbSS and 11 HbAA controls. We assessed vasodilation of the conduit brachial artery using ultrasound in 17 patients with HbSS and 41 nonanemic controls. Forearm blood flow response to methacholine was similar in HbSS and HbAA, while the response to sodium nitroprusside was greater in those with HbSS. Nitric oxide synthase inhibition with L-NMMA attenuated methacholine-induced forearm blood flow to a lesser extent in HbSS compared to HbAA, suggesting diminished nitric oxide (NO) contribution to endothelium-dependent vasodilation. Flow-mediated and nitroglycerin-induced dilation were impaired in HbSS compared to controls and were not affected by the antioxidant vitamin C or the precursor substrate for NO synthesis L-arginine. NO bioactivity is reduced but differs in peripheral conduit and resistance vessels in HbSS. Resistance vessels have preserved response to exogenous NO donors but have diminished contribution of NO to endothelium-dependent vasodilation. Conduit vessels demonstrate impaired vasodilation to endogenous and exogenous NO.

Adult↗
PubMed2003

Effects of phenolics on vascular endothelial function.

PURPOSE OF REVIEW: There continues to be considerable interest in the concept that antioxidant therapy may reduce cardiovascular risk. Phenols have antioxidant properties and may be important micronutrients. Epidemiological studies have demonstrated a strong link between phenolic intake and reduced cardiovascular risk, but the mechanism of benefit has not been determined. RECENT FINDINGS: Recent evidence has emerged that a number of phenolic compounds, particularly flavonoids, reverse vascular endothelial dysfunction. The normal endothelium plays a critical role in regulating vascular function, and endothelial dysfunction is associated with increased cardiovascular risk. The present article reviews the links between phenolic intake, endothelial function and cardiovascular risk. SUMMARY: Endothelium-derived nitric oxide bioactivity appears to be increased by supplementation with a number of phenols, and this may explain some of the favourable effects of high phenolic intake seen in epidemiological studies.

Animals↗
PubMed2002

Effects of black race on forearm resistance vessel function.

Presentation, response to therapy, and clinical outcome in hypertension differ according to race, and these observations could relate to differences in microvascular function. We examined forearm microvascular function in age-matched black (n=56) and white subjects (n=62) using intra-arterial agonist infusion and venous occlusion plethysmography. In normotensive subjects (n=70; 34 black and 36 white normotensives), methacholine-, sodium nitroprusside-, and verapamil-induced vasodilation was equivalent in black and white subjects. In hypertensive subjects (n=48; 22 black and 26 white hypertensives), the vasodilator response to methacholine was markedly lower in black subjects compared with white subjects (P<0.001). The vasodilator responses to sodium nitroprusside and verapamil, however, were equivalent in black and white hypertensive subjects. Acute ascorbic acid infusion improved the methacholine response equally in black and white hypertensive patients, suggesting that a difference in a rapidly reversible form of oxidative stress does not explain these findings. Thus, the present study demonstrates important racial differences in vascular function and a marked impairment in endothelial vasomotor function in black patients with hypertension. Further studies will be required to elucidate the mechanisms and determine whether these insights will lead to more appropriately tailored management of hypertension and its complications.

Adult↗