Melissa B. Bryant

Role of Endothelial Nitric Oxide in Shear Stress–Induced Vasodilation of Human Microvasculature Diminished Activity in Hypertensive and Hypercholesterolemic Patients

BackgroundIt has been proposed that flow-mediated shear stress regulates vascular tone; however, whether this operates in the human microcirculation is unknown. This study was designed to investigate the effect of shear stress on human microvascular tone, to assess the contribution of nitric oxide (NO), and to determine whether this mechanism is defective in hypertension and in hypercholesterolemia. Methods and ResultsIn 9 normal controls (NC), 11 hypertensive patients (HT), and 12 hypercholesterolemic patients (HChol), arteries (internal diameter 201±26 &mgr;m) isolated from gluteal fat biopsies were cannulated and perfused in chambers. Shear stress was induced by increasing the flow rate from 1 to 50 &mgr;L/min after preconstriction with norepinephrine (NE). Arterial internal diameter was expressed as percent of NE-induced constriction. In NC, shear stress induced flow-dependent vasodilation from 23±9% at 1 &mgr;L/min to 53±14% at 50 &mgr;L/min (P <0.0001), which was abolished by endothelial removal. The NO synthase inhibitor N&ohgr;-nitro-l-arginine (L-NNA) significantly blunted this response (mean vasodilation decreased from 27±6% to 6±9%;P =0.04). HT had significant impairment of flow-mediated dilation (mean vasodilation 5±6%;P =0.01 versus NC), which was not affected by L-NNA. HChol had preserved flow-mediated vasodilation (mean vasodilation 24±7%;P =0.56 versus NC), but this was not significantly modified by L-NNA. ConclusionsIn the human microvasculature, shear stress induces endothelium-dependent, NO-mediated vasodilation. This phenomenon is blunted in HT patients because of reduced activity of NO. In contrast, the HChol microvasculature has preserved shear stress-induced dilation despite diminished NO activity.

Reduced endothelium-dependent and -independent dilation of conductance arteries in African Americans.

OBJECTIVES The goal of this study was to determine whether racial differences exist in the functional behavior of conduit vessels. BACKGROUND Compared with Caucasians, African Americans have a higher prevalence of cardiovascular disease and its complications, which may be related to reduced nitric oxide (NO)-dependent and -independent vasodilation of the microvasculature. However, whether a similar impairment is also present at the level of the conductance arteries is unknown. METHODS To this end, we studied endothelium-dependent (posthyperemia flow-mediated dilation) and -independent (nitroglycerin) vascular responses of the brachial artery by high-resolution ultrasound imaging. There were 46 black subjects (23 men and 23 women; age 37 +/- 8 years and 38 +/- 9 years, respectively) and 46 white subjects (23 men and 23 women; age 38 +/- 11 years and 36 +/- 9 years, respectively) in this study. RESULTS Baseline diameter was similar in blacks and in whites (4.4 +/- 0.9 mm and 4.1 +/- 0.7 mm, respectively). Mean reactive hyperemia after cuff deflation was similar in the two groups (793 +/- 653% in black and 852 +/- 734% in white subjects, respectively; p = 0.5). Flow-mediated dilation was significantly lower in black compared with white individuals (4.79 +/- 3.5% vs. 8.87 +/- 4.5%, respectively; p < 0.0001). Nitroglycerin-mediated dilation was also significantly lower in black individuals compared with white individuals (10.99 +/- 4.6% vs. 14.98 +/- 5.4%, respectively; p = 0.0002). CONCLUSIONS African Americans show reduced responsiveness of conductance vessels to both endogenous and exogenous NO compared with Caucasian Americans. These findings expand our understanding of racial differences in vascular function and suggest a mechanistic explanation for the increased incidence and severity of cardiovascular disease observed in African Americans.

Enhanced Endothelium-Dependent Vasodilation in Fabry Disease

Background and Purpose— Fabry disease is an X-linked lysosomal storage disease secondary to deficiency of &agr;-galactosidase A with resulting glycolipid accumulation, particularly globotriaosylceramide in arterial smooth muscle and endothelial cells. A systemic vasculopathy, including early-onset stroke, is prevalent without a clear pathogenesis. Methods— Seventeen normotensive and normocholesterolemic hemizygous Fabry patients (aged 21 to 49 years) and 13 control subjects (aged 21 to 48 years) were investigated by venous plethysmography, allowing assessment of forearm blood flow. Plethysmographic measurements were obtained at baseline and during intra-arterial infusion of acetylcholine and sodium nitroprusside both with and without NG-monomethyl-l-arginine (L-NMMA). Results— Forearm blood flow was significantly higher in patients than in control subjects at all 3 acetylcholine doses (P =0.014). Patients had a greater response to acetylcholine even after the addition of L-NMMA (P =0.036). Conclusions— These results demonstrate an increased endothelium-mediated vascular reactivity in Fabry disease. The increased vessel response to acetylcholine with and without L-NMMA suggests altered functionality of non-NO endothelium-dependent vasodilatory pathways.

Transient Hypertension Directly Impairs Endothelium-Dependent Vasodilation of the Human Microvasculature

Hypertension is associated with decreased endothelium-dependent vasodilation. However, whether endothelial dysfunction is a cause or a consequence of elevated blood pressure is unknown. Therefore, to determine whether hypertension can directly induce endothelial dysfunction, we investigated the effect of increases in intra-arterial pressure on endothelium-dependent vasodilation of the human microvasculature. Small arteries (internal diameter 202±75 &mgr;m) were isolated from gluteal fat biopsies in 12 healthy normotensive subjects (8 men and 4 women; age, 46±10 years). Arteries were cannulated and perfused in chambers oxygenated at 37°C. Endothelium-dependent and -independent responses to acetylcholine (Ach; 10−9 to 10−4 mol/L) and sodium nitroprusside (SNP; 10−9 to 10−4 mol/L), respectively, were obtained after incubating the vessel with incremental intravascular pressures of 50, 80, and 120 mm Hg for 60 minutes each. The response to Ach was also obtained in different arteries after 3 consecutive incubation periods at 50 mm Hg. Arterial internal diameter was measured directly from amplified digital images. A significant reduction in the vasodilator response to Ach was observed with increases in intravascular pressure (mean vasodilation, 62%, 49%, and 26% at 50, 80, and 120 mm Hg, respectively;P <0.001). In contrast, the response to SNP showed a nonsignificant trend toward greater vasodilation with increases in pressure (mean vasodilation, 40%, 52%, and 57% at 50, 80, and 120 mm Hg, respectively;P =0.10). There was no difference in the consecutive dose-response curves to Ach obtained at the same intravascular pressure (mean vasodilation: 48%, 46%, and 49%;P =0.61). Transient increases in intravascular pressure significantly depress endothelium-dependent vasodilation in human resistance arteries. These findings suggest that elevated blood pressure per se may cause endothelial dysfunction in humans and have implications for the pathophysiology of endothelial dysfunction in hypertension.

Role of cyclooxygenase products in the regulation of vascular tone and in the endothelial vasodilator function of normal, hypertensive, and hypercholesterolemic humans

A defective vascular activity of endothelial vasoactive substances is observed in essential hypertension and hypercholesterolemia, and is believed to participate in the vascular abnormalities characteristic of these conditions. The present study aimed to determine the role of cyclooxygenase (COX) products in the maintenance of vascular tone and in the endothelium-mediated vasodilation of healthy subjects, and to investigate their contribution to the endothelial dysfunction of essential hypertensive and hypercholesterolemic patients. The effects of intra-arterial aspirin (acetylsalicylic acid [ASA], 1, 3, and 10 mg/min) were assessed on basal forearm blood flow (strain gauge plethysmography) and on responses to acetylcholine (7.5, 15 and 30 microg/min) and sodium nitroprusside (0.8, 1.6 and 3.2 microg/min) in 24 normal, 23 hypertensive, and 24 hypercholesterolemic subjects. Basal forearm blood flow was not different among the 3 groups (p = 0.95). ASA resulted in a significant reduction of forearm blood flow from baseline in normal (p = 0.003), hypertensive (p = 0.001), and hypercholesterolemic subjects (p = 0.001), without any difference among the 3 groups (p = 0.90). ASA significantly improved the effect of acetylcholine in normal (p = 0.008), hypertensive (p = 0.008), and hypercholesterolemic subjects (p = 0.022), without significant difference among the 3 groups (p = 0.46). ASA did not significantly modify the vasodilator effect of sodium nitroprusside in any of the 3 groups. These findings suggest that in humans, vasodilator prostanoids actively contribute to the maintenance of basal vascular tone, whereas vasoconstrictor products of COX activity limit endothelium-dependent vasodilation. COX products do not appear to play a major role in the endothelial dysfunction of hypertensive or hypercholesterolemic patients.