New insights into antiphospholipid-related endothelial dysfunction by assessment of vascular glycocalyx layer: results from a preliminary cross-sectional study.

INTRODUCTION: Antiphospholipid syndrome (APS) is associated with greater atherothrombotic risk and endothelial dysfunction, suggesting that endothelial glycocalyx is impaired in this disease. OBJECTIVES: The aim was to investigate the endothelial glycocalyx and the relationship between glycocalyx markers, endothelial dysfunction parameters and atherosclerotic markers in APS. METHODS: A total of 15 primary arterial APS patients and healthy controls were included in the study. Glycocalyx was assessed in both groups by sublingual sidestream dark field imaging and syndecan-1 plasma level. Endothelial function was evaluated by brachial artery flow-mediated dilatation (FMD) and early atherosclerosis by carotid intima media thickness (IMT). Thrombotic profile was also performed by measuring the plasma level of the tissue factor (TF). RESULTS: APS patients had significantly increased syndecan-1 plasma level 38.6 ± 5.0 pg/ml vs. 19.1 ± 3.5 pg/ml; p < 0.01 and a reduced glycocalyx thickness 0.26 ± 0.03 µm vs. 0.75 ± 0.07 µm; p < 0.01 compared with control. FMD was impaired in APS patients compared with control, 5.68% ± 0.42 vs. 8.29 ± 0.30, p < 0.01, respectively. IMT was significantly increased in APS patients compared with control, 0.52 ± 0.13 mm vs. 0.40 ± 0.06 mm, p < 0.01, respectively. Soluble TF, thiobarbituric acid-reactive substances levels were increased in the sera from APS patients compared with control. CONCLUSIONS: This preliminary study supports, for the first time, that in APS patients endothelial glycocalyx is impaired, which could lead to thrombosis, endothelial dysfunction and early atherosclerosis.

[Assessment of endothelial function in autoimmune diseases]. / Évaluation de la fonction endothéliale au cours des maladies auto-immunes.

Numerous autoimmune-inflammatory rheumatic diseases have been associated with accelerated atherosclerosis or other types of vasculopathy leading to an increase in cardiovascular disease incidence. In addition to traditional cardiovascular risk factors, endothelial dysfunction is an important early event in the pathogenesis of atherosclerosis, contributing to plaque initiation and progression. Endothelial dysfunction is characterized by a shift of the actions of the endothelium toward reduced vasodilation, a proinflammatory and a proadhesive state, and prothrombic properties. Therefore, assessment of endothelial dysfunction targets this vascular phenotype using several biological markers as indicators of endothelial dysfunction. Measurements of soluble adhesion molecules (ICAM-1, VCAM-1, E-selectin), pro-thrombotic factors (thrombomodulin, von Willebrand factor, plasminogen activator inhibitor-1) and inflammatory cytokines are most often performed. Regarding the functional assessment of the endothelium, the flow-mediated dilatation of conduit arteries is a non-invasive method widely used in pathophysiological and interventional studies. In this review, we will briefly review the most relevant information upon endothelial dysfunction mechanisms and explorations. We will summarize the similarities and differences in the biological and functional assessments of the endothelium in different autoimmune diseases.

Immunosuppressant regimen based on sirolimus decreases aortic stiffness in renal transplant recipients in comparison to cyclosporine.

Whether or not a cyclosporine A (CsA)-free immunosuppressant regimen based on sirolimus (SRL) prevents aortic stiffening and improves central hemodynamics in renal recipients remains unknown. Forty-four patients (48 ± 2 years) enrolled in the CONCEPT trial were randomized at week 12 (W12) to continue CsA or switch to SRL, both associated with mycophenolate mofetil. Carotid systolic blood pressure (cSBP), pulse pressure (cPP), central pressure wave reflection (augmentation index, AIx) and carotid-to-femoral pulse-wave velocity (PWV: aortic stiffness) were blindly assessed at W12, W26 and W52 together with plasma endothelin-1 (ET-1), thiobarbituric acid-reactive substances (TBARS) and superoxide dismutase (SOD) and catalase erythrocyte activities. At W12, there was no difference between groups. At follow-up, PWV, cSBP, cPP and AIx were lower in the SRL group. The difference in PWV remained significant after adjustment for blood pressure and eGFR. In parallel, ET-1 decreased in the SRL group, while TBARS, SOD and catalase erythrocyte activities increased in both groups but to a lesser extent in the SRL group. Our results demonstrate that a CsA-free regimen based on SRL reduces aortic stiffness, plasma endothelin-1 and oxidative stress in renal recipients suggesting a protective effect on the arterial wall that may be translated into cardiovascular risk reduction.

[Role of vascular calcium-activated potassium channels in the regulation of human peripheral conduit artery diameter]. / Rô1e des canaux potassiques calcium-dépendants dans la régulation du diamètre basal des artères de conductance périphériques humaines.

The role of an endothelium-derived hyperpolarizing factor (EDHF), acting through the opening of vascular calcium-activated potassium (K(Ca)) channels, in the regulation of the basal diameter of human peripheral conduit arteries has never been investigated in vivo. We measured in 7 healthy subjects the effect of the local infusion of an inhibitor of K(Ca) channels, tetraethylammonium chloride (TEA, 9 micromol/min, 8 min), on radial artery diameter (echotracking) and flow (Doppler). Endothelium-independent dilatation was assessed before and after TEA using sodium nitroprusside (SNP: 5, 10 and 15 nmol/min, 3 min each). TEA induced a decrease in radial artery diameter (2.65 +/- 0.09 to 2.52 +/- 0.09 mm: p < 0.05) and flow (9.4 +/- 1.2 to 7.4 +/- 1.1 ml/min; p < 0.01) without modification in the radial artery dilatation in response to SNP (NS). The decrease in radial artery diameter was still significant even when the decrease in flow was taken as covariate into analysis (p < 0.05). These results demonstrate the role of vascular K(Ca) channels in the regulation of basal peripheral conduit artery diameter and arteriolar tone in human strongly suggesting the involvement of an EDHF a these two levels.

[Hand skin heating: a new method for the evaluation of conduit artery endothelial function in insulin-dependent diabetic patients]. / Le chauffa e cutané distal: une nouvelle méthode d'étude de la fonction endothéliale des artères de conductance périphériques chez le diabétique insulinodépendant.

The presence of an altered endothelium-mediated flow-dependent dilatation (FDD) of peripheral conduit arteries in insulin-dependent diabetic patients without microangiopathy is still controversial. We studied 10 normotensive and non atherosclerotic insulin-dependent diabetic patients (D group) without complication (neuropathy, microalbuminuria or neuropathy) and 10 control subjects (C group) matched for age, sex and BMI. Radial artery diameter (RAD, echotracking) and flow (RAF, Doppler) were measured at baseline and during FDD in response to distal hand skin heating (from 34 to 44 degrees C). a method developed to increase RAF by stable steps by decreasing gradually hand skin vascular resistance. Endothelium-independent dilatation was evaluated by administration of glyceryl trinitrate (GTN: 0.3 mg spray). At baseline, there was no difference between group for RAF (C: 18 +/- 5 vs D: 18 +/- 2 mL/min; NS) and RAD (C: 2.51 +/- 0.12 vs D: 2.54 +/- 0.07 mm; NS). Heating induced in the diabetic group a smaller increase in RAF (C: 473 +/- 126% vs D: 262 +/- 63%; p<0.05) and RAD (C: 22.6 +/- 2.6% vs D: 16.1 +/- 1.8%; p<0.01). This last result remains significant when the increase in RAF was included into the analysis of RAD variation during heating (p<0.05). GTN-induced dilatation was similar in the 2 groups. Our results obtained by use of the hand skin heating method demonstrate the presence of an abnormal arteriolar skin reactivity and an altered peripheral conduit artery endothelium-dependent dilatation in uncomplicated insulin-dependent diabetic patients. The early identification of these anomalies, with negative prognostic value, could contribute to the management of these patients.

[Role of endothelium-derived nitric oxide in sustained flow-dependent dilatation of human peripheral conduit arteries]. / Rôle du monoxyde d'azote dans la dilatation débit-dépendante des artères de conductance périphériques en réponse à une stimulation soutenue.

Endothelial dysfunction is involved in the pathogenesis of cardiovascular diseases and is generally associated to the decrease in arterial nitric oxide (NO) availability. In humans, endothelial function can be evaluated by the post-ischaemic flow-dependent dilatation (FDD) of peripheral conduit arteries which is mainly mediated by the NO release when short duration of reactive hyperaemia are used (3 to 5 min ischaemia). However, recent studies suggest that the role of NO in this response decreases as the duration of the hyperaemic stimulation increases. The aim of the present study was thus, to evaluate, in healthy subjects, the role of NO in the FDD of conduct arteries in response to a sustained stimulation. Radial artery diameter (echotracking) and flow (Doppler) were measured, 7 cm under the elbow line, at baseline and during post-ischaemic hyperaemia (10 min wrist cuff inflation) in 10 healthy subjects (age: 24 +/- 1 years) in control period and after acute blockade of the endothelial NO-synthase by local infusion of NG-monomethyl L-arginine (L-NMMA, brachial artery, 8 mumol/min, 7 min). Endothelium-independent dilatation was studied by mean of sodium nitroprusside infusion (SNP: 5, 10 and 20 nmol/min, 3 min each dose before and after L-NMMA). L-NMMA administration decreased radial artery blood flow at base (Control: 14 +/- 2 vs L-NMMA: 10 +/- 1 ml/min, P < 0.05) and increased radial artery vasodilatation in response to SNP (P < 0.05) thus, demonstrating NO-synthase inhibition. Therefore, after L-NMMA there was a small decrease in radial FDD (Control: base: 2.52 +/- 0.05 mm, FDD: 11.3 +/- 0.6% vs L-NMMA: base: 2.51 +/- 0.04 mm: FDD: 9.0 +/- 0.9%; p < 0.05) without change in hyperaemia. In conclusion, our results demonstrate, in contrast to those obtained after short duration of hyperaemia, that the relative implication of NO in the flow-dependent vasodilatation of peripheral conduit arteries in humans decreases in response to sustained stimulation and suggest, in these experimental conditions, an associated flow-dependent vasodilating mechanism that is unaffected by the NO-synthase inhibition.

Chronic ACE inhibition enhances the endothelial control of arterial mechanics and flow-dependent vasodilatation in heart failure.

Reduced conduit arteries flow-dependent dilatation and altered compliance have been described during heart failure. However, the role of shear stress, the relation between endothelial dysfunction and mechanics, and the effect of chronic ACE inhibition on this relationship have not been investigated. The present study was designed to evaluate in heart failure patients the relationship between flow-dependent dilatation and radial artery mechanics at known shear stress levels and to assess the effect of chronic ACE inhibition. Sixteen stable congestive heart failure patients, who had never been treated with ACE inhibitors, participated in the study. Arterial pressure, cardiac output (bioimpedance), radial artery diameter (echo tracking) and flow (Doppler), total blood viscosity, and mean artery wall shear stress were assessed before and during a gradual increase in the forearm blood flow in response to gradual distal hand skin heating. Cross-sectional radial artery compliance and distensibility indexes were calculated at 34 degrees C, 40 degrees C, and 44 degrees C. The endothelium-independent vasodilatation was evaluated by use of glyceryl trinitrate. All parameters were assessed before and 24 hours after the last administration of perindopril (4 mg once daily) or placebo in a 2-month double-blind randomized study. Before treatment, there was no difference between the 2 groups for all parameters. After chronic ACE inhibition, systolic arterial pressure decreased at baseline from 126+/-11 to 118+/-10 mm Hg (P<0.05). During heating, the increase in diameter in response to shear stress was higher after ACE inhibition than after placebo (time/treatment interaction, P<0.05). Moreover, in contrast to placebo, at the same shear stress, there was a significant increase in compliance (3.23+/-0.79 x 10(-7) to 6.82+/-2.47 x 10(-7) m(2)/kPa, P<0.05) and distensibility (5.71+/-1.35 x 10(-3) to 8.87+/-1.88 x 10(-3)/kPa, P<0.05) during heating after ACE inhibition. The effect of glyceryl trinitrate did not change. The present study demonstrates that chronic administration of the ACE inhibitor perindopril increases the magnitude of the flow-dependent dilatation and restores the flow-dependent increase in compliance and distensibility of the radial artery evaluated at stable shear stress. In addition, the decrease in baseline systolic arterial pressure after ACE inhibitor suggests an associated increase in the distensibility of the proximal elastic conduit arteries.

Role of arterial smooth muscle tone and geometry in the regulation of peripheral conduit artery mechanics by shear stress.

1. Although arterial blood flow is recognized as an important modulator of vascular tone and geometry, the effect of acute changes in shear-stress on conduit artery mechanics has not been fully investigated in humans because of technical limitations. 2. To assess, respectively, the effects of decreases and increases in flow and shear stress on radial artery tone and mechanics, arterial pressure (photoplethysmography), total blood viscosity, radial artery internal diameter, wall thickness (echotracking) and blood flow (Doppler) were measured in healthy volunteers (mean (+/-SEM) age 25 +/- 1 years) during a distal flow arrest (n=12) and hand skin heating (n=18). 3. Radial artery flow decreased from 31 +/- 4 to 7 +/- 1 10(-3) L/min during distal flow arrest (P < 0.001) and increased from 10 +/- 2 to 22 +/- 4 and 69 +/- 6 10(-3) L/min during heating (P < 0.001). At mean arterial pressure, these changes in flow were respectively associated with a parallel flow-dependent reduction and increase in diameter and midwall stress. There was no significant modification in mean elastic modulus. Compliance did not change when flow decreased and only increased at the highest level of flow. Finally, the cross-sectional compliance and incremental modulus were fitted as functions of midwall stress. The decrease in flow was associated with an upward shift of the modulus-midwall stress curve and a downward shift of the compliance-midwall stress curve. The increase in flow was associated with a downward shift of the modulus-midwall stress curve and an upward shift of the compliance-midwall stress curve at each level of wall shear stress. 4. By using two different procedures, we obtained similar results concerning the direct effects of increases and decreases in flow on stiffness of the arterial wall and on arterial compliance and demonstrated the presence of a flow-dependent regulation of arterial smooth muscle tone of peripheral conduit arteries in humans.

Divergent effects of verapamil and amlodipine at rest and during exercise.

OBJECTIVE: To evaluate, in healthy volunteers, the effects of acute administration of two calcium antagonists with different pharmacological profiles, verapamil and amlodipine, on haemodynamics at rest and during exercise. SUBJECTS AND METHODS: Six healthy volunteers (aged 20-29 years) were randomly assigned to receive single oral doses of amlodipine (5 mg), slow-release verapamil (240 mg) or a placebo during a double-blind cross-over study. Systolic (SAP), diastolic and mean arterial pressures (measured using a cuff sphygmomanometer), heart rate (HR), cardiac index (CI, bioimpedance), rate-pressure product (SAP x HR), and noradrenaline and adrenaline plasma levels were measured at rest before drug administration, and at rest and during graded bicycle exercise (steps of 50, 100 and 150 W during 3, 3 and 4 min, respectively) started 3 h after drug administration. RESULTS: At rest arterial pressure, HR, rate-pressure product and catecholamine plasma levels did not change after verapamil or amlodipine administration, whereas CI significantly decreased after verapamil (from 3.9 +/- 0.4 to 3.3 +/- 0.4 l/min per m2) but not after amlodipine (3.9 +/- 0.3 and 4.1 +/- 0.5 l/m per m2) administration. During exercise the increases in SAP and HR were slightly but not significantly higher after amlodipine than after verapamil administration, rate-pressure product and CI were higher after amlodipine (22 +/- 1 x 10(3) mmHg x beats/min and 13 +/- 2 l/min per m2, respectively) than after verapamil (20 +/- 1 x 10(3) mmHg x beats/min and 10 +/- 2 l/min per m2, respectively) administration. Plasma levels of noradrenaline and adrenaline were similar at rest after each treatment and were slightly more increased after amlodipine administration during exercise. CONCLUSIONS: In contrast to amlodipine, verapamil induced a slight myocardial depressive effect at rest and did not potentiate the myocardial effects of the sympathetic stimulation induced by exercise. The myocardial action of verapamil is such as to induce some decrease in myocardial oxygen demand, both at rest and during exercise.

Role of nitric oxide in the regulation of the mechanical properties of peripheral conduit arteries in humans.

Whether nitric oxide (NO) contributes to the regulation of the mechanical properties of large arteries in humans is not known. We measured the effect of local administration of the inhibitor of NO synthesis N(G)-monomethyl-L-arginine (L-NMMA; 1 and 4 micromol x L[-1] x min[-1] for 5 minutes) and acetylcholine (3 and 30 nmol x L[-1] x min[-1] for 3 minutes) on radial artery diameter and wall thickness in 11 healthy volunteers using an echo-tracking system coupled to a measurement of radial blood flow (Doppler) and arterial pressure. At the highest dose, L-NMMA reduced radial blood flow but surprisingly decreased incremental elastic modulus (from 1.36+/-0.22 to 1.00+/-0.22 kPa x 10[3]; P<.05) and increased arterial compliance (from 3.20+/-0.46 to 4.07+/-0.45 m2 x kPa x 10(-8), P<.05), without affecting radial artery internal diameter, wall thickness or midwall stress, thus reflecting a decrease in vascular tone. Acetylcholine decreased incremental elastic modulus (from 1.27+/-0.08 to 0.88+/-0.07 kPa x 10[3]; P<.05) and increased arterial diameter, radial blood flow, and compliance (from 2.82+/-0.16 to 5.30+/-0.62m2 x kPa x 10[-8]; P<.05). These results demonstrate in vivo that NO is involved in the regulation of the mechanical properties of large arteries in humans. However, the effects of L-NMMA, ie, a decrease in arterial wall rigidity and an increase in arterial compliance, which occur in the absence of any changes in blood pressure or arterial geometry, suggest that inhibition of NO synthesis is associated in humans with a paradoxical isometric smooth muscle relaxation. This effect could be due to the development of compensatory vasodilating mechanisms after NO synthesis inhibition.

Evaluation of the determinants of flow-mediated radial artery vasodilatation in humans.

The relative importance of the early peak response during hyperaemia and of the duration of the hyperaemic phase (t1/2: blood flow velocity half time and AUCt1/2: area under the curve of flow velocity at t1/2) in the magnitude of the flow-dependent vasodilatation of the radial artery was determined in humans. Radial artery diameter was measured continuously in 18 healthy volunteers using an echo-tracking system coupled to a Doppler device for the measurement of the radial blood flow. In 9 subjects, arterial parameters were measured at baseline and during 3 hyperaemic tests performed after 2, 5 or 10 minutes of ischaemia. Reproducibility of the measured parameters was studied in 9 other subjects. Radial artery diameter, AUCt1/2 and t1/2 increased proportionally with the duration of ischaemia. In contrast, the peak flow response was already maximal after 5 minutes of ischaemia. The regression analysis showed that the best fit model after stepwise analysis only included t1/2 (r = 0.85, p < 0.001). There was no correlation between the peak flow values and the duration of hyperaemia (r = 0.29, p = 0.14). These results demonstrate that conduit arteries postischaemic flow-dependent vasodilatation in humans is both determined by the peak value and by the duration of the hyperaemic phase and suggest that these two components must be considered when comparing this index of NO release between different groups of subjects.

Altered flow-dependent vasodilatation of conduit arteries in maintenance haemodialysis.

BACKGROUND: An altered arterial nitric oxide (NO) pathway could partly explain the damage to arteries observed in haemodialyzed (HD) patients. The present study was designed to non-invasively evaluate the NO pathway of peripheral conduit arteries in HD patients. METHODS: Twelve normotensive, non-diabetic HD patients treated with erythropoietin and 12 matched healthy controls (C) were included in the study. The effect of endogenous release of NO was assessed by measuring the flow-dependent vasodilatation of the radial artery (post-ischaemic hyperaemia), and the response to exogenous NO assessed using sublingual glyceryl trinitrate administration (GTN). RESULTS: Radial artery diameter (echo-tracking), radial blood flow (RBF: Doppler) and mean arterial pressure (Finapres) were identical at baseline in HD patients and in healthy subjects. The flow-dependent vasodilatation of the radial artery was decreased in HD patients (C: 9 +/- 1% vs HD: 3 +/- 05%, P < 0.05). The decrease in radial vascular resistance (C: -44 +/- 4% vs HD: -24 +/- 2%, P < 0.05) and the increase in radial diameter (C: 31 +/- 2% vs HD: 25 +/- 2%, P < 0.05) after GTN administration were less in HD patients than in controls. The ratio between the increase in diameter after hyperaemia to the increase in diameter after GTN, was also diminished in HD patients (C: 30 +/- 3% vs HD: 13 +/- 2%, P < 0.001). CONCLUSIONS: The flow-dependent vasodilatation of peripheral conduit arteries is altered in HD patients and is associated with a slight but significant decrease in the vasodilating response to exogenous NO. These results suggest, in the absence of changes in basal radial vascular resistance and arterial diameter, more a decrease in endothelial NO bioavailability, than an increase in basal vascular tone.

Fixed-dose combination of perindopril with indapamide in spontaneously hypertensive rats: haemodynamic, biological and structural effects.

OBJECTIVE: The present study was designed to test the effects of chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor (perindopril) and of the diuretic indapamide in spontaneously hypertensive rats (SHR). METHODS: Adult SHR were treated with placebo or increasing doses of the combination of the drugs (0.3, 1 and 3 mg/kg per day; ratio of doses 0.32). In a separate set of experiments, the effects of the drugs combined (1 mg/kg per day) was compared with those induced by each drug alone. RESULTS: The drug combination dose-dependently decreased systolic blood pressure and its hypotensive effect was more marked than those induced by each treatment administered alone (untreated 208 +/- 5 mmHg, indapamide 185 +/- 5 mmHg, perindopril 150 +/- 3 and the combination 123 +/- 7 mmHg). A 12-week treatment with the drug combination (1 mg/kg per day) was not accompanied by any change in diuresis or urinary excretion of Na or K. The same treatment decreased cardiac hypertrophy and collagen. At the vascular level, the drug combination decreased aortic, carotid and femoral media cross-sectional areas, as well as aortic and carotid collagen density. This latter effect was accompanied by a significant increase in carotid artery compliance assessed in vivo at constant pressure. Finally, in isolated aortae, chronic combined drug treatment was associated with an increased basal release of nitric oxide and a decrease in the hypertension-induced endothelium-dependent contractions in response to acetylcholine. CONCLUSION: These experiments suggest that chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor and a diuretic such as indapamide may be of value in the treatment of hypertension.

Role of basal and stimulated release of nitric oxide in the regulation of radial artery caliber in humans.

Although it is well established that nitric oxide contributes to the regulation of resistance arterial tone in humans, its role at the level of large arteries is less clear. Therefore, we assessed in healthy volunteers the effect of local administration of the inhibitor of nitric oxide synthesis NG-monomethyl-L-arginine (L-NMMA) on basal radial artery diameter (transcutaneous A-mode echotracking) and radial blood flow (Doppler) as well as on the radial response to acetylcholine and the nitric oxide donor sodium nitroprusside. A catheter was inserted into the brachial artery for measurement of arterial pressure and infusion of L-NMMA (2, 4 and 8 mumol/min for 5 minutes, n = 11), acetylcholine (3, 30, 300 and 900 nmol/min for 3 minutes, n = 8), and nitroprusside (2.5, 5, 10, and 20 nmol/min for 3 minutes, n = 6). None of the treatments affected arterial blood pressure or heart rate. L-NMMA dose-dependently decreased radial blood flow (from 31 +/- 6 to 17 +/- 3 10(-3) L/min after 8 mumol/min, P < .01) but did not affect radial artery diameter (from 2.93 +/- 0.11 to 2.90 +/- 0.14 mm). Acetylcholine dose-dependently increased radial blood flow (154 +/- 43% after 900 nmol/min) and radial artery diameter (16 +/- 4%), and both effects were markedly reduced after L-NMMA (increase in radial blood flow and radial artery diameter: 22 +/- 20% and 3 +/- 2%, respectively; both P < .01 versus controls). Nitroprusside also dose-dependently increased radial artery diameter (14 +/- 4% after 20 nmol/min) but only moderately affected radial blood flow (47 +/- 21%).(ABSTRACT TRUNCATED AT 250 WORDS)

[Role of nitric oxide in the regulation of the mechanical properties of peripheral muscular arteries in man]. / Rôle du monoxyde d'azote dans la régulation des propriétés mécaniques des artères musculaires périphériques chez l'homme.

Although several experiments have demonstrated the existence of a basal NO-dependent vasodilatory tone at the arteriolar level, the contribution of NO to the mechanical properties of large arteries has not been investigated in humans. To evaluate the effect of NO-synthase inhibition on these mechanical properties, radial artery internal diameter (d, mm) and wall thickness (h, mm) were measured continuously in 11 healthy volunteers (age: 24 +/- 1 years), using an A-mode echo-tracking system coupled to a Doppler device for the measurement of radial blood flow (RBF, ml/min). A catheter was inserted in the brachial artery for measurement of arterial pressure (AP, mmHg), and infusion of the inhibitor of NO synthesis NG-monomethyl L-arginine (L-NMMA: 4 mumol/min for 5 min, infusion rate 0.8 ml/min). Arterial compliance C, 10(-3) mm2/mmHg), distensibility (D, 10(-3)/mmHg), mid-wall stress (sigma, 10(5) dynes/mm2) and incremental modulus (Ei, 10(7) dynes/mm2) were calculated before and after L-NMMA. After L-NMMA, RBF decreased from 31 +/- 6 to 23 +/- 4 (p < 0.05), radial vascular resistance increased from 2.70 +/- 0.35 to 3.77 +/- 0.55 (p < 0.05), without changes in AP or heart rate. Table shows mechanical parameters, assessed at fixed AP (80 mmHg) (*: p < 0.05 vs baseline): [table: see text] Thus, the L-NMMA-induced decrease in radial arterial wall stiffness (Ei) without changes in arterial diameter or stress demonstrates that NO-synthase inhibition induces an isometric relaxation of vascular muscle cells, which explains the increase of arterial compliance at constant mid-wall stress. These results demonstrate that NO contributes to the regulation of peripheral muscular arterial mechanics in humans. At the level of large arteries, the isometric relaxation observed after NO-synthase inhibition is probably the consequence of compensatory vasodilator mechanisms.

Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo.

BACKGROUND: Experimental evidence suggests that flow-dependent dilatation of conduit arteries is mediated by nitric oxide (NO) and/or prostacyclin. The present study was designed to assess whether NO or prostacyclin also contributes to flow-dependent dilatation of conduit arteries in humans. METHODS AND RESULTS: Radial artery internal diameter (ID) was measured continuously in 16 healthy volunteers (age, 24 +/- 1 years) with a transcutaneous A-mode echo-tracking system coupled to a Doppler device for the measurement of radial blood flow. In 8 subjects, a catheter was inserted into the brachial artery for measurement of arterial pressure and infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 8 mumol/min for 7 minutes; infusion rate, 0.8 mL/min). Flow-dependent dilatation was evaluated before and after L-NMMA or aspirin as the response of the radial artery to an acute increase in flow (reactive hyperemia after a 3-minute cuff wrist occlusion). Under control conditions, release of the occlusion induced a marked increase in radial blood flow (from 24 +/- 3 to 73 +/- 11 mL/min; P < .01) followed by a delayed increase in radial diameter (flow-mediated dilatation; from 2.67 +/- 0.10 to 2.77 +/- 0.12 mm; P < .01) without any change in heart rate or arterial pressure. L-NMMA decreased basal forearm blood flow (from 24 +/- 3 to 13 +/- 3 mL/min; P < .05) without affecting basal radial artery diameter, heart rate, or arterial pressure, whereas aspirin (1 g PO) was without any hemodynamic effect. In the presence of L-NMMA, the peak flow response during hyperemia was not affected (76 +/- 12 mL/min), but the duration of the hyperemic response was markedly reduced, and the flow-dependent dilatation of the radial artery was abolished and converted to a vasoconstriction (from 2.62 +/- 0.11 to 2.55 +/- 0.11 mm; P < .01). In contrast, aspirin did not affect the hyperemic response nor the flow-dependent dilatation of the radial artery. CONCLUSIONS: The present investigation demonstrates that NO, but not prostacyclin, is essential for flow-mediated dilatation of large human arteries. Hence, this response can be used as a test for the L-arginine/NO pathway in clinical studies.

Influence of sympathetic tone on mechanical properties of muscular arteries in humans.

Although smooth muscle tone is a key determinant of mechanical properties of arteries in animal experiments, it has not yet been studied in humans because of technical limitations. To assess the influence of tone on arterial properties in humans and to emphasize the interest of calculation at specific stress, we used echo tracking and photoplethysmographic measurement of arterial pressure to study radial arterial mechanics during a cold pressor test (CPT) in 12 healthy volunteers (28 +/- 2 yr). During CPT, mean arterial pressure rose from 83 +/- 3 to 106 +/- 5 mmHg (P < 0.05), internal diameter decreased from 2.75 +/- 0.15 to 2.54 +/- 0.14 mm (P < 0.05), and wall thickness increased from 0.576 +/- 0.027 to 0.634 +/- 0.029 mm (P < 0.05). At a specific pressure (105 mmHg), midwall stress and incremental modulus decreased whereas arterial compliance increased. The incremental modulus of elasticity and compliance were fitted as functions of pressure and of midwall stress. CPT decreased the modulus about equally at all wall stresses measured. The modulus decreased and the compliance increased at every level of pressure measured. At all levels of midwall stress, the compliance was decreased. Thus acute sympathetic stimulation induced by CPT decreases the wall stiffness of human arteries in vivo. This may be explained by an unloading of stiffer wall components during active arterial constriction.

[Changes in the mechanical properties of the arterial wall evaluated in vivo in the spontaneously hypertensive rat]. / Modification des propriétés mécaniques de la paroi artérielle évaluées in vivo chez les rats spontanément hypertendus.

Recent experiments demonstrated increased isobaric arterial compliance and distensibility in hypertensive patients, which could be explained by a decrease in arterial wall stress, when assessed at constant pressure. We investigated the effect of hypertension on the mechanical properties of the carotid arterial wall, and especially wall stress, assessed in vivo in spontaneously hypertensive rats (SHR). Right carotid artery internal diameter (ID) and wall thickness (WT) were continuously monitored in 30 week old anesthetized SHR (n = 8) or their normotensive controls (WKY, n = 7), using a high resolution (1 micron) transcutaneous A-mode echo-tracking system (NIUS 2), coupled to a measurement of left carotid arterial pressure (micromanometer). Mean arterial pressure was 123 +/- 6 in WKY and 202 +/- 2 mmHg in SHR (p < 0.01). Mechanical parameters were calculated at mean pressure from ID and WT-pressure curves (*: p < 0.01 vs WKY). There was no difference between the groups for ID (WKY: 1.13 +/- 0.07; SHR: 1.20 +/- 0.06 mm, NS) and mid-wall stress (WKY: 10.5 +/- 1.2; SHR: 10.5 +/- 0.7 10(5) dynes/cm2, NS) while WT was increased in SHR (WKY: 105 +/- 8; SHR: 191 +/- 16 microns, p < 0.01). In SHR, incremental modulus (wall rigidity) was increased (WKY: 0.86 +/- 0.09; SHR: 1.96 +/- 0.25 10(7) dynes/cm2, p < 0.01) while distensibility (WKY: 1.77 +/- 0.16; SHR: 0.54 +/- 0.06 10(-3) mmHg-1, p < 0.01) and compliance (WKY: 1.84 +/- 0.30; SHR: 0.61 +/- 0.07 10(-3) mm2/mmHg, p < 0.01) were decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

[Role of nitric oxide in flow-dependent vasodilation of human peripheral arteries in vivo]. / Rôle du monoxyde d'azote dans la vasodilatation débit-dépendante d'une artère périphérique humaine in vivo.

Experiments performed in isolated arteries or in animals suggested that flow-dependent dilatation of conduit arteries is mediated through the release of endothelium-derived nitric oxide (NO). The present study was designed to assess whether NO also contributes to flow-dependent dilatation of conduit arteries in humans. Radial artery internal diameter was measured in 8 healthy volunteers (age 22 +/- 1 years), using a transcutaneous A-mode echo-tracking system, coupled to a Doppler device for the measurement of radial blood flow. A catheter was inserted in the brachial artery for measurement of arterial pressure and infusion of the L-arginine analogue NG-monomethyl L-arginine (L-NMMA (8 mumol/min for 7 min, infusion rate 0.8 ml/min). Flow-dependent dilatation was evaluated before and after L-NMMA as the response of the radial artery to an acute increase in flow (reactive hyperemia after a 3 min distal cuff occlusion). Release of the occlusion induced a significant increase in radial blood flow (from 27 +/- 4 to 82 +/- 13 ml/min; p < 0.01) followed by a delayed increase in radial diameter (flow-mediated dilatation; from 2.77 +/- 0.13 to 2.85 +/- 0.13 min; p < 0.01), without any change in heart rate or arterial pressure. L-NMMA induced a significant decrease in basal forearm blood flow (from 27 +/- 4 to 14 +/- 2 ml/min; p < 0.05), without affecting basal radial artery diameter, heart rate or arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)