M. Iacob

Crucial role of NO and endothelium-derived hyperpolarizing factor in human sustained conduit artery flow-mediated dilatation.

Whether NO is involved or not in sustained conduit artery flow-mediated dilatation in humans remains unclear. Moreover, the role of endothelium-derived hyperpolarizing factor (EDHF), synthesized by cytochrome epoxygenases and acting through calcium-activated potassium channels, and its relationship with NO during flow-mediated dilatation have never been investigated previously. In 12 healthy subjects we measured radial artery diameter (echotracking) and blood flow (Doppler) during flow-mediated dilatation induced by gradual distal hand skin heating (34 to 44°C), during the local infusion of saline and inhibitors of NO synthase (NG-monomethyl-l-arginine [l-NMMA]: 8 to 20 &mgr;mol/min per liter), calcium-activated potassium channels (tetraethylammonium chloride: 9 &mgr;mol/min per liter), and cytochrome epoxygenases (fluconazole: 0.4 to 1.6 &mgr;mol/min per liter), alone and in combination. Mean wall shear stress, the flow-mediated dilatation stimulus, was calculated at each level of flow, and the diameter–wall shear stress relationship was constructed. During heating, compared with saline, the diameter–shear stress relationship was shifted downward by l-NMMA, tetraethylammonium, fluconazole, and, in a more pronounced manner, by the combinations of l-NMMA with tetraethylammonium or with fluconazole. Therefore, maximal radial artery flow-mediated dilatation, compared with saline (0.62±0.03 mm), was decreased under our experimental conditions by l-NMMA (−39±4%), tetraethylammonium chloride (−14±4%), fluconazole (−18±6%), and to a greater extent, by the combinations of l-NMMA with tetraethylammonium (−64±4%) or with fluconazole (−71±3%). This study demonstrates that NO and a cytochrome-related EDHF are involved in peripheral conduit artery flow-mediated dilatation in humans during sustained flow conditions. Moreover, the synergistic effects of the inhibitors strongly suggest a functional interaction between NO and EDHF pathways.

Arterial Stiffness Is Regulated by Nitric Oxide and Endothelium-Derived Hyperpolarizing Factor During Changes in Blood Flow in Humans

Cytochrome-derived epoxyeicosatrienoic acids may be important endothelium-derived hyperpolarizing factors, opening calcium-activated potassium channels, but their involvement in the regulation of arterial stiffness during changes in blood flow in humans is unknown. In healthy volunteers, we measured arterial pressure, radial artery diameter, wall thickness, and flow (NIUS02) during hand skin heating in the presence of saline or inhibitors of NO synthase (NG-monomethyl-l-arginine), calcium-activated potassium channels (tetraethylammonium), and cytochrome epoxygenases (fluconazole). Arterial compliance and elastic modulus were calculated and fitted as functions of midwall stress to suppress the confounding influence of geometric changes. Under saline infusion, heating induced an upward shift of the compliance-midwall stress curve and a downward shift of the modulus-midwall stress curve demonstrating a decrease in arterial tone and stiffness when blood flow increases. These shifts were reduced by NG-monomethyl-l-arginine and abolished by the combinations of NG-monomethyl-l-arginine+tetraethylammonium and NG-monomethyl arginine+fluconazole. In parallel, in isolated mice coronary arteries, fluconazole and tetraethylammonium reduced the relaxations to acetylcholine. However, fluconazole did not affect the relaxations to the openers of calcium-activated potassium channels of small- and intermediate-conductance NS309 and of large-conductance NS1619 excluding a direct effect on these channels. Moreover, tetraethylammonium reduced the relaxations to NS1619 but not to NS309, suggesting that the endothelium-derived hyperpolarizing factor involved mainly acts on large-conductance calcium-activated potassium channels. These results show in humans that, during flow variations, arterial stiffness is regulated by the endothelium through the release of both NO and cytochrome-related endothelium-derived hyperpolarizing factor.

AT1 receptor blockade prevents the decrease in conduit artery flow-mediated dilatation during NOS inhibition in humans.

Whether AT(1) (angiotenin II type 1) receptor blockade can prevent the decrease in conduit artery FMD (flow-mediated dilatation) during NOS (nitric oxide synthase) inhibition by alternative endothelial pathways has not been explored previously in humans. In 12 healthy subjects, we measured radial artery diameter (echotracking) and flow (Doppler) during FMD induced by sustained reactive hyperaemia during a control period and following NOS inhibition [1.5 mg.min(-1).l(-1) L-NMMA (N(G)-monomethyl-L-arginine)], after a single oral administration of telmisartan (80 mg) or placebo, using a randomized double-blind cross-over design. In six volunteers, we also assessed the roles of prostacyclin and EDHF (endothelium-derived hyperpolarizing factor) during radial FMD after AT(1) receptor blockade by oral administration of aspirin (500 mg) alone, aspirin+L-NMMA or aspirin+L-NMMA+fluconazole (a cytochrome epoxygenases inhibitor; 0.37 mg.min(-1).l(-1)). Telmisartan did not affect radial artery FMD in the control period (10.9+/-0.6% with placebo compared with 9.9+/-0.7% with telmisartan), but prevented its decrease after L-NMMA (9.3+/-0.8% with placebo compared with 12.6+/-1.2% with telmisartan; P<0.05) with no modification in baseline parameters, hyperaemia and radial artery endothelium-independent dilatation to sodium nitroprusside. Moreover, in telmisartan-treated subjects, radial artery FMD, compared with control (9.0+/-1.0%), was not modified by aspirin alone (9.4+/-0.7%) or associated with L-NMMA (9.5+/-0.5%), but was reduced by the combination of aspirin, L-NMMA and fluconazole (7.5+/-0.6%; P<0.05). These results demonstrate that AT(1) receptor blockade prevents the decrease in conduit artery FMD during NOS inhibition in humans, suggesting the development of a compensatory endothelial mechanism. This mechanism appears to be independent of prostacyclin and could possibly be related to an EDHF release.

Hypertrophic remodeling and increased arterial stiffness in patients with intracranial aneurysms

OBJECTIVEnBecause an underlying arteriopathy might contribute to the development of intracranial aneurysms (IAs), we assessed the elastic properties of proximal conduit arteries in patients with IA.nnnMETHODSnIn 27 patients with previous ruptured IA and 27 control subjects matched for age, gender and BMI, we determined arterial pressure, internal diameter, intima-media thickness (IMT), circumferential wall stress (CWS) and elastic modulus (wall stiffness) in common carotid arteries using applanation tonometry and echotracking. Moreover, carotid augmentation index (AIx, arterial wave reflections) and carotid-to-femoral pulse wave velocity (PWV, aortic stiffness) were assessed.nnnRESULTSnCompared with controls, patients with IA exhibited higher brachial and carotid systolic and diastolic blood pressures, with similar brachial but higher carotid artery pulse pressure (35 + or - 6mm Hg vs. 41 + or - 8mm Hg, P=0.014). Moreover, patients have higher PWV (7.8 + or - 1.2ms(-1) vs. 8.3 + or - 1.1ms(-1), P=0.048) and AIx (15.8 + or - 10.8% vs. 21.1 + or - 8.5%, P<0.001) which contributes to increase carotid blood pressures. Furthermore, carotid IMT was higher in patients (546 + or - 64 microm vs. 642 + or - 70 microm, P<0.001) without difference in diameter suggesting an adaptive hypertrophy. However, patients display a lower CWS (61.6 + or - 9.2 kPa vs. 56.9 + or - 10.3 kPa, P=0.007) and no correlation between IMT and pulse pressure (r=0.152, P=NS) in contrast to controls (r=0.539, P<0.001) showing the contribution of a pressure-independent process. Finally, despite this lesser CWS, elastic modulus was increased in patients (310 + or - 105 kPa vs. 383 + or - 174 kPa, P=0.026).nnnCONCLUSIONnThis study demonstrates that patients with IA display a particular carotid artery phenotype with an exaggerated hypertrophic remodeling and altered elastic properties. Thus, a systemic arteriopathy might contribute, together with the arterial wall fatiguing effect of the increased pulsatile stress, to the pathogenesis of IA.

I029 The regulation of large artery stiffness by the vascular endothelium includes the control of arterial wall viscosity

Although the viscoelasticity of large arteries has been extensively investigated, few studies have focused on arterial wall viscosity (AWV) itself and its regulation by the endothelium in vivo. This is of particular importance since AWV is a major source of energy dissipation through the vascular system reducing the efficiency of cardiovascular coupling. We simultaneously measured in 8 healthy volunteers (age: 22±1 years) radial artery diameter and arterial pressure (NIUS02) before and after 8xa0min local infusion of L-NMMA (8xa0mmol/min) as NO-synthase inhibitor, tetraethylammonium (TEA: 9xa0mmol/ min), as blocker of calcium-activated potassium channels, the target of endothelium-derived hyperpolarizing factors (EDHF), and L-NMMA+TEA. Arterial pressure and diameter were carefully synchronized and the pressure-diameter relationship were constructed at each cardiac cycle. AWV was estimated from the ratio of the area of the hysteresis loop of the pressure-diameter relationship to the area representing the whole energy exchanged during each cardiac cycle (figure). Radial artery stiffness was evaluated during the whole cardiac cycle by the calculation of cross-sectional distensibility and during the ventricular ejection period by the slope of the ascending loop. L-NMMA did not modify significantly arterial distensibility and ascending slope but, paradoxically reduced AWV (from 29.5±0.7 to 24.9±0.7 %, P=0.05). Conversely, TEA reduced arterial distensibility (from 6.50±0.19 to 5.53±0.2 10-5.kPa, P=0.002) and the ascending slope (from 1.03±0.01 to 0.86±0.03xa0mm.mmHg, P These results demonstrate in vivo in humans that the vascular endothelium contributes, in addition to large artery elasticity, to the regulation of AWV through the release of NO and EDHF Download : Download full-size image .