Miriam Kooijman

Flow-mediated dilatation in the superficial femoral artery is nitric oxide mediated in humans

Flow‐mediated dilatation (FMD) of the brachial and radial arteries is an important research tool for assessment of endothelial function in vivo, and is nitric oxide (NO) dependent. The leg skeletal muscle vascular bed is an important territory for studies in exercise physiology. However, the role of endothelial NO in the FMD response of lower limb arteries has never been investigated. The purpose of this study was to examine the contribution of NO to FMD in the superficial femoral artery in healthy subjects. Since physical inactivity may affect endothelial function, and therefore NO availability, spinal cord‐injured (SCI) individuals were included as a model of extreme deconditioning. In eight healthy men (34 ± 13 years) and six SCI individuals (37 ± 10 years), the 5 min FMD response in the superficial femoral artery was assessed by echo‐Doppler, both during infusion of saline and during infusion of the NO synthase blocker NG‐monomethyl‐l‐arginine (l‐NMMA). In a subset of the controls (n= 6), the 10 min FMD response was also examined using the same procedure. The 5 min FMD response in controls (4.2 ± 0.3%) was significantly diminished during l‐NMMA infusion (1.0 ± 0.2%, P < 0.001). In SCI, l‐NMMA also significantly decreased the FMD response (from 8.2 ± 0.4% during saline to 2.4 ± 0.5% during l‐NMMA infusion). The hyperaemic flow response during the first 45 s after cuff deflation was lower in both groups during infusion of l‐NMMA, but the effect of l‐NMMA on FMD persisted in both groups after correction for the shear stress stimulus. The 10 min FMD was not affected by l‐NMMA (saline: 5.4 ± 1.6%, l‐NMMA: 5.6 ± 1.5%). Superficial femoral artery FMD in response to distal arterial occlusion for a period of 5 min is predominantly mediated by NO in healthy men and in the extremely deconditioned legs of SCI individuals.

A Causal Role for Endothelin-1 in the Vascular Adaptation to Skeletal Muscle Deconditioning in Spinal Cord injury

Objective—Endothelin-1 (ET-1) contributes to the increased peripheral resistance in heart failure and hypertension. Physical inactivity is associated with cardiovascular disease and characterized by increased vascular tone. In this study, we assess the contribution of ET-1 to the increased vascular tone in the extremely deconditioned legs of spinal cord-injured (SCI) individuals before and after exercise training. Methods and Results—In 8 controls and 8 SCI individuals, bilateral thigh blood flow was measured by plethysmography before and during the administration of an ETA/ETB-receptor blocker into the femoral artery. In SCI, this procedure was repeated after 6 weeks of electro-stimulated training. In a subset of SCI (n=4), selective ETA-receptor blockade was performed to determine the role of the ETA-receptors. In controls, dual ET-receptor blockade increased leg blood flow at the infused side (10%, P<0.05), indicating a small contribution of ET-1 to leg vascular tone. In SCI, baseline blood flow was lower compared with controls (P=0.05). In SCI, dual ET-receptor blockade increased blood flow (41%, P<0.001). This vasodilator response was significantly larger in SCI compared with controls (P<0.001). The response to selective ETA-receptor blockade was similar to the effect of dual blockade. Electro-stimulated training normalized baseline blood flow in SCI and reduced the response to dual ET-receptor blockade in the infused leg (29%, P=0.04). Conclusion—ET-1 mediates the increased vascular tone of extremely inactive legs of SCI individuals by increased activation of ETA-receptors. Physical training reverses the ET-1-pathway, which normalizes basal leg vascular tone.

Preserved α-Adrenergic Tone in the Leg Vascular Bed of Spinal Cord–Injured Individuals

Background—Supraspinal sympathetic control of leg vascular tone is lost in spinal cord–injured individuals, but this does not result in a reduced leg vascular tone: Leg vascular resistance is even increased. The aim of this study was to assess the &agr;-adrenergic contribution to the increased vascular tone in the lower extremity in patients without central sympathetic control of leg circulation. Methods and Results—Upper-leg vascular resistance responses to local infusion of incremental doses of phentolamine (a competitive antagonist of the &agr;-adrenoceptor) into the femoral artery were determined in 10 spinal cord–injured individuals (SCI) and 8 healthy age-matched control subjects during local &bgr;-adrenergic receptor blockade with propranolol. Basal leg vascular resistance was higher in SCI than in control subjects (41±6 arbitrary units [AU] versus 24±4 AU; P =0.034). The same accounts for minimal leg vascular resistance, assessed during reactive hyperemia, which was higher in SCI compared with control subjects (6.9±1.0 AU versus 2.5±0.2 AU; P <0.01). The maximal phentolamine-induced reduction in leg vascular resistance normalized to each individual’s minimal resistance did not differ between the groups (68±17% and 51±4% for SCI and control subjects, respectively; P >0.1). A decline in mean arterial pressure was observed in both groups with increasing dosage of phentolamine. In response, baroreceptor-mediated vasoconstriction was observed in the noninfused leg of the control subjects, whereas in SCI individuals this reaction was absent. Conclusions—These results indicate that the &agr;-adrenoceptor–mediated vascular tone in the leg is preserved in spinal cord–injured individuals without sympathetic supraspinal control.

Preserved contribution of nitric oxide to baseline vascular tone in deconditioned human skeletal muscle

Deconditioning is a risk factor for cardiovascular disease. Exercise reduces this risk, possibly by improving the vascular endothelial nitric oxide (NO) pathway. The effect of deconditioning on the NO pathway is largely unknown. This study was designed to assess baseline NO availability in the leg vascular bed after extreme, long‐term deconditioning (spinal cord‐injured individuals, SCI) as well as after moderate, short‐term deconditioning (4 weeks of unilateral lower limb suspension, ULLS). For this purpose, seven SCI were compared with seven matched controls. Additionally, seven healthy subjects were studied pre‐ and post‐ULLS. Leg blood flow was measured by venous occlusion plethysmography at baseline and during infusion of 5 incremental dosages of NG‐monomethyl‐l‐arginine (l‐NMMA) into the femoral artery. Sodium nitroprusside (SNP) was infused to test vascular responsiveness to NO. Baseline leg vascular resistance tended to be higher in SCI compared with controls (37 ± 4 versus 31 ± 2 arbitrary units (AU), P= 0.06). Deconditioning altered neither the vasoconstrictor response to l‐NMMA (increase in resistance in SCI versus controls: 102 ± 33%versus 69 ± 9%; pre‐ versus post‐ULLS: 95 ± 18%versus 119 ± 15%), nor the vascular responsiveness to NO. In conclusion, two human in vivo models of deconditioning show a preserved baseline NO availability in the leg skeletal muscle vascular bed.

Leg intravenous pressure during head-up tilt

Leg vascular resistance is calculated as the arterial-venous pressure gradient divided by blood flow. During orthostatic challenges it is assumed that the hydrostatic pressure contributes equally to leg arterial, as well as to leg venous pressure. Because of venous valves, one may question whether, during orthostatic challenges, a continuous hydrostatic column is formed and if leg venous pressure is equal to the hydrostatic pressure. The purpose of this study was, therefore, to measure intravenous pressure in the great saphenous vein of 12 healthy individuals during 30 degrees and 70 degrees head-up tilt and compare this with the calculated hydrostatic pressure. The height difference between the heart and the right medial malleolus level represented the hydrostatic column. The results demonstrate that there were no differences between the measured intravenous pressure and the calculated hydrostatic pressure during 30 degrees (47.2 +/- 1.0 and 46.9 +/- 1.5 mmHg, respectively) and 70 degrees head-up tilt (83.9 +/- 0.9 and 85.1 +/- 1.2 mmHg, respectively). Steady-state levels of intravenous pressure were reached after 95 +/- 12 s during 30 degrees and 161 +/- 15 s during 70 degrees head-up tilt. In conclusion, the measured leg venous pressure is similar to the calculated hydrostatic pressure during orthostatic challenges. Therefore, the assumption that hydrostatic pressure contributes equally to leg arterial as well as to leg venous pressure during orthostatic challenges can be made.

Endothelium-dependent and -independent vasodilation of the superficial femoral artery in spinal cord-injured subjects

Extreme inactivity of the legs in spinal cord-injured (SCI) individuals does not result in an impairment of the superficial femoral artery flow-mediated dilation (FMD). To gain insight into the underlying mechanism, the present study examined nitric oxide (NO) responsiveness of vascular smooth muscles in controls and SCI subjects. In eight healthy men (34 +/- 13 yr) and six SCI subjects (37 +/- 10 yr), superficial femoral artery FMD response was assessed by echo Doppler. Subsequently, infusion of incremental dosages of sodium nitroprusside (SNP) was used to assess NO responsiveness. Peak diameter was examined on a second day after 13 min of arterial occlusion in combination with sublingual administration of nitroglycerine. Resting and peak superficial femoral artery diameter in SCI subjects were smaller than in controls (P < 0.001). The FMD response in controls (4.2 +/- 0.9%) was lower than in SCI subjects (8.2 +/- 0.9%, P < 0.001), but not after correcting for area under the curve for shear rate (P = 0.35). When expressed as relative change from baseline, SCI subjects demonstrate a significantly larger diameter increase compared with controls at each dose of SNP. However, when expressed as a relative increase within the range of diameter changes [baseline (0%) - peak diameter (100%)], both groups demonstrate similar changes in response to SNP. Changes in diameter during SNP infusion and FMD response are larger in SCI subjects compared with controls. When these results are corrected, superficial femoral artery FMD and NO sensitivity in SCI subjects are not different from those in controls. This illustrates the importance of appropriate data presentation and suggests that, subsequent to structural inward remodeling of conduit arteries as a consequence of extreme physical inactivity, arterial function is normalized.

Attenuated peripheral vasoconstriction during an orthostatic challenge in older men

BACKGROUND orthostatic hypotension is common in older men and associated with morbidity and mortality. During orthostatic challenges, older men maintain their blood pressure by an augmented increase in total peripheral resistance. Changes in the leg vascular bed contribute importantly to blood pressure regulation during orthostatic challenges, partly because of blood pooling in the legs. Little is known about the contribution of the leg vascular bed to the augmented increase in total peripheral resistance. OBJECTIVE to examine tilt-induced peripheral vasoconstriction in the leg vascular bed of young and older men. METHODS we measured forearm and calf blood flow in 12 young and 12 older men, using venous occlusion plethysmography during 30 degrees head-up tilt (HUT). Forearm and calf vascular resistance were calculated as mean arterial blood pressure divided by blood flow. RESULTS during HUT, calf and forearm vascular resistance increased in older and young men. The increase in forearm vascular resistance was similar between older (40 +/- 6%) and young men (51 +/- 12%). However, the increase in calf vascular resistance was lower in older (96 +/- 15%) than in young men (175 +/- 30%). CONCLUSION advancing age leads to an attenuated tilt-induced increase in calf vascular resistance, which may contribute to age-related orthostatic hypotension.