Jan T. Groothuis

Angiotensin II contributes to the increased baseline leg vascular resistance in spinal cord-injured individuals.

Objective Spinal cord-injured (SCI) individuals demonstrate an increased baseline leg vascular resistance (LVR). In addition, despite the lack of sympathetic control, an increase in LVR is observed during orthostatic challenges. On the basis of the vasoconstrictive characteristics of angiotensin II, we examined the hypothesis that angiotensin II contributes to the LVR at baseline and during head-up tilt (HUT) in SCI individuals. Methods Supine baseline leg and forearm blood flow were measured using venous occlusion plethysmography and leg blood flow during 30° HUT using duplex ultrasound. Measurements were performed before and 4 h after an angiotensin II antagonist (irbesartan, 150 mg) administered in eight SCI individuals and eight age-matched and sex-matched able-bodied controls. Vascular resistance was calculated as the arterial–venous pressure gradient divided by blood flow. Results Angiotensin II blockade significantly decreased baseline LVR in SCI individuals (P = 0.02) but not in controls, whereas no changes in forearm vascular resistance were found in both groups. Angiotensin II blockade did not alter the increase in LVR during HUT in SCI individuals nor in controls. Conclusion Our results indicate that angiotensin II contributes to the increased baseline LVR in SCI individuals. As angiotensin II does not contribute to forearm vascular resistance, the contribution to LVR may relate to the extreme inactivity of the legs in SCI individuals. Angiotensin II does not contribute to the increase in LVR during HUT in SCI individuals nor in controls.

Complete absence of evening melatonin increase in tetraplegics

Individuals with a spinal cord injury (SCI), especially with tetraplegia, experience poor sleep quality, and this may be related to impaired control of circadian rhythmicity. Here, we examined the evening onset of melatonin secretion, an important hormone for the initiation of sleep, in people with a complete cervical (tetraplegia) and thoracic (paraplegia) SCI, and age‐ and sex‐matched able‐bodied control participants. Multiple samples of salivary melatonin were obtained during the evening hours and analyzed by ELISA methods in 10 control partcipants, 9 individuals with paraplegia, and 6 individuals with tetraplegia. Sleep quality was assessed using questionnaires. Interactive effects of group and time were found for melatonin levels (P=0.022). In the control and paraplegia groups, the mean melatonin level increased significantly from 2.59 ± 1.04 and 4.28 ± 3.28 pg/ml at 7 PM to 10.62 ± 4.59 and 13.10 ± 7.39 pg/ml at 11 PM, respectively (P<0.001). In the tetraplegia group, melatonin level was 5.25 ± 3.72 at 7 PM but only 2.41 ± 1.25 pg/ml at 11 PM (P>0.05). Decreased sleep quality was more prevalent in individuals with tetraplegia (83%) and paraplegia (75%) compared with controls (20%; P= 0.02). Unlike in the control and paraplegia groups, the evening increase in melatonin concentration was completely absent in the tetraplegia group. This provides biological insight into sleep regulation in humans and provides better understanding of the poor sleep quality in people with tetraplegia.—Verheggen, R. J., Jones, H., Nyakayiru, J., Thompson, A., Groothuis, J. T., Atkinson, G., Hopman, M. T., Thijssen, D. H. Complete absence of evening melatonin increase in tetraplegics. FASEB J. 26, 3059–3064 (2012). www.fasebj.org

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.

Leg crossing with muscle tensing, a physical counter-manoeuvre to prevent syncope, enhances leg blood flow

In patients with orthostatic intolerance, the mechanisms to maintain BP (blood pressure) fail. A physical counter-manoeuvre to postpone or even prevent orthostatic intolerance in these patients is leg crossing combined with muscle tensing. Although the central haemodynamic effects of physical counter-manoeuvres are well documented, not much is known about the peripheral haemodynamic events. Therefore the purpose of the present study was to examine the peripheral haemodynamic effects of leg crossing combined with muscle tensing during 70 degrees head-up tilt. Healthy subjects (n=13) were monitored for 10 min in the supine position followed by 10 min in 70 degrees head-up tilt and, finally, for 2 min of leg crossing with muscle tensing in 70 degrees head-up tilt. MAP (mean arterial BP), heart rate, stroke volume, cardiac output and total peripheral resistance were measured continuously by Portapres. Leg blood flow was measured using Doppler ultrasound. Leg vascular conductance was calculated as leg blood flow/MAP. A significant increase in MAP (13 mmHg), stroke volume (27%) and cardiac output (18%), a significant decrease in heart rate (-5 beats/min) and no change in total peripheral resistance during the physical counter-manoeuvre were observed when compared with baseline 70 degrees head-up tilt. A significant increase in leg blood flow (325 ml/min) and leg vascular conductance (2.9 arbitrary units) were seen during the physical counter-manoeuvre when compared with baseline 70 degrees head-up tilt. In conclusion, the present study indicates that the physical counter-manoeuvre of leg crossing combined with muscle tensing clearly enhances leg blood flow and, at the same time, elevates MAP.

Does peripheral nerve degeneration affect circulatory responses to head-up tilt in spinal cord-injured individuals?

Despite the loss of centrally mediated sympathetic vasoconstriction, spinal cord-injured (SCI) individuals cope surprisingly well with orthostatic challenges. In the pathophysiology of this intriguing observation spinal sympathetic—, veno-arteriolar—(VAR), and myogenic reflexes seem to play a role. The purpose of this study was to assess whether central (stroke volume, heart rate, blood pressure and total peripheral resistance) and peripheral (leg blood flow, leg vascular resistance and femoral arterial diameter) hemodynamic responses to head-up tilt are different in two groups of SCI patients, i. e., SCI individuals with upper motor neuron lesions (who have spinal reflexes, VAR and myogenic reflexes) (U; n=6) and those with lower motor neuron lesion (who have no spinal reflexes, perhaps no VAR due to nerve degeneration, but intact myogenic reflexes) (L; n=5). Ten healthy male individuals served as controls (C) (normal supraspinal sympathetic control and presence of all reflexes). After 10 min supine rest all individuals were tilted to 30° head-up tilt. Red blood cell velocity (measured by echo Doppler ultrasound) in the femoral artery decreased and vascular resistance increased significantly in all three groups in the upright position compared with supine. Mean arterial pressure (MAP) remained unchanged in U and L and increased significantly in C in the upright versus supine position. The present study shows that all SCI individuals were able to maintain MAP by increasing leg vascular resistance during head-up tilt, despite nerve degeneration in L and lack of centrally mediated sympathetic control in all SCI individuals. Results of the present study suggest that not spinal reflexes but local (myogenic) reflex activity plays a pivotal role in peripheral vascular responses upon head-up tilt when central control mechanisms fail.

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.

Sympathetic Nonadrenergic Transmission Contributes to Autonomic Dysreflexia in Spinal Cord–Injured Individuals

Autonomic dysreflexia is a hypertensive episode in spinal cord–injured individuals induced by exaggerated sympathetic activity and thought to be &agr;-adrenergic mediated. &agr;-Adrenoceptor antagonists have been a rational first choice; nevertheless, calcium channel blockers are primarily used in autonomic dysreflexia management. However, &agr;-adrenoceptor blockade may leave a residual vasoconstrictor response to sympathetic nonadrenergic transmission unaffected. The aim was to assess the &agr;-adrenergic contribution and, in addition, the role of supraspinal control to leg vasoconstriction during exaggerated sympathetic activity provoked by autonomic dysreflexia in spinal cord–injured individuals and by a cold pressure test in control individuals. Upper leg blood flow was measured using venous occlusion plethysmography during supine rest and during exaggerated sympathetic activity in 6 spinal cord–injured individuals and 7 able-bodied control individuals, without and with phentolamine (&agr;-adrenoceptor antagonist) and nicardipine (calcium channel blocker) infusion into the right femoral artery. Leg vascular resistance was calculated. In spinal cord–injured individuals, phentolamine significantly reduced the leg vascular resistance increase during autonomic dysreflexia (8±5 versus 24±13 arbitrary units; P=0.04) in contrast to nicardipine (15±10 versus 24±13 arbitrary units; P=0.12). In controls, phentolamine completely abolished the leg vascular resistance increase during a cold pressure test (1±2 versus 18±14 arbitrary units; P=0.02). The norepinephrine increase during phentolamine infusion was larger (P=0.04) in control than in spinal cord–injured individuals. These results indicate that the leg vascular resistance increase during autonomic dysreflexia in spinal cord–injured individuals is not entirely &agr;-adrenergic mediated and is partly explained by nonadrenergic transmission, which may, in healthy subjects, be suppressed by supraspinal control.

Lower vascular tone and larger plasma volume in Parkinson's disease with orthostatic hypotension

The pathophysiology of orthostatic hypotension in Parkinsons disease (PD) is incompletely understood. The primary focus has thus far been on failure of the baroreflex, a central mediated vasoconstrictor mechanism. Here, we test the role of two other possible factors: 1) a reduced peripheral vasoconstriction (which may contribute because PD includes a generalized sympathetic denervation); and 2) an inadequate plasma volume (which may explain why plasma volume expansion can manage orthostatic hypotension in PD). We included 11 PD patients with orthostatic hypotension (PD + OH), 14 PD patients without orthostatic hypotension (PD - OH), and 15 age-matched healthy controls. Leg blood flow was examined using duplex ultrasound during 60° head-up tilt. Leg vascular resistance was calculated as the arterial-venous pressure gradient divided by blood flow. In a subset of 9 PD + OH, 9 PD - OH, and 8 controls, plasma volume was determined by indicator dilution method with radiolabeled albumin ((125)I-HSA). The basal leg vascular resistance was significantly lower in PD + OH (0.7 ± 0.3 mmHg·ml(-1)·min) compared with PD - OH (1.3 ± 0.6 mmHg·ml(-1)·min, P < 0.01) and controls (1.3 ± 0.5 mmHg·ml(-1)·min, P < 0.01). Leg vascular resistance increased significantly during 60° head-up tilt with no significant difference between the groups. Plasma volume was significantly larger in PD + OH (3,869 ± 265 ml) compared with PD - OH (3,123 ± 377 ml, P < 0.01) and controls (3,204 ± 537 ml, P < 0.01). These results indicate that PD + OH have a lower basal leg vascular resistance in combination with a larger plasma volume compared with PD - OH and controls. Despite the increase in leg vascular resistance during 60° head-up tilt, PD + OH are unable to maintain their blood pressure.

Leg vasoconstriction during head-up tilt in patients with autonomic failure is not abolished

Maintaining blood pressure during orthostatic challenges is primarily achieved by baroreceptor-mediated activation of the sympathetic nervous system, which can be divided into preganglionic and postganglionic parts. Despite their preganglionic autonomic failure, spinal cord-injured individuals demonstrate a preserved peripheral vasoconstriction during orthostatic challenges. Whether this also applies to patients with postganglionic autonomic failure is unknown. Therefore, we assessed leg vasoconstriction during 60° head-up tilt in five patients with pure autonomic failure (PAF) and two patients with autonomic failure due to dopamine-β-hydroxylase (DBH) deficiency. Ten healthy subjects served as controls. Leg blood flow was measured using duplex ultrasound in the right superficial femoral artery. Leg vascular resistance was calculated as the arterial-venous pressure gradient divided by blood flow. DBH-deficient patients were tested off and on the norepinephrine pro-drug l-threo-dihydroxyphenylserine (l-DOPS). During 60° head-up tilt, leg vascular resistance increased significantly in PAF patients [0.40 ± 0.38 (+30%) mmHg·ml(-1)·min(-1)]. The increase in leg vascular resistance was not significantly different from controls [0.88 ± 1.04 (+72%) mmHg·ml(-1)·min(-1)]. In DBH-deficient patients, leg vascular resistance increased by 0.49 ± 0.01 (+153%) and 1.52 ± 1.47 (+234%) mmHg·ml(-1)·min(-1) off and on l-DOPS, respectively. Despite the increase in leg vascular resistance, orthostatic hypotension was present in PAF and DBH-deficient patients. Our results demonstrate that leg vasoconstriction during orthostatic challenges in patients with PAF or DBH deficiency is not abolished. This indicates that the sympathetic nervous system is not the sole or pivotal mechanism inducing leg vasoconstriction during orthostatic challenges. Additional vasoconstrictor mechanisms may compensate for the loss in sympathetic nervous system control.

The effect of inspired oxygen fraction on peak oxygen uptake during arm exercise

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