Aortic baroreflex control of heart rate after 15 days of simulated microgravity exposure.

To determine the effects of simulated microgravity on aortic baroreflex control of heart rate, we exposed seven male subjects (mean age 38 +/- 3 yr) to 15 days of bed rest in the 6 degrees head-down position. The sensitivity of the aortic-cardiac baroreflex was determined during a steady-state phenylephrine-induced increase in mean arterial pressure combined with lower body negative pressure to counteract central venous pressure increases and neck pressure to offset the increased carotid sinus transmural pressure. The aortic-cardiac baroreflex gain was assessed by determining the ratio of the change in heart rate to the change in mean arterial pressure between baseline conditions and aortic baroreceptor-isolated conditions (i.e., phenylephrine + lower body negative pressure + neck pressure stage). Fifteen days of head-down tilt increased the gain of the aortic-cardiac baroreflex (from 0.45 +/- 0.07 to 0.84 +/- 0.18 beats.min-1.mmHg-1; P = 0.03). Reductions in blood volume and/or maximal aerobic capacity may represent the underlying mechanism(s) responsible for increased aortic baroreflex responsiveness after exposure to a ground-based analogue of microgravity.

Altered thermoregulatory responses after 15 days of head-down tilt.

To determine whether extended exposure to a simulation of microgravity alters thermoregulatory reflex control of skin blood flow, six adult males (mean age 40 +/- 2 yr) were exposed to 15 days of 6 degrees head-down tilt (HDT). On an ambulatory control day before HDT exposure and on HDT day 15, the core temperature of each subject was increased by 0.5-1.0 degree C by whole body heating with a water-perfused suit. Mean skin temperature, oral temperature (Tor), mean arterial pressure, and forearm blood flow were measured throughout the protocol. Forearm vascular conductance (FVC) was calculated from the ratio of forearm blood flow to mean arterial pressure. After HDT exposure, the Tor threshold at which reflex thermally induced increases in FVC began was elevated (36.87 +/- 0.06 to 37.00 +/- 0.09 degrees C; P = 0.043), whereas the slope of the Tor-FVC relationship after this threshold was reduced (13.7 +/- 2.3 to 9.5 +/- 1.1 FVC units/degrees C; P = 0.038). Moreover, normothermic FVC and FVC at the highest common Tor between pre- and post-HDT trials were reduced after HDT (normothermic: 4.2 +/- 0.5 to 3.0 +/- 0.4 ml.100 ml-1.min-1.100 mmHg-1, P = 0.04; hyperthermic: 12.4 +/- 1.0 to 7.8 +/- 0.7 ml.100 ml-1.min-1.100 mmHg-1, P < 0.001). These data suggest that HDT exposure reduces thermoregulatory responses to heat stress. The mechanisms resulting in such an impaired thermoregulatory response are unknown but are likely related to the relative dehydration that accompanies this exposure.

Contribution of nitric oxide and prostaglandins to reactive hyperemia in human forearm.

We investigated the separate and combined contributions of nitric oxide (NO) and vasodilating prostaglandins as mediators of reactive hyperemia in the human forearm. Forearm blood flow (FBF) was measured with venous occlusion plethysmography after 5 min of ischemia. In one protocol (n = 12), measurements were made before and after intra-arterial administration of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) to one forearm. In a separate protocol (n = 7), measurements were made before and after systemic administration of the cyclooxygenase inhibitor ibuprofen and again after L-NMMA. L-NMMA reduced baseline FBF at rest (2.7 +/- 0.4 to 1.6 +/- 0.2 ml.100 ml-1.min-1; P < 0.05) and had a modest effect on peak forearm vascular conductance and flow (forearm vascular conductance = 31.1 +/- 3.1 vs. 25.7 +/- 2.5 ml.min-1.100 ml forearm-1.100 mmHg of perfusion pressure-1.min-1, P < 0.05; FBF = 26.6 +/- 2.9 vs. 22.8 +/- 2.6 ml.100 ml-1.min-1, P = 0.055). Total excess flow above baseline during reactive hyperemia was unaffected by L-NMMA (14.3 +/- 3.0 vs. 13.1 +/- 2.4 ml/100 ml; P < 0.05). Ibuprofen did not change FBF at rest, reduced peak FBF from 27.6 +/- 1.9 to 20.3 +/- 2.7 ml.100 ml-1.min-1 (P < 0.05), but had no effect on total excess flow above baseline, Infusion of L-NMMA after ibuprofen reduced FBF at rest by 40%, had no effect on peak flow, but reduced total excess flow above baseline from 12.0 +/- 2.5 to 7.6 +/- 1.3 ml/100 ml (P < 0.05). These date demonstrate that NO synthase inhibition has a modest effect on peak vasodilation during reactive hyperemia but plays a minimal role later. Prostaglandins appear to be important determinants of peak flow. The effects of NO synthase inhibition during reactive hyperemia may also be potentiated by concurrent cyclooxygenase inhibition.

Effects of exercise on hip range of motion, trunk muscle performance, and gait economy.

BACKGROUND AND PURPOSE: The purposes of this study were (1) to examine the effects of a passive hip extension stretching exercise program on hip extension range of motion (ROM), (2) to examine the effects of a trunk flexor exercise program on trunk flexor muscle performance, and (3) to examine the effects of passive hip extension stretching or trunk flexor exercises on walking and running economy. ("Gait economy" is defined as the steady-state oxygen consumption per unit of body weight required to walk or run at a specified velocity.) SUBJECTS: Twenty-five healthy, athletic, male college students (mean age = 21 years, mean weight = 75 kg, mean height = 172 cm) were randomly assigned to one of three groups: a control group (n = 7), a hip extension stretching group (n = 9), or a trunk flexor exercise group (n = 9). METHODS: Before and after 3 weeks of intervention, the following measurements were obtained: right and left hip extension ROM, trunk flexor muscle performance, and walking and running economy. A three x two-way (groups x test sessions) analysis of variance (ANOVA) for repeated measures for unequal subject numbers was performed on each of the five dependent measures, with analysis of simple main effects applied when significant interactions were found. RESULTS: The ANOVA on right and left hip extension ROM revealed a significant interaction. Analyses of simple main effects showed that 3 weeks (six sessions) of passive hip extension stretching significantly improved right hip extension ROM (pretest = -20.4 degrees, posttest = -8.3 degrees) and left hip extension ROM (pretest = -16.8 degrees, posttest = -7.0 degrees). There also was a significant interaction for trunk flexor muscle performance. The analysis of simple main effects revealed that 3 weeks of daily trunk flexor exercises significantly improved trunk flexor muscle performance (pretest = 41.5 degrees, posttest = 60.4 degrees). The 3-week intervention program of hip extension stretching or trunk flexion exercises, however, did not produce significant changes in walking or running economy. CONCLUSION AND DISCUSSION: The results suggest that (1) six treatment sessions of passive stretching were sufficient to improve hip extension ROM; (2) 3 weeks of exercises performed daily improved trunk flexor muscle performance; and (3) training of isolated tasks, such as hip flexibility or trunk strengthening activities, did not produce the desired outcome in the economy of walking or running. Possible reasons for the results are discussed.

Catecholamine response to maximal exercise following 16 days of simulated microgravity.

INTRODUCTION: We tested the hypothesis that the elevated peak heart rate (HR) response to maximal exercise following microgravity exposure is associated with increased plasma levels of catecholamines. METHODS: To do this, plasma norepinephrine (NE) and epinephrine (E) were measured in venous blood samples obtained from 7 subjects before and immediately after graded supine cycle exercise to volitional fatigue performed prior to and at the conclusion of 16 d of 6 degrees head-down tilt (HDT). RESULTS: Resting HR was increased (p = 0.014) following HDT (56 +/- 3 to 63 +/- 2 bpm), but pre-exercise NE concentration (217 +/- 18 pg.ml-1) was not different (p = 0.224) from that measured before HDT (183 +/- 23 pg.ml-1). Peak exercise HR was greater (p = 0.001) after simulated microgravity exposure compared to pre-HDT (181 +/- 3 bpm vs. 172 +/- 4 bpm). NE measured at volitional fatigue was 64% higher (p = 0.004) after HDT compared to that measured prior to HDT (1337 +/- 181 vs. 2191 +/- 189 pg.ml-1 for pre- and post-HDT, respectively). Plasma E concentration at exhaustion was unchanged by microgravity exposure. CONCLUSIONS: Our observation of greater levels of plasma NE and peak exercise HR suggests that sympathetic influences on cardiac chronotropic control may be altered by exposure to prolonged microgravity.

Power spectral and time based analysis of heart rate variability following 15 days head-down bed rest.

Power spectral and time based analyses were applied to the cardiac inter-beat interval (RRI) of 8 healthy men before and after 15 d of bed rest in the 6 degrees head-down tilt position (HDT) to determine changes in indices of cardiac parasympathetic and sympathetic activity after this exposure. At 24 h prior to HDT and on HDT day 15, a minimum of 256 RRI's were obtained from an electrocardiogram (ECG) while the subjects were in the supine position. RRI was subjected to power spectral and two methods of time-based analyses. Power spectral analysis demonstrated that the index of cardiac vagal activity was reduced (95.2 +/- 28.5 to 48.2 +/- 17.4 ms2) without affecting the index of cardiac sympathetic activity (1.18 +/- 0.7 to 0.69 +/- 0.4). The two methods of time-based analyses, time series and standard deviation analyses, further demonstrated a reduction of cardiac vagal activity post-HDT (5.5 +/- 4 to 4.8 +/- 0.6 ms2; and 42.8 +/- 4.8 to 33.9 +/- 3.3 ms, respectively). These data suggest that exposure to 15 d of HDT reduces cardiac vagal activity, while changes in cardiac sympathetic activity were indistinguishable.

Restoration of peak vascular conductance after simulated microgravity by maximal exercise.

We sought to determine if (i) peak vascular conductance of the calf was reduced following prolonged exposure to simulated microgravity, and (ii) if maximal cycle ergometry performed at the end of microgravity exposure stimulated a restoration of peak calf vascular conductance. To do this, peak vascular conductance of the calf was recorded following ischaemic plantar flexion exercise to fatigue in seven men after 16 days of head-down tilt (HDT) under two conditions: (i) after one bout of maximal supine cycle ergometry completed 24 h prior to performance of ischaemic plantar flexion exercise, and (ii) in a control (no cycle ergometry) condition. Following HDT, peak vascular conductance was reduced in the control condition (0.38 +/- 0.02 to 0.24 +/- 0.02 ml 100 ml-1 min-1 mmHg-1; P = 0.04), but was restored when subjects performed cycle ergometry (0.33 +/- 0.05 to 0.28 +/- 0.04 ml 100 ml-1 min-1 mmHg-1; P = 0.46). After HDT, time to fatigue during ischaemic plantar flexion exercise was not different from pre-HDT 24 h after performance of exhaustive cycle ergometry (120 +/- 24 vs. 122 +/- 19 s), but was decreased in the control condition (116 +/- 11 vs. 95 +/- 8 s; P = 0.07). These data suggest that a single bout of maximal exercise can provide a stimulus to restore peak vascular conductance and maintain time to fatigue during performance of ischaemic plantar flexion exercise.

A single bout of exhaustive exercise affects integrated baroreflex function after 16 days of head-down tilt.

We tested the hypothesis that one bout of maximal exercise performed 24 h before reambulation from 16 days of 6 degrees head-down tilt (HDT) could increase integrated baroreflex sensitivity. Isolated carotid-cardiac and integrated baroreflex function was assessed in seven subjects before and after two periods of HDT separated by 11 mo. On the last day of one HDT period, subjects performed a single bout of maximal cycle ergometry (exercise). Subjects did not exercise after the other HDT period (control). Carotid-cardiac baroreflex sensitivity was evaluated using a neck collar device. Integrated baroreflex function was assessed by recording heart rate (HR) and blood pressure (MAP) during a 15-s Valsalva maneuver (VM) at a controlled expiratory pressure of 30 mmHg. The ratio of change in HR to change in MAP (delta HR/ delta MAP) during phases II and IV of the VM was used as an index of cardiac baroreflex sensitivity. Baroreflex-mediated vasoconstriction was assessed by measuring the late phase II rise in MAP. Following HDT, carotid-cardiac baroreflex sensitivity was reduced (2.8 to 2.0 ms/mmHg; P = 0.05) as was delta HR/ delta MAP during phase II (-1.5 to -0.8 beats/mmHg; P = 0.002). After exercise, isolated carotid baroreflex activity and phase II delta HR/ delta MAP returned to pre-HDT levels but remained attenuated in the control condition. Phase IV delta HR/ delta MAP was not altered by HDT or exercise. The late phase II increase of MAP was 71% greater after exercise compared with control (7 vs. 2 mmHg; P = 0.041).(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced carotid-cardiac baroreflex response and elimination of orthostatic hypotension 24 hours after acute exercise in paraplegics.

To test the hypothesis that an acute bout of maximal exercise can ameliorate orthostatic hypotension consequent to prolonged wheelchair confinement, we evaluated heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure responses during 15 minutes of 70 degrees head-up tilt (HUT) in 10 paraplegic subjects 24 hours after arm crank exercise designed to elicit maximal effort, and during a control (no exercise) conditions. Additionally, the carotid baroreceptor stimulus-cardiac response relationship was determined by measurement of R-R interval during external application of graded pressures to the carotid sinuses. One week separated the treatment conditions. The maximum slope of the carotid-cardiac baroreflex response was increased (p = 0.049) by exercise (6.2 +/- 1.7 msec/mmHg) compared to control (3.3 +/- 0.6). During control HUT, HR increased from 61 +/- 1 to 90 +/- 7 bpm (p = 0.001) while SBP decreased from 118 +/- 5 to 106 +/- 9 mmHg (p = 0.025). During HUT 24 hours after exercise, HR increased from 60 +/- 2 to 90 +/- 4 bpm (p = 0.001), but the reduction in SBP was essentially eliminated (116 +/- 5 to 113 +/- 5 mmHg). The reduction in SBP during control HUT (-12.0 +/- 4.6 mmHg) was four-fold larger (p = 0.017) than during HUT following exercise (-3.1 +/- 3.9 mmHg). DBP during HUT was not altered in either condition. A single bout of intense, dynamic arm crank exercise eliminated orthostatic hypotension in paraplegics. Equal HR response with smaller reduction in SBP during HUT after exercise was consistent with a measured increased sensitivity of the carotid-cardiac baroreflex.(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic functions and orthostatic responses 24 h after acute intense exercise in paraplegic subjects.

We tested the hypothesis that a bout of graded exercise designed to elicit maximal effort would increase the sensitivity of autonomically mediated baroreflexes and enhance blood pressure (BP) stability in subjects prone to postural hypotension. Therefore, we measured heart rate (HR), BP, forearm vascular resistance (FVR), and vasoactive hormone responses before and during 15 min of 70 degrees head-up tilt (HUT) in 10 paraplegic subjects (21-65 yr) on two occasions: 1) 24 h after maximal arm-crank exercise (postexercise) and 2) without exercise (control). During HUT, HR increased 30 beats/min in both postexercise and control, but the reduction in systolic BP (SBP) during control (-12.0 +/- 4.6 mmHg) was larger (P = 0.017) than that during HUT after exercise (-0.3 +/- 4.3 mmHg). The postexercise increase in FVR from supine to HUT of 17.0 +/- 2.4 to 24.8 +/- 3.2 peripheral resistance units (PRU) was greater (P = 0.042) than the increase observed during control (18.3 +/- 3.7 to 19.5 +/- 3.1 PRU). The gain of the carotid-cardiac baroreflex was also increased (P = 0.049) after exercise. Responses in norepinephrine, vasopressin, and plasma renin-angiotensin induced by HUT were similar for control and postexercise, and there was no difference in either leg compliance or plasma volume between the two conditions. Additionally, HR and SBP responses to phases II and IV of the Valsalva maneuver, indexes of integrated baroreflex sensitivity, were increased (P < 0.05) after maximal exercise compared with control. Thus acute intense exercise eliminated orthostatic hypotension in paraplegics, was associated with increased FVR and baroreflex sensitivity, and was independent of blood volume changes.

Restoration of plasma volume after 16 days of head-down tilt induced by a single bout of maximal exercise.

Seven healthy men performed maximal exercise 24 h before the end of 16 days exposure to 6 degrees head-down tilt (HDT) to test the hypothesis that such an exercise technique could restore plasma volume (PV) at the end of a simulated space mission. Exercise consisted of supine cycling with graded work rates increasing by 16 W/min to volitional fatigue and required an average of 16 min. The experimental protocol was a standard cross-over design in which the order of treatment (exercise or control) was counterbalanced across all seven subjects. PV, fluid intake (ad libitum), urine output, renal function, and hormones associated with fluid homeostasis were measured before HDT, 24 h before the end of HDT just prior to exercise, and at the end of HDT 24 h after exercise. HDT reduced PV by 16% in both control and exercise conditions. Maximal exercise completely restored plasma volume within 24 h to 3.9 +/- 3.2% of pre-HDT levels despite continued HDT. Compared with control, exercise induced a 660-ml larger positive fluid balance because of greater fluid intake and reduced urine volume during the 24 h after exercise. These results suggest that one bout of maximal leg exercise before return from 16 days of spaceflight may be completely effective in stimulating thirst and restoring plasma volume to preflight levels.

Application of acute maximal exercise to protect orthostatic tolerance after simulated microgravity.

We tested the hypothesis that one bout of maximal exercise performed at the conclusion of prolonged simulated microgravity would improve blood pressure stability during an orthostatic challenge. Heart rate (HR), mean arterial blood pressure (MAP), norepinephrine (NE), epinephrine (E), arginine vasopressin (AVP), plasma renin activity (PRA), atrial natriuretic peptide (ANP), cardiac output (Q), forearm vascular resistance (FVR), and changes in leg volume were measured during lower body negative pressure (LBNP) to presyncope in seven subjects immediately prior to reambulation from 16 days of 6 degrees head-down tilt (HDT) under two experimental conditions: 1) after maximal supine cycle ergometry performed 24 h before returning to the upright posture (exercise) and 2) without exercise (control). After HDT, the reduction of LBNP tolerance time from pre-HDT levels was greater (P = 0.041) in the control condition (-2.0 +/- 0.2 min) compared with the exercise condition (-0.4 +/- 0.2 min). At presyncope after HDT, FVR and NE were higher (P < 0.05) after exercise compared with control, whereas MAP, HR, E, AVP, PRA, ANP, and leg volume were similar in both conditions. Plasma volume (PV) and carotid-cardiac baroreflex sensitivity were reduced after control HDT, but were restored by the exercise treatment. Maintenance of orthostatic tolerance by application of acute intense exercise after 16 days of simulated microgravity was associated with greater circulating levels of NE, vasoconstriction, Q, baroreflex sensitivity, and PV.

Does sympathetic activation blunt nitric oxide-mediated hyperemia in the human forearm?

To determine if the vasodilating substance nitric oxide (NO) interferes with the ability of sympathetic nerves to regulate blood flow in humans, forearm blood flow (FBF) was measured during brachial artery infusions of acetylcholine (ACh) to evoke endothelial NO release, and during infusions of the NO donor nitroprusside (NTP) in five healthy volunteers. Sympathetic activity was increased by application of lower body suction and antagonized by brachial artery infusions of phentolamine. In the control condition, FBF was 2.4 +/- 0.4 ml/100 ml per min and rose by 16.9 +/- 3.6 ml/100 ml per min during ACh at 16 micrograms/min and by 17.0 +/- 4.3 ml/100 ml per min at 64 micrograms/min. With suction, FBF was 1.7 +/- 0.6 ml/100 ml per min (p < 0.05 versus control) and rose by 11.4 +/- 3.2 ml/100 ml per min during ACh at 16 micrograms/min (p < 0.05 versus control). After phentolamine, FBF was 3.8 +/- 0.5 ml/100 ml per min at baseline (p < 0.05 versus control) and the increases in flow with ACh at either 16 or 64 micrograms/min were identical to control. During the control NTP trial, FBF rose by 6.3 +/- 1.1 ml/100 ml per min with NTP at 2.5 micrograms/min and by 12.1 +/- 1.4 ml/100 ml per min at 10 micrograms/min. Suction blunted and phentolamine augmented the increases in flow with NTP by approximately 50% (p < 0.05). Due to the unexpected results with ACh, the effects of suction and pharmacological sympathectomy with both phentolamine and bretylium on ACh-mediated dilation were evaluated with lower doses of ACh (8 and 32 micrograms/min) in six additional studies. Again, altered sympathetic activity had inconsistent effects on the rise in FBF with ACh administration. The effects of altered sympathetic activity on the blood flow responses to NTP indicate that sympathetic activity can modulate NO-mediated vasodilation, suggesting that NO does not have a major sympatholytic effect in the human forearm. That sympathetic activity did not consistently alter ACh-mediated vasodilation suggests that vasodilating mechanisms, in addition to NO release, can be activated by arterial administration of ACh in the human forearm.

Increased beta-adrenergic responsiveness induced by 14 days exposure to simulated microgravity.

Increased sensitivity of end-organ responses to neuroendocrine stimuli as a result of prolonged exposure to the relative inactivity of microgravity has recently been hypothesized. This notion is based on the inverse relationship between circulating norepinephrine and beta-adrenoreceptor sensitivity. Beta-adrenoreceptor activity is reduced in individuals who have elevated plasma norepinephrine as as a result of regular exposure to upright posture and physical exercise. In contrast, adrenoreceptor hypersensitivity has been reported in patients with dysautonomias in which circulating catecholamines are absent or reduced. Taken together, these studies and the observation that circulating plasma norepinephrine has been reduced during spaceflight and in groundbased simulations of microgravity prompt the suggestion that adrenoreceptor hypersensitivity may be a consequence of the adaptation to spaceflight. We conducted an experiment designed to measure cardiovascular responses to adrenoreceptor agonists in human subjects before and after prolonged exposure to 6 degrees head-down tilt (HDT) to test the hypothesis that adaptation to microgravity increases adrenoreceptor responsiveness, and that this adaptation is associated with reduced levels of circulating norepinephrine.

Evidence for increased beta-adrenoreceptor responsiveness induced by 14 days of simulated microgravity in humans.

We studied hemodynamic responses to alpha- and beta-receptor agonists in eight healthy men before and after 14 days of 6 degrees head-down tilt (HDT) to test the hypothesis that increased adrenoreceptor responsiveness is induced by prolonged exposure to simulated microgravity. Steady-state infusions of isoproterenol (Iso) at rates of 0.005, 0.01, and 0.02 microgram.kg-1.min-1 were used to assess beta 1- and beta 2-adrenoreceptor responsiveness. Infusions of phenylephrine (PE) at rates of 0.25, 0.50, and 1.00 microgram.kg-1.min-1 were used to assess responsiveness of alpha 1-vascular adrenoreceptors. Slopes calculated from linear regressions between Iso and PE doses and changes in beat-to-beat heart rate, blood pressure, and leg vascular resistance (occlusion plethysmography) for each subject were used as an index of alpha- and beta-adrenoreceptor responsiveness. HDT increased the slopes of heart rate (1,056 +/- 107 to 1,553 +/- 83 beats micrograms-1.kg-1.min-1; P = 0.014) and vasodilation (-469 +/- 111 to -1,446 +/- 309 peripheral resistance units.microgram-1.kg-1.min-1; P = 0.0224) to Iso infusion. There was no alteration in blood pressure or vascular resistance responses to PE infusion after HDT. Our results provide evidence that simulated microgravity causes selective increases in beta 1- and beta 2-adrenoreceptor responsiveness without affecting alpha 1-vascular adrenoreceptor responses.

Evidence for nitric oxide-mediated sympathetic forearm vasodiolatation in humans.

1. Our aim was to determine if sympathetic vasodilatation occurs in the human forearm, and if the vasodilating substance nitric oxide contributes to this dilatation. We also sought to determine if the nitric oxide might be released as a result of cholinergic stimulation of the vascular endothelium. 2. Blood flow was measured in the resting non-dominant forearm with venous occlusion plethysmography. To increase sympathetic traffic to the resting forearm, rhythmic handgrip exercise to fatigue followed by post-exercise ischaemia was performed by the dominant forearm. A brachial artery catheter in the non-dominant arm was used to selectively infuse drugs. 3. During control conditions, there was mild vasodilatation in the resting forearm during exercise followed by constriction during post-exercise ischaemia. When exercise was performed after brachial artery administration of bretylium (to block noradrenaline release) and phentolamine (an alpha-adrenergic antagonist), profound vasodilatation was seen in the resting forearm during both exercise and post-exercise ischaemia. 4. When the nitric oxide synthase blocker NG-monomethyl-L-arginine (L-NMMA) was administered in the presence of bretylium and phentolamine prior to another bout of handgripping, little or no vasodilatation was seen either during exercise or post-exercise ischaemia. Atropine also blunted the vasodilator responses to exercise and post-exercise ischaemia after bretylium and phentolamine. 5. These results support the existence of active sympathetic vasodilatation in the human forearm and the involvement of nitric oxide in this phenomenon. They also suggest nitric oxide might be released as a result of cholinergic stimulation of the vascular endothelium.