Human baroreflex rhythms persist during handgrip and muscle ischaemia.

AIM: To determine whether physiological, rhythmic fluctuations of vagal baroreflex gain persist during exercise, post-exercise ischaemia and recovery. METHODS: We studied responses of six supine healthy men and one woman to a stereotyped protocol comprising rest, handgrip exercise at 40% maximum capacity to exhaustion, post-exercise forearm ischaemia and recovery. We measured electrocardiographic R-R intervals, photoplethysmographic finger arterial pressures and peroneal nerve muscle sympathetic activity. We derived vagal baroreflex gains from a sliding (25-s window moved by 2-s steps) systolic pressure-R-R interval transfer function at 0.04-0.15 Hz. RESULTS: Vagal baroreflex gain oscillated at low, nearly constant frequencies throughout the protocol (at approx. 0.06 Hz - a period of about 18 s); however, during exercise, most oscillations were at low-gain levels, and during ischaemia and recovery, most oscillations were at high-gain levels. CONCLUSIONS: Vagal baroreflex rhythms are not abolished by exercise, and they are not overwhelmed after exercise during ischaemia and recovery.

Simultaneous determination of the accuracy and precision of closed-circuit cardiac output rebreathing techniques.

Foreign and soluble gas rebreathing methods are attractive for determining cardiac output (Q(c)) because they incur less risk than traditional invasive methods such as direct Fick and thermodilution. We compared simultaneously obtained Q(c) measurements during rest and exercise to assess the accuracy and precision of several rebreathing methods. Q(c) measurements were obtained during rest (supine and standing) and stationary cycling (submaximal and maximal) in 13 men and 1 woman (age: 24 +/- 7 yr; height: 178 +/- 5 cm; weight: 78 +/- 13 kg; Vo(2max): 45.1 +/- 9.4 ml.kg(-1).min(-1); mean +/- SD) using one-N(2)O, four-C(2)H(2), one-CO(2) (single-step) rebreathing technique, and two criterion methods (direct Fick and thermodilution). CO(2) rebreathing overestimated Q(c) compared with the criterion methods (supine: 8.1 +/- 2.0 vs. 6.4 +/- 1.6 and 7.2 +/- 1.2 l/min, respectively; maximal exercise: 27.0 +/- 6.0 vs. 24.0 +/- 3.9 and 23.3 +/- 3.8 l/min). C(2)H(2) and N(2)O rebreathing techniques tended to underestimate Q(c) (range: 6.6-7.3 l/min for supine rest; range: 16.0-19.1 l/min for maximal exercise). Bartlett's test indicated variance heterogeneity among the methods (P < 0.05), where CO(2) rebreathing consistently demonstrated larger variance. At rest, most means from the noninvasive techniques were +/-10% of direct Fick and thermodilution. During exercise, all methods fell outside the +/-10% range, except for CO(2) rebreathing. Thus the CO(2) rebreathing method was accurate over a wider range (rest through maximal exercise), but was less precise. We conclude that foreign gas rebreathing can provide reasonable Q(c) estimates with fewer repeat trials during resting conditions. During exercise, these methods remain precise but tend to underestimate Q(c). Single-step CO(2) rebreathing may be successfully employed over a wider range but with more measurements needed to overcome the larger variability.

A 30-year follow-up of the Dallas Bedrest and Training Study: I. Effect of age on the cardiovascular response to exercise.

BACKGROUND: Cardiovascular capacity declines with aging, as evidenced by declining maximal oxygen uptake (VO(2)max ), with little known about the specific mechanisms of this decline. Our study objective was to assess the effect of a 30-year interval on body composition and cardiovascular response to acute exercise in 5 healthy subjects originally evaluated in 1966. METHODS AND RESULTS: Anthropometric parameters and the cardiovascular response to acute maximal exercise were assessed with noninvasive techniques. On average, body weight increased 25% (77 versus 100 kg) and percent body fat increased 100% (14% versus 28%), with little change in fat-free mass (66 versus 72 kg). On average, VO(2)max decreased 11% (3.30 versus 2.90 L/min). Likewise, VO(2)max decreased when indexed to total body mass (43 versus 31 mL. kg(-1). min(-1)) or fat-free mass (50 versus 43 mL/kg fat-free mass per minute). Maximal heart rate declined 6% (193 versus 181 bpm) and maximal stroke volume increased 16% (104 versus 121 mL), with no difference observed in maximal cardiac output (20.0 versus 21.4 L/min). Maximal AV oxygen difference declined 15% (16.2 versus 13.8 vol%) and accounted for the entire decrease in cardiovascular capacity. CONCLUSIONS: Cardiovascular capacity declined over the 30-year study interval in these 5 middle-aged men primarily because of an impaired efficiency of maximal peripheral oxygen extraction. Maximal cardiac output was maintained with a decline in maximal heart rate compensated for by an increased maximal stroke volume. Most notably, 3 weeks of bedrest in these same men at 20 years of age (1966) had a more profound impact on physical work capacity than did 3 decades of aging.

A 30-year follow-up of the Dallas Bedrest and Training Study: II. Effect of age on cardiovascular adaptation to exercise training.

BACKGROUND: Aerobic power declines with age. The degree to which this decline is reversible remains unclear. In a 30-year longitudinal follow-up study, the cardiovascular adaptations to exercise training in 5 middle-aged men previously trained in 1966 were evaluated to assess the degree to which the age-associated decline in aerobic power is attributable to deconditioning and to gain insight into the specific mechanisms involved. Methods and Results-- The cardiovascular response to acute submaximal and maximal exercise were assessed before and after a 6-month endurance training program. On average, VO(2max) increased 14% (2.9 versus 3.3 L/min), achieving the level observed at the baseline evaluations 30 years before. Likewise, VO(2max) increased 16% when indexed to total body mass (31 versus 36 mL/kg per minute) or fat-free mass (44 versus 51 mL/kg fat-free mass per minute). Maximal heart rate declined (181 versus 171 beats/min) and maximal stroke volume increased (121 versus 129 mL) after training, with no change in maximal cardiac output (21.4 versus 21.7 L/min); submaximal heart rates also declined to a similar degree. Maximal AVDO(2) increased by 10% (13.8 versus 15.2 vol%) and accounted for the entire improvement of aerobic power associated with training. CONCLUSIONS: One hundred percent of the age-related decline in aerobic power among these 5 middle-aged men occurring over 30 years was reversed by a 6-month endurance training program. However, no subject achieved the same maximal VO(2) attained after training 30 years earlier, despite a similar relative training load. The improved aerobic power after training was primarily the result of peripheral adaptation, with no effective improvement in maximal oxygen delivery.

Cardiac atrophy after bed rest and spaceflight.

Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity of cardiac muscle under different loading conditions.

Regulation of muscle sympathetic nerve activity after bed rest deconditioning.

Cardiovascular deconditioning reduces orthostatic tolerance. To determine whether changes in autonomic function might produce this effect, we developed stimulus-response curves relating limb vascular resistance, muscle sympathetic nerve activity (MSNA), and pulmonary capillary wedge pressure (PCWP) with seven subjects before and after 18 days of -6 degrees head-down bed rest. Both lower body negative pressure (LBNP; -15 and -30 mmHg) and rapid saline infusion (15 and 30 ml/kg body wt) were used to produce a wide variation in PCWP. Orthostatic tolerance was assessed with graded LBNP to presyncope. Bed rest reduced LBNP tolerance from 23.9 +/- 2.1 to 21.2 +/- 1.5 min, respectively (means +/- SE, P = 0.02). The MSNA-PCWP relationship was unchanged after bed rest, though at any stage of the LBNP protocol PCWP was lower, and MSNA was greater. Thus bed rest deconditioning produced hypovolemia, causing a shift in operating point on the stimulus-response curve. The relationship between limb vascular resistance and MSNA was not significantly altered after bed rest. We conclude that bed rest deconditioning does not alter reflex control of MSNA, but may produce orthostatic intolerance through a combination of hypovolemia and cardiac atrophy.

Effects of spaceflight on human calf hemodynamics.

Chronic microgravity may modify adaptations of the leg circulation to gravitational pressures. We measured resting calf compliance and blood flow with venous occlusion plethysmography, and arterial blood pressure with sphygmomanometry, in seven subjects before, during, and after spaceflight. Calf vascular resistance equaled mean arterial pressure divided by calf flow. Compliance equaled the slope of the calf volume change and venous occlusion pressure relationship for thigh cuff pressures of 20, 40, 60, and 80 mmHg held for 1, 2, 3, and 4 min, respectively, with 1-min breaks between occlusions. Calf blood flow decreased 41% in microgravity (to 1.15 +/- 0.16 ml x 100 ml(-1) x min(-1)) relative to 1-G supine conditions (1.94 +/- 0.19 ml x 100 ml(-1) x min(-1), P = 0.01), and arterial pressure tended to increase (P = 0.05), such that calf vascular resistance doubled in microgravity (preflight: 43 +/- 4 units; in-flight: 83 +/- 13 units; P < 0.001) yet returned to preflight levels after flight. Calf compliance remained unchanged in microgravity but tended to increase during the first week postflight (P > 0.2). Calf vasoconstriction in microgravity qualitatively agrees with the "upright set-point" hypothesis: the circulation seeks conditions approximating upright posture on Earth. No calf hemodynamic result exhibited obvious mechanistic implications for postflight orthostatic intolerance.

Nine months in space: effects on human autonomic cardiovascular regulation.

We studied three Russian cosmonauts to better understand how long-term exposure to microgravity affects autonomic cardiovascular control. We recorded the electrocardiogram, finger photoplethysmographic pressure, and respiratory flow before, during, and after two 9-mo missions to the Russian space station Mir. Measurements were made during four modes of breathing: 1) uncontrolled spontaneous breathing; 2) stepwise breathing at six different frequencies; 3) fixed-frequency breathing; and 4) random-frequency breathing. R wave-to-R wave (R-R) interval standard deviations decreased in all and respiratory frequency R-R interval spectral power decreased in two cosmonauts in space. Two weeks after the cosmonauts returned to Earth, R-R interval spectral power was decreased, and systolic pressure spectral power was increased in all. The transfer function between systolic pressures and R-R intervals was reduced in-flight, was reduced further the day after landing, and had not returned to preflight levels by 14 days after landing. Our results suggest that long-duration spaceflight reduces vagal-cardiac nerve traffic and decreases vagal baroreflex gain and that these changes may persist as long as 2 wk after return to Earth.

Central venous pressure and cardiac function during spaceflight.

Early in spaceflight, an apparently paradoxical condition occurs in which, despite an externally visible headward fluid shift, measured central venous pressure is lower but stroke volume and cardiac output are higher, and heart rate is unchanged from reference measurements made before flight. This paper presents a set of studies in which a simple three-compartment, steady-state model of cardiovascular function is used, providing insight into the contributions made by the major mechanisms that could be responsible for these events. On the basis of these studies, we conclude that, during weightless spaceflight, the chest relaxes with a concomitant shape change that increases the volume of the closed chest cavity. This leads to a decrease in intrapleural pressure, ultimately causing a shift of blood into the vessels of the chest, increasing the transmural filling pressure of the heart, and decreasing the central venous pressure. The increase in the transmural filling pressure of the heart is responsible, through a Starling-type mechanism, for the observed increases in heart size, left ventricular end-diastolic volume, stroke volume, and cardiac output.

General recommendations.

NASA: Recommendations from a workshop on Space Neuroscience Research held in Paris on April 22-24, 1997 are summarized. Research areas include the autonomic nervous system, development and neurobiology, posture and movement, visual perception, vestibular function, cognition, and human factors. Long-term neuroscience research studies are being planned for the International Space Station. Experiments in microgravity should be accompanied by appropriate, ground-based research on the effects of gravity.^ieng

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.

Effect of microgravity on renal and femoral flows during LBNP & intravenous saline load.

NASA: Renal and femoral hemodynamics were studied in crew members at rest and during lower body negative pressure before and after the D-2 Spacelab mission and with intravenous saline loading. Specific measurements included renal vascular resistance, femoral arterial flow, and vascular resistance, along with other cardiovascular parameters. Cardiovascular adaptation to microgravity is discussed with a focus on changes observed in femoral and renal vascular resistance.^ieng

Maximal exercise performance after adaptation to microgravity.

The cardiovascular system appears to adapt well to microgravity but is compromised on reestablishment of gravitational forces leading to orthostatic intolerance and a reduction in work capacity. However, maximal systemic oxygen uptake (Vo2) and transport, which may be viewed as a measure of the functional integrity of the cardiovascular system and its regulatory mechanisms, has not been systematically measured in space or immediately after return to Earth after spaceflight. We studied six astronauts (4 men and 2 women, age 35-50 yr) before, during, and immediately after 9 or 14 days of microgravity on two Spacelab Life Sciences flights (SLS-1 and SLS-2). Peak Vo2 (Vo2peak) was measured with an incremental protocol on a cycle ergometer after prolonged submaximal exercise at 30 and 60% of Vo2peak. We measured gas fractions by mass spectrometer and ventilation via turbine flowmeter for the calculation of breath-by-breath Vo2, heart rate via electrocardiogram, and cardiac output (Qc) via carbon dioxide rebreathing. Peak power and Vo2 were well maintained during spaceflight and not significantly different compared with 2 wk preflight. Vo2peak was reduced by 22% immediately postflight (P < 0.05), entirely because of a decrease in peak stroke volume and Qc. Peak heart rate, blood pressure, and systemic arteriovenous oxygen difference were unchanged. We conclude that systemic Vo2peak is well maintained in the absence of gravity for 9-14 days but is significantly reduced immediately on return to Earth, most likely because of reduced intravascular blood volume, stroke volume, and Qc.

Central venous pressure in space.

Gravity affects cardiac filling pressure and intravascular fluid distribution significantly. A major central fluid shift occurs when all hydrostatic gradients are abolished on entry into microgravity (microG). Understanding the dynamics of this shift requires continuous monitoring of cardiac filling pressure; central venous pressure (CVP) measurement is the only feasible means of accomplishing this. We directly measured CVP in three subjects: one aboard the Spacelab Life Sciences-1 space shuttle flight and two aboard the Spacelab Life Sciences-2 space shuttle flight. Continuous CVP measurements, with a 4-Fr catheter, began 4 h before launch and continued into microG. Mean CVP was 8.4 cmH2O seated before flight, 15.0 cmH2O in the supine legs-elevated posture in the shuttle, and 2.5 cmH2O after 10 min in microG. Although CVP decreased, the left ventricular end-diastolic dimension measured by echocardiography increased from a mean of 4.60 cm supine preflight to 4.97 cm within 48 h in microG. These data are consistent with increased cardiac filling early in microG despite a fall in CVP, suggesting that the relationship between CVP and actual transmural left ventricular filling pressure is altered in microG.

Orthostatic intolerance after spaceflight.

Orthostatic intolerance occurs commonly after spaceflight, and important aspects of the underlying mechanisms remain unclear. We studied 14 individuals supine and standing before and after three space shuttle missions of 9-14 days. After spaceflight, 9 of the 14 (64%) crew members could not complete a 10-min stand test that all completed preflight. Pre- and postflight supine hemodynamics were similar in both groups except for slightly higher systolic and mean arterial pressures preflight in the finishers [15 +/- 3.7 and 8 +/- 1.2 (SE) mmHg, respectively; P < 0.05]. Postflight, finishers and nonfinishers had equally large postural reductions in stroke volume (-47 +/- 3.7 and -48 +/- 3.3 ml, respectively) and increases in heart rate (35 +/- 6.6 and 51 +/- 5.2 beats/min, respectively). Cardiac output during standing was also similar (3.6 +/- 0.4 and 4.1 +/- 0.3 l/min, respectively). However, the finishers had a greater postflight vasoconstrictor response with higher total peripheral resistance during standing (22.3 +/- 1.2 units preflight and 29.4 +/- 2.3 units postflight) than did the nonfinishers (20.1 +/- 1.1 units preflight and 19.9 +/- 1.4 units postflight). We conclude that 1) the primary systemic hemodynamic event, i.e., the postural decrease in stroke volume, was similar in finishers and nonfinishers and 2) the heart rate response and cardiac output during standing were not significantly different, but 3) the postural vasoconstrictor response was significantly greater among the finishers (P < 0.01).

Pharmacologic atrial natriuretic peptide reduces human leg capillary filtration.

Atrial natriuretic peptide (ANP) is produced and secreted by atrial cells. We measured calf capillary filtration rate with prolonged venous-occlusion plethysmography of supine healthy male subjects during pharmacologic infusion of ANP (48 pmol/kg/min for 15 min; n = 6) and during placebo infusion (n = 7). Results during infusions were compared to prior control measurements. ANP infusion increased plasma [ANP] from 30 +/- 4 to 2,568 +/- 595 pmol/l. Systemic hemoconcentration occurred during ANP infusion: mean hematocrit and plasma colloid osmotic pressure increased 4.6 and 11.3%, respectively, relative to preinfusion baseline values (p < 0.05). Mean calf filtration, however, was significantly reduced from 0.15 to 0.08 ml/100 ml/min with ANP. Heart rate increased 20% with ANP infusion, whereas blood pressure was unchanged. Calf conductance (blood flow/arterial pressure) and venous compliance were unaffected by ANP infusion. Placebo infusion had no effect relative to prior baseline control measurements. Although ANP induced systemic capillary filtration, in the calf, filtration was reduced with ANP. Therefore, pharmacologic ANP infusion enhances capillary filtration from the systemic circulation, perhaps at upper body or splanchnic sites or both, while having the opposite effect in the leg.

Calf venous compliance measured with head-up tilt equals supine calf compliance.

Elevated calf compliance may contribute to orthostatic intolerance following space flight and bed rest. Calf venous compliance is measured conventionally with venous occulusion plethysmography in supine subjects. With this well-established technique, subjects undergo inflation of a pressure cuff around the thigh just above the knee, which increases calf venous pressure. A plethysmograph simultaneously measures calf volume elevation. Compliance equals calf volume elevation per mm Hg thigh occlusion (calf venous) pressure in relaxed legs of the supine subjects. Compliance may also be measured during stepwise head-up tilt (HUT) as calf volume elevation per mm Hg gravitational venous pressure elevation produced by HUT. However, during HUT on a tilt table with a footplate, calf muscles activate to counteract gravity: this is an obvious and natural response to gravitational force. Such muscle activation conceivably could reduce calf compliance, yet relatively little calf muscle activation occurs during HUT and orthostasis (<10% of maximal voluntary levels). Also, this activation produces minimal calf volume change (<0.3%). Therefore, we hypothesized that calf compliance measured with HUT equals that measured with supine venous occlusion.

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.

Cerebral versus systemic hemodynamics during graded orthostatic stress in humans.

BACKGROUND: Orthostatic syncope is usually attributed to cerebral hypoperfusion secondary to systemic hemodynamic collapse. Recent research in patients with neurocardiogenic syncope has suggested that cerebral vasoconstriction may occur during orthostatic hypotension, compromising cerebral autoregulation and possibly contributing to the loss of consciousness. However, the regulation of cerebral blood flow (CBF) in such patients may be quite different from that of healthy individuals, particularly when assessed during the rapidly changing hemodynamic conditions associated with neurocardiogenic syncope. To be able to interpret the pathophysiological significance of these observations, a clear understanding of the normal responses of the cerebral circulation to orthostatic stress must be obtained, particularly in the context of the known changes in systemic and regional distributions of blood flow and vascular resistance during orthostasis. Therefore, the specific aim of this study was to examine the changes that occur in the cerebral circulation during graded reductions in central blood volume in the absence of systemic hypotension in healthy humans. We hypothesized that cerebral vasoconstriction would occur and CBF would decrease due to activation of the sympathetic nervous system. We further hypothesized, however, that the magnitude of this change would be small compared with changes in systemic or skeletal muscle vascular resistance in healthy subjects with intact autoregulation and would be unlikely to cause syncope without concomitant hypotension. METHODS AND RESULTS: To test this hypothesis, we studied 13 healthy men (age, 27 +/- 7 years) during progressive lower body negative pressure (LBNP). We measured systemic flow (Qc is cardiac output; C2H2 rebreathing), regional forearm flow (FBF; venous occlusion plethysmography), and blood pressure (BP; Finapres) and calculated systemic (SVR) and forearm (FVR) vascular resistances. Changes in brain blood flow were estimated from changes in the blood flow velocity in the middle cerebral artery (VMCA) using transcranial Doppler. Pulsatility (systolic minus diastolic/mean velocity) normalized for systemic arterial pressure pulsatility was used as an index of distal cerebral vascular resistance. End-tidal PACO2 was closely monitored during LBNP. From rest to maximal LBNP before the onset of symptoms or systemic hypotension, Qc and FBF decreased by 29.9% and 34.4%, respectively. VMCA decreased less, by 15.5% consistent with a smaller decrease in CBF. Similarly, SVR and FVR increased by 62.8% and 69.8%, respectively, whereas pulsatility increased by 17.2%, suggestive of a mild degree of small-vessel cerebral vasoconstriction. Seven of 13 subjects had presyncope during LBNP, all associated with a sudden drop in BP (29 +/- 9%). By comparison, hyperventilation alone caused greater changes in VMCA (42 +/- 2%) and pulsatility but never caused presyncope. In a separate group of 3 subjects, superimposition of hyperventilation during highlevel LBNP caused a further decrease in VMCA (31 +/- 7%) but no change in BP or level of consciousness. CONCLUSIONS: We conclude that cerebral vasoconstriction occurs in healthy humans during graded reductions in central blood volume caused by LBNP. However, the magnitude of this response is small compared with changes in SVR or FVR during LBNP or other stimuli known to induce cerebral vasoconstriction (hypocapnia). We speculate that this degree of cerebral vasoconstriction is not by itself sufficient to cause syncope during orthostatic stress. However, it may exacerbate the decrease in CBF associated with hypotension if hemodynamic instability develops.