Rapid adaptation of vagal baroreflexes in humans.

We evaluated the time course of carotid baroreflex adaptation to arterial pressure elevations induced by phenylephrine infusion (1 microgram/kg per min) in 13 normotensive volunteers. Vagally-mediated carotid baroreceptor-cardiac reflex responses were assessed serially with a staircase pressure/suction sequence delivered to a neck chamber. Carotid baroreflex stimulus-response relations shifted up the response (R-R interval) axis and to the right on the stimulus (pressure) axis (determined as the carotid distending pressure at saturation) within 90-120 s (time between measurements) during the first 10 min. The shifts in position of the reflex relation were sustained throughout the infusion. The position of operational point pressure, relative to carotid distending pressure at saturation, was unchanged throughout the infusion period. These data suggest that human carotid baroreceptor reflex relations change within minutes to retain beat-to-beat pressure regulation as the prevailing pressure increases.

How should human baroreflexes be tested?

A new approach to the study of arterial baroreflexes was developed for use during the National Aeronautics and Space Administration Spacelab Life Sciences-1 Space Shuttle mission. This method holds promise as a means to characterize the vagal limb of human baroreflex responses comprehensively and efficiently.

Attenuation of human carotid-cardiac vagal baroreflex responses after physical detraining.

Astronauts who are occupied with prelaunch schedules may have to limit their regular physical exercise routines. To assess a potential effect on blood pressure control, carotid baroreceptor-cardiac reflex responses of 16 men (30-45 years of age) were evaluated before and after 2 weeks of exercise detraining that followed 10 weeks of regular scheduled exercise (30 min/d, 4 d/week at 75% Vo2max). At mid-expiration, the subjects held their breath and 40 mm Hg of pressure was applied to a neck chamber for four heart beats, followed by 15-mm Hg, R-wave triggered decrements to -65 mm Hg. Changes of R-R intervals were plotted against carotid distending pressure (systolic-neck chamber pressure). After detraining, the baroreflex stimulus-response relationship had a reduced slope [4.0 +/- 0.5 vs. 2.8 +/- 0.4 msec/mmHg (p = 0.0008)] and range of response [191 +/- 19 vs. 145 +/- 17 ms (p = 0.002)]. In addition, there was a resetting of the relationship on the R-R interval axis. Both the minimum and maximum R-R interval responses to the stimulus were significantly reduced after detraining [953 +/- 32 vs. 909 +/- 36 ms (p = 0.035) and 1145 +/- 36 vs. 1054 +/- 39 (p = 0.002)]. Baseline systolic pressure did not change with detraining (116 +/- 2 vs. 114 +/- 2 mm Hg) and the carotid baroreceptor-cardiac response relationship did not shift on the pressure axis. These results suggest that detraining from regular exercise can compromise vagally-mediated mechanisms of blood pressure regulation.

Short-duration spaceflight impairs human carotid baroreceptor-cardiac reflex responses.

Orthostatic intolerance is a predictable but poorly understood consequence of space travel. Because arterial baroreceptors modulate abrupt pressure transients, we tested the hypothesis that spaceflight impairs baroreflex mechanisms. We studied vagally mediated carotid baroreceptor-cardiac reflex responses (provoked by neck pressure changes) in the supine position and heart rate and blood pressure in the supine and standing positions in 16 astronauts before and after 4- to 5-day Space Shuttle missions. On landing day, resting R-R intervals and standard deviations, and the slope, range, and position of operational points on the carotid transmural pressure-sinus node response relation were all reduced relative to preflight. Stand tests on landing day revealed two separate groups (one maintained standing arterial pressure better) that were separated by preflight slopes, operational points, and supine and standing R-R intervals and by preflight-to-postflight changes in standing pressures, body weights, and operational points. Our results suggest that short-duration spaceflight leads to significant reductions in vagal control of the sinus node that may contribute to, but do not account completely for, orthostatic intolerance.

Reproducibility of human vagal carotid baroreceptor-cardiac reflex responses.

Published information on the reproducibility of human baroreflex responses in the absence of interventions is limited. Therefore, we analyzed retrospectively vagally mediated carotid baroreceptor-cardiac reflex responses of 34 healthy young adult volunteers whom we studied twice, 7-10 days apart (all 34 subjects) or 10 wk apart (8 subjects). We delivered a sequence of neck pressure changes during held expiration: A computer-driven bellows initially raised pressure to approximately 40 mmHg for five heart beats, and then reduced pressure in a stepwise series of R-wave-triggered 15-mmHg decrements to about -65 mmHg. R-R interval changes were plotted as functions of the carotid distending (systolic less neck) pressure occurring within each interval. Each experimental session yielded one stimulus-response relation, which comprised the average of seven separate trials. Six measures were derived from these relations: minimum, maximum, and range of R-R intervals; maximum slope; and operational point [(R-R interval shortening/R-R interval range) x 100%]. Linear regression correlation coefficients for measurements made on two occasions were all highly significant (range: 0.64-0.99). Our results indicate that human vagally mediated carotid baroreceptor-cardiac reflex responses, studied serially under exacting experimental conditions, are highly reproducible.

Influence of ten-day head-down bedrest on human carotid baroreceptor-cardiac reflex function.

We studied the effects of simulated microgravity on baroreceptor-cardiac reflex mechanisms, with complex pressure changes delivered to neck chambers worn by six healthy young men, before, during (days 1, 3, 6, and 10), and after ten days' 6 degrees head-down bedrest. During held expiration, a computer-driven bellows increased neck pressure to 40 mmHg for about 4 s, and then decreased pressure to -65, by 15 mmHg R-wave triggered decrements. We plotted R-R intervals as functions of carotid distending pressures (systolic less neck chamber pressures). Each experimental session comprised seven stimulus sequences delivered over about 15 min and averaged. Comparisons between results before bedrest and on the tenth day of bedrest showed that average baseline R-R intervals increased from 933 +/- (SEM) 24 to 1077 +/- 35 msec (P less than 0.05, Wilcoxon signed rank test); maximum slopes (R-R interval/carotid distending pressure) decreased from 4.5 +/- 0.4 to 3.6 +/- 0.7 msec/mmHg (P = 0.11); R-R interval response ranges decreased from 263 +/- 31 to 182 +/- 18 msec (P = 0.03); and operational points (positions of R-R intervals at resting pressures on the stimulus-response relation) remained constant. Our results suggest that head-down bedrest progressively impairs baroreceptor-cardiac reflex responses in healthy human subjects.

Human autonomic responses to actual and simulated weightlessness.

Orthostatic dysfunction occurs after exposure to microgravity, and is not completely understood. The authors developed a device for stimulating carotid baroreceptors to test the hypothesis that exposure to microgravity leads to impairment of arterial baroreflex mechanisms. Data obtained before and after two head-down bedrest studies and before and after brief Space Shuttle missions indicate that baroreceptor-cardiac reflex control is impaired by simulated or actual weightlessness. The authors speculate that arterial baroreflex derangements combine with blood volume reductions and increased venous compliance to provoke orthostatic hypotension after microgravity exposure. Altered baroreflex function after missions may result from autonomic neuronal plasticity that develops during missions secondary to changes of cardiopulmonary and arterial dimensions and consequent changes of autonomic sensory input profiles.

Differential baroreflex modulation of human vagal and sympathetic activity.

We compared baroreflex modulation of human vagal-cardiac and sympathetic muscle activity in healthy volunteers by measuring R-R interval and peroneal nerve responses to a profile of positive and negative (40-65 mmHg) R-wave-triggered neck pressure steps during held expiration. R-R interval responses were sigmoid. Sympathetic activity increased abruptly with 40 mmHg pressure but returned to baseline levels as this pressure was maintained. The first decremental pressure step reduced sympathetic activity to below baseline, and the next three steps inhibited activity. During the final three steps, sympathetic activity increased to baseline, and after the return of neck pressure to ambient levels sympathetic activity increased to the highest levels recorded. Our results suggest that on a second-by-second basis human vagal-cardiac responses are determined simply by the net level of baroreceptor stimulation. Sympathetic muscle responses are determined complexly by the direction of changes (rising or falling) more than absolute arterial pressure levels and importantly by inputs from both carotid and aortic baroreceptors.

Physical fitness and cardiovascular regulation: mechanisms of orthostatic intolerance.

We studied three groups of eight men each--high, mid, and low fit (peak O2 consumption 60.0 +/- 0.8, 48.9 +/- 1.0, and 35.7 +/- 0.9 ml.min-1.kg-1)--to determine the mechanism of orthostatic intolerance in endurance athletes. Tolerance was defined by progressive lower body negative pressure (LBNP) to presyncope. Maximal calf vascular conductance (Gmax) was measured. The carotid baroreflex was characterized using both stepwise R-wave-triggered and sustained (2 min) changes in neck chamber pressure. High-fit subjects tended to have lower LBNP tolerance than mid- and low-fit subjects but similar baroreflex responses. Subjects with poor LBNP tolerance had larger stroke volumes (SV) (120 +/- 6 vs. 103 +/- 3 ml) and greater decline in SV with LBNP to -40 mmHg (40 +/- 2 vs. 26 +/- 4%). Stepwise multiple linear regression analysis revealed that Gmax and steady-state gain of the carotid baroreflex contributed significantly toward explaining interindividual variations in LBNP tolerance. Thus endurance athletes may have decreased LBNP tolerance, but apparently not as a simple linear function of aerobic fitness. Orthostatic tolerance depends on complex interactions among functional characteristics that appear both related (Gmax and SV) and unrelated (baroreflex function) to fitness or exercise training.

Autonomic pathophysiology in heart failure: carotid baroreceptor-cardiac reflexes.

We evaluated reflex cardiac responses mediated by carotid baroreceptors in 14 patients with treated congestive heart failure and 14 age-matched healthy subjects. We used a neck chamber to deliver two types of pressure change: 5 s of continuous 50-mmHg suction and an R wave triggered, ramped neck pressure-suction sequence. Reflex latencies (functions of baroreflex arc duration) were comparable in heart failure patients and healthy subjects. However, the average maximum baroreflex slope (gain) was less in heart failure patients than healthy subjects (2.0 vs. 3.5 ms/mmHg, P less than 0.010), the R-R interval response range was smaller (91 vs. 188 ms, P = 0.002), and the resting R-R interval position on stimulus-response relation (operational point) was significantly (13 vs. 40%, P = 0.001) closer to threshold. Stepwise regression analysis suggested that baseline R-R interval variability, used as an index of ongoing vagal-cardiac nerve traffic, and the inverse of antecubital vein plasma norepinephrine level, used as an index of sympathetic nerve activity, contributed significantly to the prediction of abnormal carotid baroreceptor-cardiac reflex responses. Thus our results suggest that in heart failure patients, carotid baroreceptor-cardiac reflex abnormalities are related significantly to ongoing abnormalities of vagal and sympathetic cardiovascular outflow.

Autonomic pathophysiology in heart failure patients. Sympathetic-cholinergic interrelations.

We conducted this study in an effort to characterize and understand vagal abnormalities in heart failure patients whose sympathetic activity is known. We measured sympathetic (peroneal nerve muscle sympathetic recordings and antecubital vein plasma norepinephrine levels) and vagal (R-R intervals and their standard deviations) activities in eight heart failure patients and eight age-matched healthy volunteers, before and after parasympathomimetic and parasympatholytic intravenous doses of atropine sulfate. At rest, sympathetic and parasympathetic outflows were related reciprocally: heart failure patients had high sympathetic and low parasympathetic outflows, and healthy subjects had low sympathetic and high parasympathetic outflows. Low dose atropine, which is known to increase the activity of central vagal-cardiac motoneurons, significantly increased R-R intervals in healthy subjects, but did not alter R-R intervals in heart failure patients. Thus, our data document reciprocal supranormal sympathetic and subnormal parasympathetic outflows in heart failure patients and suggest that these abnormalities result in part from abnormalities within the central nervous system.

Relation of plasma norepinephrine and sympathetic traffic during hypotension in humans.

We compared changes in antecubital venous plasma levels of norepinephrine (NE) and peroneal nerve muscle sympathetic activity (MSA) during and after nitroprusside (NP)-induced hypotension in nine healthy volunteers. During NP, MSA increased at 98.7%/min, peaked at 4 min at 399 +/- 77% (SE) of base line, and then decreased, so that at the end of the infusion MSA was 298 +/- 39% of base line. NE increased at 9.2%/min and peaked at 14.5 min at 231 +/- 31% of base line just before the end of the infusion. Percent increases of MSA and NE near the end of NP were not significantly different. The time-to-peak NE lagged the time-to-peak MSA by nearly 10 min. These results suggest that during increases of sympathetic outflow diffusion and washout of NE from neuroeffector junctions result in delayed increases in NE in the venous drainage; percent changes in MSA and NE during prolonged stable mild hypotension are similar. The findings provide conditional support for the use of changes in NE to indicate changes in sympathetic traffic.

Head-down bed rest impairs vagal baroreflex responses and provokes orthostatic hypotension.

We studied vagally mediated carotid baroreceptor-cardiac reflexes in 11 healthy men before, during, and after 30 days of 6 degrees head-down bed rest to test the hypothesis that baroreflex malfunction contributes to orthostatic hypotension in this model of simulated microgravity. Sigmoidal baroreflex response relationships were provoked with ramped neck pressure-suction sequences comprising pressure elevations to 40 mmHg followed by serial R-wave-triggered 15-mmHg reductions to -65 mmHg. Each R-R interval was plotted as a function of systolic pressure minus the neck chamber pressure applied during the interval. Compared with control measurements, base-line R-R intervals and the minimum, maximum, range, and maximum slope of the R-R interval-carotid pressure relationships were reduced (P less than 0.05) from bed rest day 12 through recovery day 5. Baroreflex slopes were reduced more in four subjects who fainted during standing after bed rest than in six subjects who did not faint (-1.8 +/- 0.7 vs. -0.3 +/- 0.3 ms/mmHg, P less than 0.05). There was a significant linear correlation (r = 0.70, P less than 0.05) between changes of baroreflex slopes from before bed rest to bed rest day 25 and changes of systolic blood pressure during standing after bed rest. Although plasma volume declined by approximately 15% (P less than 0.05), there was no significant correlation between reductions of plasma volume and changes of baroreflex responses. There were no significant changes of before and after plasma norepinephrine or epinephrine levels before and after bed rest during supine rest or sitting.(ABSTRACT TRUNCATED AT 250 WORDS)

Carotid baroreflex resetting during drug-induced arterial pressure changes in humans.

We studied human baroreflex resetting during 25 min of drug-induced arterial pressure changes in 10 healthy volunteers. Average (+/- SE) base-line systolic pressure of 113 +/- 4 fell to 102 +/- 3 during nitroprusside infusions and rose to 135 +/- 6 mmHg during phenylephrine infusions. Average base-line R-R intervals of 932 +/- 37 shortened to 820 +/- 39 during nitroprusside infusions and lengthened to 1,251 +/- 61 ms during phenylephrine infusions. Carotid baroreceptor-cardiac reflex responses were evaluated with a complex series of neck chamber pressure changes, and R-R intervals were plotted as functions of carotid distending pressure. Baroreceptor-cardiac reflex relations shifted on both R-R interval and arterial pressure axes during drug infusions, but there was no significant change of the maximum slope or range of R-R interval responses. The position of baseline R-R intervals on the reflex relation (operational point) changed significantly. Resting R-R intervals were closer to threshold during pressure reductions and closer to saturation for baroreceptor-cardiac responses during pressure elevations. These results document short-term partial resetting of human baroreceptor-cardiac reflex responses as early as 25 min after the onset of arterial pressure changes.

Continuous resetting of the human carotid baroreceptor-cardiac reflex.

Although human baroreflex responses have been studied during night as well as day, there has been no attempt to distinguish circadian changes of baroreflex function from those related to sleep. We measured carotid baroreceptor-cardiac reflex responses serially during a 24-h period in 11 normotensive volunteers who were awake and cooperative during testing. We applied sequences of ramped R-wave-triggered neck chamber pressure changes from +40 to -65 mmHg, during held expiration, at 3-h intervals. Subjects maintained their usual sleep-wake cycles but were awakened for three 30-min periods for night testing. There was no systematic change of baroreflex slope during the 24-h period. There were, however, parallel shifts of the entire sigmoid baroreceptor-cardiac reflex response relation along its R-R interval and arterial pressure axes associated with small, but significant, circadian changes of baseline R-R intervals and arterial pressures. Thus, although our data do not point toward major circadian variability of baro-reflex responsiveness, they provide evidence for an ongoing process of human baroreflex resetting.

Arterial pressure ramps provoke linear increases of heart period in humans.

A variety of methods has been used experimentally to increase baroreceptor activity and provoke transient, vagally mediated cardiac slowing in humans. We studied baroreceptor-cardiac reflex physiology in eight resting volunteers by measuring R-R interval changes during and after spontaneous brief elevations of arterial pressure, preceded by bursts of muscle sympathetic nerve activity. Arterial pressure was measured with a catheter in a brachial artery, and muscle sympathetic activity was measured with a microelectrode positioned transcutaneously in a peroneal nerve. R-R intervals were related to preceding systolic pressures with linear regression analysis. When systolic pressures were correlated with R-R intervals of the next cardiac cycle, slopes (+/- SE) averaged 12.4 +/- 2.2 ms/mmHg and correlation coefficients averaged 0.81 +/- 0.09. Baroreflex slopes were inversely related to base-line systolic pressures. These results are similar to those obtained when baroreceptors are stimulated experimentally; they suggest that elevations of arterial pressure, which are preceded by bursts of muscle sympathetic activity, trigger with one heart-beat latency highly linear increases of efferent vagal-cardiac nerve activity.

Baroreflex control of plasma norepinephrine and heart period in healthy subjects and diabetic patients.

Resting diabetic patients may have excessively rapid heart rates, reduced heart rate variability, and subnormal plasma catecholamine levels. Although all of these abnormalities may relate in some way to baroreceptor reflex function, there have been surprisingly few attempts to evaluate systematically baroreflex mechanisms in diabetic patients. Accordingly, we studied autonomic responses over a range of pharmacologically induced arterial pressure changes in 10 unselected young adult insulin-dependent diabetic patients who had no symptoms of autonomic neuropathy, and 12 age-matched nondiabetic subjects. Sympathetic responses were estimated from antecubital vein plasma norepinephrine levels, and parasympathetic responses were estimated from electrocardiographic R-R intervals and their variability (standard deviation). Both were correlated with other noninvasive indexes of peripheral and central nervous system function. Multiple derangements of baroreflex function were found in the diabetic patients studied. Sympathetic abnormalities included subnormal baseline norepinephrine levels, virtual absence of changes of norepinephrine levels during changes of arterial pressure, and supranormal pressor responses to phenylephrine infusions. Parasympathetic abnormalities included subnormal baseline standard deviations of R-R intervals, and R-R interval prolongations during elevations of arterial pressure which were unmistakably present, but subnormal. Our data suggest that in diabetic patients, subnormal baseline plasma norepinephrine levels may signify profound, possibly structural defects of sympathetic pathways. Subnormal resting levels of respiratory sinus arrhythmia may have different implications, however, since vagal, unlike sympathetic reflex abnormalities, can be reversed partly by arterial pressure elevations.