Nonhypotensive Lower Body Negative Pressure Research Articles

Reliability of measuring resting spontaneous cardiac baroreflex sensitivity using short sampling durations in healthy humans: Impact of central blood volume mobilization

IntroductionCalculation of spontaneous cardiac baroreflex sensitivity (cBRS) is used commonly to quantify arterial baroreflex buffering of beat‐to‐beat changes in blood pressure (BP). Studies report large interindividual variability in resting cBRS, which may be exacerbated by the supine posture and the use of shorter sampling duration (1‐3 min). However, this has yet to be reported in humans. Therefore, the purpose of the present study was to examine the impact of sampling duration on the intratest reliability of resting cBRS in healthy subjects. To accomplish this, we sought to compare resting cBRS derived from a standard 10‐min epoch (control) with values sampled over 7, 5, 3, and 1 min epoch durations. In addition, we examined the impact of central blood volume (CBV) mobilization on intratest reliability of resting cBRS.MethodsIn 30 healthy subjects (28 men; 22±3yrs) beat‐to‐beat measurements of BP and heart rate were recorded for 10‐min during both sitting and supine position. The cBRS was derived by sequence technique. Randomly selected epochs of 1‐min, 3‐min, 5‐min and 7‐min were then compared to the 10‐min control. To calculate the relative and absolute reliability we analyzed the technical error of the measurement (TEM), the intraclass correlation coefficients (ICC), Bland‐Altman analysis and coefficient of variations (CV). To test the impact of CBV mobilization on resting cBRS, ten subjects were also randomized to a non‐hypotensive lower body negative pressure (LBNP) trial at ‐20mmHg.ResultscBRS was lower in the sitting position than in the supine position (P<0.01). All cBRS values were similar between each sampling duration compared to the 10‐min control (P>0.12). The ICC obtained for cBRS ranged from very good to excellent in the supine position, whereas in the sitting position values demonstrated excellent between‐sampling duration reliability. The absolute and relative TEM increased with a shorter sampling duration (Table 1). In the LBNP trial, no significant differences in cBRS were observed within sampling durations in the LBNP trial (P=0.27). No significant differences in cBRS were observed between supine LBNP, sitting and supine positions (P=0.17). During LBNP trial, TEM increased with shorter sampling durations [10 vs. 7‐min: 0.7 ms/mmHg (4%), 10 vs. 5‐min: 1.4 ms/mmHg (8%), 10 vs. 3‐min: 1.9 ms/mmHg (11%), 10 vs. 1‐min: 3.1 ms/mmHg (17%), which was similar to the sitting position when compared to the supine posture.ConclusionOur findings show that 1) reliability decreased progressively using the 3‐ and 1‐min sampling durations; 2) the sitting position provides more reliable measures than all epoch durations measured in the supine position and; 3) the increases in the limits of agreement with shorter durations were attenuated by supine LBNP, suggesting that a cardiopulmonary baroreflex mechanism may play a role in the level of variability in resting cBRS.

Stretching our understanding of baroreflex control in humans: evidence of a positive feedback pulmonary baroreflex.

Stretching our understanding of baroreflex control in humans: evidence of a positive feedback pulmonary baroreflex.

Evidence for differential control of muscle sympathetic single units during mild sympathoexcitation in young, healthy humans.

Two subpopulations of muscle sympathetic single units with opposite discharge characteristics have been identified during low-level cardiopulmonary baroreflex loading and unloading in middle-aged adults and patients with heart failure. The present study sought to determine whether similar subpopulations are present in young healthy adults during cardiopulmonary baroreflex unloading ( study 1) and rhythmic handgrip exercise ( study 2). Continuous hemodynamic and multiunit and single unit muscle sympathetic nerve activity (MSNA) data were collected at baseline and during nonhypotensive lower body negative pressure (LBNP; n = 12) and 40% maximal voluntary contraction rhythmic handgrip exercise (RHG; n = 24). Single unit MSNA responses were classified as anticipated or paradoxical based on whether changes were concordant or discordant with the multiunit MSNA response, respectively. LBNP and RHG both increased multiunit MSNA burst frequency (∆5 ± 3 bursts/min, P < 0.001; ∆5 ± 8 bursts/min, P = 0.005), burst amplitude (∆5 ± 7%, P = 0.04; ∆13 ± 14%, P < 0.001), and total MSNA (∆302 ± 191 AU/min, P = 0.001; ∆585 ± 556 AU/min, P < 0.001). During LBNP and RHG, 43 and 64 muscle single units were identified, respectively, which increased spike frequency (∆9 ± 11 spikes/min, P < 0.001; ∆10 ± 19 spikes/min, P < 0.001) and the probability of multiple spike firing (∆10 ± 12%, P < 0.001; ∆11 ± 26%, P = 0.001). During LBNP and RHG, 36 (84%) and 39 (61%) single units possessed anticipated firing responses (∆12 ± 10 spikes/min, P < 0.001; ∆19 ± 19 spikes/min, P < 0.001), whereas 7 (16%) and 25 (39%) single units exhibited paradoxical reductions (∆-3 ± 1 spikes/min, P = 0.003; ∆-4 ± 5 spikes/min, P < 0.001). The observation of divergent subpopulations of muscle sympathetic single units in healthy young humans during two mild sympathoexcitatory stressors supports differential control at the fiber level as a fundamental characteristic of human sympathetic regulation. NEW & NOTEWORTHY The activity of muscle sympathetic single units was recorded during cardiopulmonary baroreceptor unloading and rhythmic handgrip exercise in young healthy humans. During both stressors, the majority of single units (84% and 61%) exhibited anticipated behavior concordant with the integrated muscle sympathetic response, whereas a smaller proportion (16% and 39%) exhibited paradoxical sympathoinhibition. These results support differential control of postganglionic muscle sympathetic fibers as a characteristic of human sympathetic regulation during mild sympathoexcitatory stress. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/differential-control-of-sympathetic-outflow-in-young-humans/ .

Paradoxical muscle sympathetic reflex activation in human heart failure.

Muscle sympathetic activation in heart failure with reduced ejection fraction (HFrEF) has been attributed, on the basis of multiunit recordings, to attenuated inhibitory feedback from stretch-sensitive cardiopulmonary mechanoreceptors. However, such preparations integrate 2 populations of single units exhibiting directionally opposite firing when atrial pressure is perturbed. We tested the hypothesis that the proportion of single units firing paradoxically when filling pressure increases is augmented in HFrEF. Muscle sympathetic nerve activity and estimated central venous pressure were recorded during nonhypotensive lower body negative pressure (LBNP; -10 mm Hg) and nonhypertensive positive pressure (LBPP; +10 mm Hg) in 11 treated HFrEF (left ventricular ejection fraction 25 ± 6% [mean ± standard deviation]) patients and 14 similarly aged controls. Single-unit muscle sympathetic nerve activity discharge was termed either anticipated, if firing frequency exhibited classic negative-feedback responses, or paradoxical. LBNP and LBPP had no heart rate, stroke volume, or blood pressure effects (P>0.05). Estimated central venous pressure decreased with LBNP (P<0.05), increased with LBPP (P<0.05), and was consistently higher in HFrEF (P<0.05). During LBNP, the ratio of single units with anticipated and paradoxical discharge was similar in HFrEF (18:7) and controls (27:5), whereas LBPP elicited paradoxical reflex excitation in a greater proportion of HFrEF single units (7:18 versus 24:6; P=0.0001). Consequently, LBPP increased mean single-unit firing frequency (P<0.05) and did not inhibit multiunit muscle sympathetic nerve activity of HFrEF subjects (P<0.05 versus controls). Firing of 12/18 HFrEF (but no control) single units increased during both LBPP and LBNP. These findings provide the first evidence in human HFrEF for an augmented excitatory cardiopulmonary-muscle sympathetic nerve activity reflex response to increased preload, incorporating 2 distinct single-unit populations with differing firing properties.

Microneurographic evidence in healthy middle-aged humans for a sympathoexcitatory reflex activated by atrial pressure

Atrial mechanoreceptors, stimulated by increased pressure or volume, elicit in healthy humans a net sympathoinhibitory response. The co-existence of an atrial reflex eliciting muscle sympathoexcitation has been postulated but undetected by conventional multi-unit muscle sympathetic nerve activity (MSNA). We hypothesized that in response to a selective increase in atrial pressure, single-unit MSNA would reveal a subpopulation of efferent sympathetic neurons with firing patterns opposite to the integrated multi-unit MSNA envelope. Multi- and single-unit MSNA recordings were acquired in eight healthy middle-aged subjects (age, 57 ± 8 years; body mass index, 25 ± 2 kg/m(2)) submitted to selective decreases or increases in atrial pressure by nonhypotensive lower body negative pressure (LBNP; -10 mmHg) or nonhypertensive lower body positive pressure (LBPP; +10 mmHg), respectively. Single-unit MSNA firing responses were classified as anticipated if spike frequency and incidence increased with LBNP or decreased with LBPP and paradoxical if they decreased with LBNP or increased with LBPP. LBNP decreased (3.2 ± 2.8 to 1.4 ± 3.1 mmHg, P < 0.01) and LBPP increased (3.3 ± 2.7 to 4.9 ± 2.8 mmHg, P < 0.01) estimated central venous pressure without affecting stroke volume, systemic pressure, or resistance. Multi-unit MSNA increased with LBNP (31 ± 17 to 38 ± 19 bursts/min, P < 0.01) and diminished with LBPP (33 ± 15 to 28 ± 15 bursts/min, P < 0.01). Of 21 single-units identified, 76% exhibited firing responses to both LBNP and LBPP concordant with multi-unit MSNA, whereas 24% demonstrated discordant or paradoxical responses. The detection of two subpopulations of single-units within the multi-unit MSNA recording, exhibiting opposite firing characteristics, establishes the first evidence in humans for the existence of an excitatory cardiac-muscle sympathetic reflex activated by increasing atrial pressure.

Abstract 19395: Increased Multiple Firing of Single Muscle Vasoconstrictor Neurons during Lower Body Positive Pressure in Human Heart Failure

Introduction: Functionally specific efferent renal sympathetic nerves fire selectively in response to distinct hemodynamic afferent inputs. Using norepinephrine spillover, our group detected a heart failure (HF)-specific cardio-cardiac sympathoexcitatory reflex stimulated by high atrial pressure. Efferent discharge directed at other vascular beds similarly activated by atrial stretch might not be detected by multi-unit sympathetic recordings. Hypothesis: In contrast to healthy controls (CON), in HF some muscle sympathetic fibers respond paradoxically (i.e. increase firing) to increases in filling pressure. Methods: Single-unit muscle sympathetic nerve activity (sMSNA; microneurography) and peripheral venous pressure (PVP; forearm catheter) were recorded from 11 CON and 10 treated HF (LVEF 27±6%) patients at baseline and during non-hypotensive lower body negative pressure (LBNP; -10mmHg) and non-hypertensive lower body positive pressure (LBPP; +10mmHg). sMSNA firing frequency and incidence, and the percentage of multiple within-burst firing was calculated for each condition. Results: PVP was reduced with LBNP (p&lt;0.05) and increased with LBPP (p&lt;0.05) in both groups, with PVP greater in HF across each condition (p&lt;0.05). Blood pressure and heart rate were unchanged by LBNP or LBPP in both groups (p&gt;0.05). We identified 26 and 22 single-units in CON and HF patients, respectively. sMSNA firing frequency was similar (p&gt;0.05) in CON and HF at baseline (30±18 vs. 35±15 spikes/min) and during LBNP (45±24 vs. 42±23 spikes/min) but higher in HF during LBPP (28±17 vs. 40±22 spikes/min, p=0.05). sMSNA firing incidence was similar (p&gt;0.05) in both groups across each condition. The percentage of within-burst multiple spike firing was similar (p&gt;0.05) in CON and HF during baseline (24±9% vs. 24±7%) and LBNP (25±11% vs. 28±14%) but higher in HF during LBPP (17±8% vs. 34±16%, p&lt;0.001). Conclusions: In HF, increases in PVP with non-hypertensive LBPP cause a paradoxical increase in muscle sympathetic single-unit firing frequency and multiple within-burst firing, compared to CON. This provides evidence of a sympathoexcitatory cardiac-skeletal muscle vasoconstrictor reflex in human HF that may be attenuated by normalizing filling pressures.

Comment on Point:Counterpoint: “Cardiovascular variability is/is not an index of autonomic control of circulation”

POINT-COUNTERPOINT COMMENTSComment on Point:Counterpoint: “Cardiovascular variability is/is not an index of autonomic control of circulation”Catherine F. Notarius, and John S. FlorasCatherine F. Notarius, and John S. FlorasPublished Online:01 Jun 2007https://doi.org/10.1152/japplphysiol.00283.2007MoreSectionsPDF (27 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations The following letter is in response to Point:Counterpoint “Cardiovascular variability is/is not an index of autonomic control of circulation” that appeared in the August issue (vol. 101, pages 676–682, 2006).To the Editor: Changes in heart rate variability (HRV) or blood pressure variability (BPV) may well track qualitatively changes in vagal or sympathetic nerve traffic induced by some interventions in experimental models or human volunteers (6). However, contextual and interpretive limitations to their broader application to between-person comparisons or cardiovascular disease states have not been emphasized sufficiently in prior correspondence.HRV is a marker of sinoatrial node responsiveness to oscillations in sympathetic and vagal nerve traffic, not necessarily of nerve firing rates (5). Thus conditions of high but relatively invariate sympathetic nerve firing and heart rates, such as exercise (2) or advanced heart failure (4), are characterized by loss, rather than gain, of low frequency (LF) HRV spectral power. Even within healthy subjects, a very modest (1.6 mmHg) reduction in central venous pressure without effect on stroke volume or blood pressure elicits marked discordance between muscle sympathetic nerve firing rates (increased) and both LF power and the LF/HF ratio (unchanged; Ref. 3). Although BPV in the LF range tracks sympathetic nerve discharge within healthy subjects (6), it is not increased, but similar in subjects with and without heart failure (1). There is evidence from large population studies that low HRV increases the risk of premature cardiovascular death, but as yet none that such data quantify reliably risk in a specific individual or that selectively increasing HRV pharmacologically or non-pharmacologically without affecting other known modifiable risk markers improves outcome.Thus HRV and BPV analyses are best reserved for focused within-subject mechanistic investigations.REFERENCES1 Butler GC, Ando S, Floras JS. Fractal component of variability of heart rate and systolic blood pressure in congestive heart failure. Clin Sci (Colch) 92: 543–550, 1997.Crossref | Google Scholar2 Casadei B, Cochrane S, Johnston J, Conway J, Sleight P. Pitfalls in the interpretation of spectral analysis of the heart rate variability during exercise in humans. Acta Physiol Scand 153: 125–131, 1995.Crossref | PubMed | Google Scholar3 Floras JS, Butler GC, Ando S, Brooks SC, Pollard MJ, Picton P. Differential sympathetic nerve and heart rate spectral effects of nonhypotensive lower body negative pressure. Am J Physiol Regul Integr Comp Physiol 281: R468–R475, 2001.Link | ISI | Google Scholar4 Notarius CF, Butler GC, Ando S, Pollard MJ, Senn B, Floras JS. Dissociation between microneurographic and heart rate variability estimates of sympathetic tone in normal subjects and patients with heart failure. Clin Sci (Colch) 96: 557–565, 1999.Crossref | Google Scholar5 Notarius CF, Floras JS. Limitations of the use of spectral analysis of heart rate variability for the estimation of cardiac sympathetic activity in heart failure. Europace 3: 29–38, 2001.Crossref | PubMed | ISI | Google Scholar6 Parati G, Mancia G, Di Rienzo M, Castiglioni J, Taylor A, Studinger P. Point:Counterpoint: Cardiovascular variability is/is not an index of autonomic control of circulation. J Appl Physiol 101: 676–682, 2006.Link | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByDifferent equestrian sports horses’ reactivity to startleJournal of Veterinary Behavior, Vol. 57Mild Hypothermia Attenuates Circulatory and Pulmonary Dysfunction During Experimental Endotoxemia*Critical Care Medicine, Vol. 41, No. 12 More from this issue > Volume 102Issue 6June 2007Pages 2406-2406 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00283.2007PubMed17551108History Published online 1 June 2007 Published in print 1 June 2007 Metrics

Effect of Exercise Intensity on Mild Rhythmic-handgrip-exercise-Induced functional Sympatholysis

This study attempts to clarify whether intensity of exercise influences functional sympatholysis during mild rhythmic handgrip exercise (RHG). We measured muscle oxygenation in both exercising and non-exercising muscle in the same arm in 11 subjects using near infrared spectroscopy (NIRS), heart rate, and blood pressure. We used the total labile signal to assess the relative muscle oxygenation by occlusion for 6 min. Subjects performed RHG (20 times/min) for 6 min at 10%, 20%, and 30% of maximal voluntary contraction (MVC) at random. We used a non-hypotensive lower body negative pressure (LBNP) of 220 mmHg for 2 min to elicit reproducible enhancement in muscle sympathetic nerve activity (MSNA) at rest and during RHG. LBNP caused decreases of 16.4% and 17.7% of the level of muscle oxygenation at rest (pre) in exercising (forearm) and non-exercising (upper arm) muscle respectively. Muscle oxygenation in non-exercising muscle with the application of LBNP during RHG did not change significantly at each intensity. In contrast, the decrease in muscle oxygenation in exercising muscle attenuated progressively as exercise intensity increased (10% MVC 8.8+/-2.8%, 20% MVC 7.1+/-2.0%, 30% MVC 4.6+/-3.0%), when LBNP was applied during RHG. The attenuation of the decrease in muscle oxygenation due to LBNP during RHG at 10%, 20%, and 30% was significantly different from that at rest (p<0.01). These findings indicate that functional sympatholysis during mild RHG might be attributed to exercise intensity.

Arterial baroreceptor and cardiopulmonary reflex control of sympathetic outflow in human heart failure.

Several observations indicate that the arterial baroreflex control of sympathetic nerve activity is preserved, even in advanced heart failure. These include: (1) augmentation of muscle sympathetic nerve activity burst amplitude and duration following a premature beat; (2) rapid recognition of changes in blood pressure induced by ventricular arrhythmias; (3) muscle sympathetic alternans and a steep inverse relationship between changes in diastolic pressure and the subsequent sympathetic burst amplitude during pulsus alternans; (4) similar inhibition of muscle sympathetic nerve activity in subjects with normal and impaired left ventricular systolic function by increases in intrathoracic aortic transmural pressure; (5) documentation, by cross-spectral analysis, of similar gain in the transfer function between blood pressure and muscle sympathetic nerve activity in these two groups; and (6) during sodium nitroprusside infusion, similar reflex increases in total body norepinephrine spillover in normal and heart-failure subjects. When nonhypotensive lower-body negative pressure was applied to test the hypothesis that selective reduction of atrial and pulmonary pressures would exert a cardiac sympathoinhibitory response in heart failure, there was no effect in control subjects, but cardiac norepinephrine spillover fell by 25% (P < .05) in those with systolic dysfunction. In summary, human heart failure is characterized by a rapidly responsive and sensitive arterial baroreflex, and by activation of a cardiac sympathoexcitatory reflex related to increased cardiopulmonary filling pressures.

Reducing Cardiac Filling Pressure Lowers Norepinephrine Spillover in Patients With Chronic Heart Failure

We studied the cardiac sympathetic response to selective unloading of cardiopulmonary baroreceptors in subjects with normal left ventricular (LV) function and congestive heart failure (CHF). Eight patients with normal LV function (age 57+/-5 years, ejection fraction 58+/-2%) and 8 patients with CHF (age 60+/-2 years; ejection fraction 19+/-2%) were studied. Instrumentation consisted of an arterial line, a pulmonary artery catheter, and a coronary sinus thermodilution catheter. The radiotracer technique was used for measurement of cardiac norepinephrine spillover (CANESP) and total-body norepinephrine spillover. Lower-body negative pressure (LBNP) was applied at 2 levels: nonhypotensive and hypotensive LBNP. Nonhypotensive LBNP reduced filling pressures significantly in both groups. Arterial pressure did not change. This reduction in filling pressures caused a significant reduction in CANESP in the CHF group (from 167+/-53 to 125+/-37 pmol/min, P<0.05) but no change in the normal LV function group. Hypotensive LBNP caused a significant increase in CANESP in the normal group (73+/-13 vs 122+/-27 pmol/min, P<0.05) but no significant change in those with CHF. We conclude that selective reduction in filling pressures lowers cardiac norepinephrine spillover in patients with CHF. These findings suggest that a goal of CHF management should be to reduce cardiac filling pressures while avoiding systemic hypotension.

Neurohumoral antecedents of vasodepressor reactions

Vasodepressor (vasovagal) syncope, the most common cause of acute loss of consciousness, can occur in otherwise vigorously healthy people during exposure to stimuli decreasing cardiac filling. Antecedent physiological or neuroendocrine conditions for this dramatic syndrome are poorly understood. This study compared neurocirculatory responses to non-hypotensive lower body negative pressure (LBNP) in subjects who subsequently developed vasodepressor reactions during hypotensive LBNP with responses in subjects who did not. In 26 healthy subjects, LBNP at -15 and -40 mmHg was applied to inhibit cardiopulmonary and arterial baroreceptors. All the subjects tolerated 30 min of LBNP at -15 mmHg, but during subsequent LBNP at -40 mmHg 11 subjects had vasodepressor reactions, with sudden hypotension, nausea, and dizziness. In these subjects, arterial plasma adrenaline responses to LBNP both at -15 and at -40 mmHg exceeded those in subjects who did not experience these reactions. In 16 of the 26 subjects, forearm noradrenaline spillover was measured; in the eight subjects with a vasodepressor reaction, mean forearm noradrenaline spillover failed to increase during LBNP at -15 mmHg (delta = -0.06 +/- (SEM) 0.04 pmol min-1 100mL-1), whereas in the eight subjects without a vasodepressor reaction, mean forearm noradrenaline spillover increased significantly (delta = 0.31 +/- 0.13 pmol min-1 100mL-1). Plasma levels of beta-endorphin during LBNP at -15 mmHg increased in some subjects who subsequently had a vasodepressor reaction during LBNP at -40mmHg. The findings suggest that a neuroendocrine pattern including adrenomedullary stimulation, skeletal sympathoinhibition, and release of endogenous opioids can precede vasodepressor syncope.

Increase of sympathetic discharge to skeletal muscle but not to skin during mild lower body negative pressure in humans.

1. Haemodynamic studies in humans have concluded that the cutaneous circulation is regulated by cardiopulmonary baroreceptors. In contrast, neurophysiological studies have indicated that skin sympathetic outflow, unlike muscle sympathetic outflow, is unaffected by perturbations in baroreceptor activity. 2. Thus, in an attempt to resolve this discrepancy, both muscle and skin sympathetic nerve activity was recorded during unloading of mainly cardiopulmonary afferents with non-hypotensive lower body negative pressure (LBNP) performed in both normothermic and hyperthermic conditions. The function of the sympathetic activity was studied by estimations of skin blood flow (laser Doppler velocimetry), of calf blood flow (plethysmography) and of sudomotor activity (electrodermal responses). 3. A level of LBNP that caused robust increases in sympathetic outflow and vascular resistance in the skeletal muscle of the lower leg had no effect on sympathetic activity and vascular resistance in the skin of the same region in the same subjects. Both at normothermia and during hyperthermia LBNP decreased electrodermal activity. Experiments performed during sham LBNP and with skin temperature kept constant suggest that the electrodermal response was due to a decrease in skin temperature produced by the LBNP. 4. In conclusion, these findings challenge the concept that the cutaneous circulation participates importantly in the peripheral circulatory adjustments to unloading of cardiopulmonary afferents during orthostatic stress in humans. During non-hypotensive LBNP, the skeletal muscle bed accounts for all of the reflex vasoconstriction in the calf.

Abnormalities in the renal and vascular responses to LBNP in humans with early diabetes.

Plasma atrial natriuretic factor (ANF) concentrations are increased in subjects with insulin-dependent diabetes mellitus (IDDM). A potential contribution of ANF to the maintenance of abnormalities in renal hemodynamic function has been considered but not proven in human diabetic subjects. The aim of these experiments was to determine the response of renal blood flow (RBF), glomerular filtration rate (GFR), filtration fraction (FF), and urinary sodium excretion (UNaV) to a reduction of plasma ANF concentrations induced by application of nonhypotensive lower body negative pressure (LBNP) in a group of subjects with early, uncomplicated, well-controlled IDDM compared with control subjects. Baseline supine measurements before LBNP revealed the diabetic subjects to have a significantly higher plasma ANF (31 +/- 2 vs. 24 +/- 2 pg/ml, P = 0.05). GFR tended to be higher (118 +/- 11 vs. 104 +/- 9 ml/min) and UNaV tended to be depressed (188 +/- 25 vs. 240 +/- 25 mumol/min) despite equal sodium intake, but not significantly so. In addition IDDM subjects exhibited significantly lower baseline plasma norepinephrine (PNE) concentrations (0.91 +/- 0.20 vs. 1.60 +/- 0.2 nmol/l, P = 0.03). Forearm vascular resistance (FVR) was not significantly different between the two groups (29 +/- 5 vs. 33 +/- 5 units). LBNP induced comparable decreases in ANF and central venous pressure (CVP) in both groups. The anticipated renal response to ANF reduction (declines in GFR, FF, and UNaV) occurred only in the normal control group. The percent decline in GFR (11% vs. 34.5%, P = 0.01) was markedly attenuated in IDDM subjects. The expected reflexive increase in PNE and FVR also did not occur in IDDM subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of left atrial baroreceptors in the cardiopulmonary baroreflex of normal humans.

In animals, sympathetic responses to orthostasis are regulated in part by cardiopulmonary afferents arising from atrial and ventricular baroreceptors. To determine the relative importance of these baroreceptor regions in the cardiopulmonary baroreflex of normal humans, simultaneous measurements of left atrial and right and left ventricular volumes (cine computed tomography), invasive hemodynamics, forearm vascular resistance (plethysmography), and efferent sympathetic nerve activity to muscle (microneurography) were obtained under control conditions and with nonhypotensive lower body negative pressure (-10 mmHg, LBNP-10) in nine normal human subjects. LBNP-10 did not alter heart rate or mean systemic arterial pressure, but it did produce significant decreases in pulmonary artery diastolic and right atrial pressures. This reduction in cardiac filling pressures resulted in efferent sympathoexcitation evidenced by increases in forearm vascular resistance and efferent sympathetic nerve activity to the muscle. LBNP-10 did not alter end-diastolic volume of the left or the right ventricle. Similarly, ventricular stroke volume was unchanged during LBNP-10, as assessed by cine computed tomography or thermodilution techniques. In contrast, LBNP-10 resulted in a significant decrease in left atrial volume. Thus, LBNP produced a significant decrease in cardiac filling pressures and left atrial volumes with resultant reflex sympathoexcitation, whereas ventricular volumes were unchanged. These observations suggest an important role for left atrial (nonventricular) baroreceptor afferents in the cardiopulmonary baroreflex of normal humans.

Effect of detraining on the cardiopulmonary reflex in professional runners and hammer throwers

In professional athletes with marked cardiac hypertrophy, reflex influences originating from cardiopulmonary receptors are impaired. To determine whether the reflex is restored after termination of physical training and regression of cardiac hypertrophy 8 former athletes (age 31 ± 6 years, mean ± SD) who stopped agonistic activity for 5 ±1 years were compared with 15 sedentary subjects (27 ± 7 years) and 19 active professional athletes (22 ± 7 years). Cardiopulmonary receptor stimulation and deactivation were obtained by increasing and reducing left ventricular end-diastolic diameter (echocardiography) through leg raising and nonhypotensive lower body negative pressure, respectively. Left ventricular mass index (echocardiography) was markedly and significantly (p < 0.01) greater in athletes (135 ± 6 g/m 2) than in former athletes (105 ± 4 g/m 2) whose value was similar to that of sedentary subjects (98 ± 4 g/m 2). The reduction in forearm vascular resistance and plasma norepinephrine induced by increasing left ventricular end-diastolic diameter was 24 and 23% less in athletes than in former athletes whose responses were similar to those of sedentary subjects. This was the case also for the responses induced by reducing left ventricular end-diastolic diameter. In contrast, the hemodynamic responses to cold presser test were similar in the 3 groups. It is concluded that the impairment of the cardiopulmonary reflex observed in athletes is largely reversible when physical training is terminated. This may be due to regression of left ventricular hypertrophy.

Norepinephrine kinetics and cardiac output during nonhypotensive lower body negative pressure

Recently we have shown that arterial norepinephrine (NE) concentration increases significantly during lower body negative pressure (LBNP) of -15 mmHg. Interestingly, the increase was found to be related predominantly to a decrease in arterial NE clearance. We postulated that this reduction in clearance would be related to a reduction in cardiac output. Accordingly, we measured both cardiac output (2-dimensional echocardiographic/Doppler technique) and arterial NE kinetics ([3H]NE continuous infusion radiotracer technique) during LBNP of -15 mmHg. These measures of cardiac output and arterial NE spillover and clearance were obtained in 12 normal subjects at baseline, 5 and 10 min (Early) and 25 and 30 min (Late) of LBNP. We found that arterial NE concentration increased significantly, by 25% Early and 22% Late (P = 0.001). Spillover, however, did not change (P = 0.258), whereas clearance decreased by 12% Early and 19% Late (P = 0.014), and cardiac output decreased by 15% Early and 19% Late (P = 0.001). These reductions in clearance and cardiac output correlated significantly (r = 0.61, P = 0.001). No correlation was noted between spillover and cardiac output (r = 0.027, P = 0.874). We conclude that the increases in arterial NE concentration during nonhypotensive LBNP are predominantly due to decreased cardiac output with resultant decreases in systemic clearance of NE. These findings suggest that the ability to clear NE from the circulation is linked to the level of cardiac output and that low cardiac output states by themselves may lead to an elevation in arterial plasma NE concentrations.

An atrial natriuretic factor analogue at low doses attenuates forearm reflex vasoconstriction to cardiopulmonary receptor deactivation in patients with hypertension

Contrasting data exist about a possible modulation of the autonomic function by atrial natriuretic factor (ANF) in human beings, particularly at low, biologically, significant concentrations. We have evaluated that possibility by increasing plasma ANF levels through the infusion of a synthetic analogue (WY-47,663, anaritide) in five male patients with mild to moderate uncomplicated hypertension. Nonhypotensive lower body negative pressure (−10 mm Hg × 5 min) was used to selectively deactivate cardiopulmonary receptors and to stimulate sympathetic efferent tone reflexogenically. ANF was given at either a low rate (0.005 μg/kg/min × 60 min, which was previously shown to increase plasma ANF in a range compatible with physiologic stimuli) or at a high rate (0.05 μg/kg/min × 60 min, each). Administration of ANF was preceded and followed by vehicle infusion (Haemacell × 30 min). Forearm blood flow (venous plethysmography), intraarterial blood pressure, and heart rate were monitored continuously, and venous immunoreactive ANF, plasma renin activity, aldosterone level, and venous hematocrit were measured at the end of both control and infusion periods. Arterial norepinephrine values, an indirect index of sympathetic discharge, were measured at rest and during lower body negative pressure conditions. Graded systemic ANF infusion increased immunoreactive ANF and venous hematocrit, decreased aldosterone level and plasma renin activity, whereas resting norepinephrine levels, blood pressure, and heart rate did not change. Lower body negative pressure decreased forearm blood flow during vehicle infusion, but it lost its vasoconstrictor effect during infusion of ANF. To identify the site of that inhibitory action, ANF was also infused into the brachial artery at rates that raised local but not systemic levels of immunoreactive ANF. Blood flow increased dose-relatedly during the local administration of ANF, but lower body negative pressure still constricted forearm arterioles. Thus the effect of the peptide, event at low, possibly physiologic concentrations, was not related to a direct vasorelaxant action and was more likely related to an interaction with the cardiopulmonary baroreceptor control system. Autonomic modulation may be a relevant blologic action of ANF in patients with hypertension.

Baroreflex control of muscle sympathetic nerve activity in borderline hypertension.

Patients with borderline hypertension have exaggerated vascular responses to orthostatic stress produced by tilt or lower body negative pressure (LBNP). It has been suggested that 1) in the supine position, these patients have augmented activity of cardiopulmonary baroreceptors that exerts an increased restraint on sympathetic vasoconstrictor tone; 2) withdrawal of this augmented inhibitory baroreceptor activity during orthostatic stress elicits augmented reflex sympathetic vasoconstrictor outflow; and 3) augmented cardiopulmonary baroreceptor activity may be secondary to impaired arterial baroreflex mechanisms. To test these hypotheses, we recorded muscle sympathetic nerve activity from the peroneal nerve in seven borderline hypertensive subjects and seven age-, sex-, and weight-matched normotensive subjects during three levels of nonhypotensive LBNP and infusions of phenylephrine and nitroprusside. During LBNP, reductions of central venous pressure were similar in borderline hypertensive and normotensive subjects, and arterial pressure and heart rate values were unchanged. Increases of sympathetic nerve activity, however, were significantly greater in borderline hypertensive than in normotensive subjects at each level of LBNP, indicating an augmented gain of the cardiopulmonary baroreflex. To determine whether this augmentation is related to impairment of arterial baroreflexes, we measured changes of sympathetic nerve activity during increases and decreases of arterial pressure produced with infusions of intravenous phenylephrine and nitroprusside. Central venous pressure was held at control levels by LBNP during phenylephrine and saline infusion during nitroprusside. Changes of sympathetic nerve activity during alterations of arterial pressure were similar in borderline hypertensive and normotensive subjects. These data show that cardiopulmonary baroreflex control of SNA is augmented in borderline hypertensive subjects and that this augmentation does not result from an attenuation of the arterial baroreflex.

Sympathoinhibitory effects of atrial natriuretic factor in normal humans.

In rats, atrial natriuretic factor (ANF) reduces sympathetic nerve activity (SNA) reflexively by sensitizing cardiac mechanoreceptors with inhibitory vagal afferents. We performed three series of experiments in 26 normal young men to document whether ANF inhibits SNA in humans and if so, to determine potential mechanisms for this phenomenon. First, we recorded muscle SNA before and during brief infusions of ANF, vehicle (saline solution), and sodium nitroprusside, titrated to achieve reductions similar to those produced by ANF in diastolic pressure and central venous pressure, and we also assessed the effect of ANF on sympathetic nerve responses to a cold pressor test (CPT). Second, we determined the effect of ANF on Doppler-derived measurements of cardiac output and responses to hypotensive (-40 mm Hg) lower-body negative pressure (LBNP) and its sudden cessation. Third, we applied nonhypotensive (-15 mm Hg) LBNP to selectively unload cardiopulmonary baroreceptors, and we released LBNP to stimulate these inhibitory afferents during sequential infusions of nitroglycerin, vehicle (saline solution), and ANF. Our key findings were that 1) reductions in arterial and central venous pressures during ANF infusion were not accompanied by anticipated reflex increases in muscle SNA; 2) ANF blunted the increase in SNA with CPT; 3) ANF increased stroke volume and cardiac output; and 4) sympathoneural responses to both the application and the sudden cessation of nonhypotensive LBNP were attenuated, not augmented, by ANF. Changes in plasma norepinephrine concentrations reflected these sympathetic nerve responses to ANF. These results do not support the concept that ANF inhibits sympathetic outflow reflexively in humans by increasing discharge from cardiac mechanoreceptors with inhibitory vagal afferents but are consistent with either a central or a ganglionic sympathoinhibitory action of ANF. ANF could facilitate hypotension and natriuresis in humans by attenuating the reflex sympathetic response to baroreceptor deactivation.

Relation between sympathetic outflow and vascular resistance in the calf during perturbations in central venous pressure. Evidence for cardiopulmonary afferent regulation of calf vascular resistance in humans.

Vascular studies in humans have advanced the concept that, during orthostatic stress, cardiopulmonary afferents reflexly regulate vascular resistance in the forearm but exert surprisingly little if any effects on vascular resistance in the calf. In contrast, neurophysiological studies have indicated that unloading of cardiopulmonary afferents during lower body negative pressure evokes comparable increases in sympathetic outflow to the muscles of both the forearm and the calf. The aim of this study, therefore, was to determine if alterations in central venous pressure over the physiological range trigger reflex changes in muscle sympathetic outflow that not only are statistically significant but also are large enough to alter vascular resistance in the calf. To accomplish this aim, we measured calf blood flow with plethysmography and simultaneously performed microelectrode recordings of sympathetic outflow to calf muscles in conscious humans during maneuvers designed to alter the loading conditions of the cardiopulmonary afferents. We found that calf vascular resistance increased by 33 +/- 7% (mean +/- SEM, p less than 0.05) during decreases in central venous pressure produced by nonhypotensive lower body negative pressure (LBNP) and decreased by 26 +/- 5% (p less than 0.05) during increases in central venous pressure produced by nonhypertensive infusion of normal saline. These changes in calf resistance were at least as large as the changes in forearm resistance evoked by these maneuvers and were accompanied by parallel changes in peroneal muscle sympathetic nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)