Systemic vascular resistance during brief withdrawal of angiotensin converting enzyme inhibition in heart failure.

We tested the hypothesis that moderate increases in endogenous angiotensin II (Ang II) concentrations, induced by withdrawal of angiotensin converting enzyme inhibition (ACE-I) in patients with compensated heart failure (HF) on chronic medical therapy, do not increase or impair control of systemic vascular resistance (SVR). SVR was determined in supine and seated positions in 12 HF patients [NYHA class II-III; ejection fraction=0.29 +/- 0.03 (mean +/- SE)] and 9 control subjects. HF patients were investigated during high (n=11; withdrawal of ACE-I treatment for 24 h) and low (n=9; sustained ACE-I therapy) endogenous plasma Ang II concentrations. Withdrawal of ACE-I therapy in HF caused moderately increased Ang II concentrations of 30 +/- 5 pg/ml compared with 12 +/- 2 pg/ml in controls (p<0.05 vs. HF patients). Despite this, SVR was similar in HF (supine: 1503 +/- 159; seated: 1957 +/- 262 dyn s/cm5, p<0.05 vs. supine) and controls (supine: 1438 +/- 104; seated: 1847 +/- 127 dyn s/cm5, p<0.05 vs. supine). During sustained ACE-I therapy in HF, plasma Ang II concentrations were lower (6 +/- 2pg/ml, p<0.05 vs. withdrawal of ACE-I in HF) with no effect on supine SVR. However, the posture-induced increase in SVR in response to the seated position was attenuated. In conclusion, brief moderate increases in circulating plasma Ang II concentrations in compensated HF do not increase SVR compared to control subjects or impair control of SVR in response to a posture change.

Atrial distension, haemodilution, and acute control of renin release during water immersion in humans.

We tested the hypothesis that atrial distension (stimulation of cardiopulmonary baroreceptors) is not the single pivotal stimulus for the acute suppression of renin release during water immersion in humans and that immersion-induced haemodilution constitutes an important additional stimulus. In nine healthy male subjects, identical increases in atrial distension were induced by two immersion procedures (of 30 min each); one without (WI) and one with attenuation (WI + cuff) of the concomitant haemodilution (estimated from changes in plasma protein concentration) by inflating thigh cuffs during immersion. During WI, central venous pressure (CVP) and left atrial diameter (LAD) increased (P < 0.05) by 5.5 +/- 0.4 mmHg and 4.6 +/- 0.5 mm, respectively, and plasma protein concentration and plasma renin activity (PRA) progressively decreased (P < 0.05) by 4.8 +/- 0.5 g L(-1) and 1.6 +/- 0.2 ng mL(-1) h(-1) (to 49 +/- 4% of baseline values), respectively. The WI + cuff caused similar atrial distension as WI (CVP and LAD increased by 6.9 +/- 0.5 mmHg and 5.5 +/- 0.5 mm, respectively), attenuated haemodilution (plasma protein concentration decreased by 1.9 +/- 0.4 g L(-1), P < 0.05 vs. WI), and markedly inhibited suppression of PRA, which decreased by 0.4 +/- 0.1 ng mL(-1) h(-1) (to 87 +/- 4% of baseline values, P < 0.05 vs. WI). Differences in renin release could not be accounted for by differences in mean arterial pressure. In conclusion, baroreceptor stimulation induced by atrial distension is not the single pivotal stimulus for the acute suppression of renin release in response to intravascular volume expansion by water immersion in humans. Haemodilution constitutes a significant and conceivably the principal stimulus for the acute immersion-induced suppression of renin-angiotensin system activity.

Validity of microgravity simulation models on earth.

Many studies have used water immersion and head-down bed rest as experimental models to simulate responses to microgravity. However, some data collected during space missions are at variance or in contrast with observations collected from experimental models. These discrepancies could reflect incomplete knowledge of the characteristics inherent to each model. During water immersion, the hydrostatic pressure lowers the peripheral vascular capacity and causes increased thoracic blood volume and high vascular perfusion. In turn, these changes lead to high urinary flow, low vasomotor tone, and a high rate of water exchange between interstitium and plasma. In contrast, the increase in thoracic blood volume during a space mission is combined with stimulated orthosympathetic tone and lowered urine flow. During bed rest, body tissues are compressed by pressure from gravity, whereas microgravity causes a negative pressure around the body. The differences in renal function between space and experimental models appear to be explained by the physical forces affecting tissues and hemodynamics as well as by the changes secondary to these forces. These differences may help in selecting experimental models to study possible effects of microgravity.

Renal and sympathoadrenal responses in space.

According to a classic hypothesis, weightlessness should promote the renal excretion rate of sodium and water and lead to a fluid- and electrolyte-depleted state. This hypothesis is based on experiments in which weightlessness has been simulated in humans by head-down bed rest and water immersion. However, after 5 to 6 days of space mission, the diuretic and natriuretic responses to an intravenous isotonic saline load were attenuated and plasma norepinephrine and renin concentrations increased compared with those of the acute supine position before flight. Renal fluid excretion after an oral water load was also attenuated in space. Similar decreases were not observed during head-down bed rest. Sympathetic activity is of major importance in regulating blood volume and renal function. Studies in space have indicated that, compared with that while in a supine position on Earth, sympathoadrenal activity is increased during space flights as measured using plasma concentration and urinary excretion of norepinephrine and epinephrine. The space-induced activation of antinatriuretic mechanisms and sympathoadrenal activity could have been caused by early in-flight reduction in total and central blood volume. The decreased plasma volume may be explained by such factors as redistribution of plasma from the lower to the upper body (thin legs and puffy face), reduced food intake, and decreased muscle activity. The decrease in plasma volume and the subsequent increase in sympathetic activity is due, at least in part, to the abrupt cessation of activity in large muscle groups during microgravity, which normally counteracts the effects of gravity in the upright posture. This would lead to accumulation of albumin and fluid in the interstitial space.

Water and sodium balance in space.

We have previously shown that fluid balances and body fluid regulation in microgravity (microG) differ from those on Earth (Drummer et al, Eur J Physiol 441:R66-R72, 2000). Arriving in microG leads to a redistribution of body fluid-composed of a shift of fluid to the upper part of the body and an exaggerated extravasation very early in-flight. The mechanisms for the increased vascular permeability are not known. Evaporation, oral hydration, and urinary fluid excretion, the major components of water balance, are generally diminished during space flight compared with conditions on Earth. Nevertheless, cumulative water balance and total body water content are stable during flight if hydration, nutritional energy supply, and protection of muscle mass are at an acceptable level. Recent water balance data disclose that the phenomenon of an absolute water loss during space flight, which has often been reported in the past, is not a consequence of the variable microG. The handling of sodium, however, is considerably affected by microG. Sodium-retaining endocrine systems, such as renin-aldosterone and catecholamines, are much more activated during microG than on Earth. Despite a comparable oral sodium supply, urinary sodium excretion is diminished and a considerable amount of sodium is retained-without accumulating in the intravascular space. An enormous storage capacity for sodium in the extravascular space and a mechanism that allows the dissociation between water and sodium handling likely contribute to the fluid balance adaptation in weightlessness.

Revised hypothesis and future perspectives.

Results from space have been unexpected and not predictable from the results of ground-based simulations. Therefore, the concept of how weightlessness and gravity modulates the regulation of body fluids must be revised and a new simulation model developed. The main questions to ask in the future are the following: Does weightlessness induce a diuresis and natriuresis during the initial hours of space flight leading to an extracellular and intravascular fluid volume deficit? Can sodium in excess be stored in a hitherto unknown way, particularly during space flight? Why are fluid and sodium retaining systems activated by spaceflight? Why are the renal responses to saline and water stimuli in space attenuated compared with those of ground simulations? How can the effects of weightlessness on fluid and electrolyte regulation be correctly simulated on the ground? The information obtained from space may be of relevance to fluid and electrolyte balance in edematous patients.

Atrial distension, arterial pulsation, and vasopressin release during negative pressure breathing in humans.

During an antiorthostatic posture change, left atrial (LA) diameter and arterial pulse pressure (PP) increase, and plasma arginine vasopressin (AVP) is suppressed. By comparing the effects of a 15-min posture change from seated to supine with those of 15-min seated negative pressure breathing in eight healthy males, we tested the hypothesis that with similar increases in LA diameter, suppression of AVP release is dependent on the degree of increase in PP. LA diameter increased similarly during the posture change and negative pressure breathing (-9 to -24 mmHg) from between 30 and 31 +/- 1 to 34 +/- 1 mm (P < 0.05). The increase in PP from 38 +/- 2 to 44 +/- 2 mmHg (P < 0.05) was sustained during the posture change but only increased during the initial 5 min of negative pressure breathing from 36 +/- 3 to 42 +/- 3 mmHg (P < 0.05). Aortic transmural pressure decreased during the posture change and increased during negative pressure breathing. Plasma AVP was suppressed to a lower value during the posture change (from 1.5 +/- 0.3 to 1.2 +/- 0.2 pg/ml, P < 0.05) than during negative pressure breathing (from 1.5 +/- 0.3 to 1.4 +/- 0.3 pg/ml). Plasma norepinephrine was decreased similarly during the posture change and negative pressure breathing compared with seated control. In conclusion, the results are in compliance with the hypothesis that during maneuvers with similar cardiac distension, suppression of AVP release is dependent on the increase in PP and, furthermore, probably unaffected by static aortic baroreceptor stimulation.

Central volume expansion is pivotal for sustained decrease in heart rate during seated to supine posture change.

During prolonged, static carotid baroreceptor stimulation by neck suction (NS) in seated humans, heart rate (HR) decreases acutely and thereafter gradually increases. This increase has been explained by carotid baroreceptor adaptation and/or buffering by aortic reflexes. During a posture change from seated to supine (Sup) with similar carotid stimulation, however, the decrease in HR is sustained. To investigate whether this discrepancy is caused by changes in central blood volume, we compared (n = 10 subjects) the effects of 10 min of seated NS (adjusted to simulate carotid stimulation of a posture change), a posture change from seated to Sup, and the same posture change with left atrial (LA) diameter maintained unchanged by lower body negative pressure (Sup + LBNP). During Sup, the prompt decreases in HR and mean arterial pressure (MAP) were sustained. HR decreased similarly within 30 s of NS (65 +/- 2 to 59 +/- 2 beats/min) and Sup + LBNP (65 +/- 2 to 58 +/- 2 beats/min) and thereafter gradually increased to values of seated. MAP decreased similarly within 5 min during Sup + LBNP and NS (by 7 +/- 1 to 9 +/- 1 mmHg) and thereafter tended to increase toward values of seated subjects. Arterial pulse pressure was increased the most by Sup, less so by Sup + LBNP, and was unchanged by NS. LA diameter was only increased by Sup. In conclusion, static carotid baroreceptor stimulation per se causes the acute (<30 s) decrease in HR during a posture change from seated to Sup, whereas the central volume expansion (increased LA diameter and/or arterial pulse pressure) is pivotal to sustain this decrease. Thus the effects of central volume expansion override adaptation of the carotid baroreceptors and/or buffering of aortic reflexes.

Neuroendocrine and renal effects of intravascular volume expansion in compensated heart failure.

To examine if the neuroendocrine link between volume sensing and renal function is preserved in compensated chronic heart failure [HF, ejection fraction 0.29 +/- 0.03 (mean +/- SE)] we tested the hypothesis that intravascular and central blood volume expansion by 3 h of water immersion (WI) elicits a natriuresis. In HF, WI suppressed ANG II and aldosterone (Aldo) concentrations, increased the release of atrial natriuretic peptide (ANP), and elicited a natriuresis (P < 0.05 for all) compared with seated control. Compared with control subjects (n = 9), ANG II, Aldo, and ANP concentrations were increased (P < 0.05) in HF, whereas absolute and fractional sodium excretion rates were attenuated [47 +/- 16 vs. 88 +/- 15 micromol/min and 0.42 +/- 0.18 vs. 0.68 +/- 0.12% (mean +/- SE), respectively, both P < 0.05]. When ANG II and Aldo concentrations were further suppressed (P < 0.05) during WI in HF (by sustained angiotensin-converting enzyme inhibitor therapy, n = 9) absolute and fractional sodium excretion increased (P < 0.05) to the level of control subjects (108 +/- 34 micromol/min and 0.70 +/- 0.23%, respectively). Renal free water clearance increased during WI in control subjects but not in HF, albeit plasma vasopressin concentrations were similar in the two groups. In conclusion, the neuroendocrine link between volume sensing and renal sodium excretion is preserved in compensated HF. The natriuresis of WI is, however, modulated by the prevailing ANG II and Aldo concentrations. In contrast, renal free water clearance is attenuated in response to volume expansion in compensated HF despite normalized plasma AVP concentrations.

Fluid volume and osmoregulation in humans after a week of head-down bed rest.

Body fluid homeostasis was investigated during chronic bed rest (BR) and compared with that of acute supine conditions. The hypothesis was tested that 6 degrees head-down BR leads to hypovolemia, which activates antinatriuretic mechanisms so that the renal responses to standardized saline loading are attenuated. Isotonic (20 ml/kg body wt) and hypertonic (2.5%, 7.2 ml/kg body wt) infusions were performed in eight subjects over 20 min following 7 and 10 days, respectively, of BR during constant sodium intake (200 meq/day). BR decreased body weight (83.0 +/- 4.8 to 81.8 +/- 4.4 kg) and increased plasma osmolality (285.9 +/- 0.6 to 288.5 +/- 0.9 mosmol/kgH(2)O, P < 0.05). Plasma ANG II doubled (4.2 +/- 1.2 to 8.8 +/- 1.8 pg/ml), whereas other endocrine variables decreased: plasma atrial natriuretic peptide (42 +/- 3 to 24 +/- 3 pg/ml), urinary urodilatin excretion rate (4.5 +/- 0.3 to 3.2 +/- 0.1 pg/min), and plasma vasopressin (1.7 +/- 0.3 to 0.8 +/- 0.2 pg/ml, P < 0.05). During BR, the natriuretic response to the isotonic saline infusion was augmented (39 +/- 8 vs. 18 +/- 6 meq sodium/350 min), whereas the response to hypertonic saline was unaltered (32 +/- 8 vs. 29 +/- 5 meq/350 min, P < 0.05). In conclusion, BR elicits antinatriuretic endocrine signals, but it does not attenuate the renal natriuretic response to saline stimuli in men; on the contrary, the response to isotonic saline is augmented.

Mechanisms of hypotensive effects of a posture change from seated to supine in humans.

The hypothesis tested was that the hydrostatic stimulation of carotid baroreceptors is pivotal to decrease mean arterial pressure at heart level during a posture change from seated to supine. In eight males, the cardiovascular responses to a 15-min posture change from seated to supine were compared with those of water immersion to the xiphoid process and to the neck, respectively. Left atrial diameter and cardiac output (rebreathing) increased similarly during the posture change and water immersion to the xiphoid process and further so during neck immersion. Mean arterial pressure decreased by 12 +/- 2 mmHg during the posture change, by 5 +/- 1 mmHg during xiphoid immersion, and was unchanged during neck immersion. Arterial pulse pressure increased by 12 +/- 3 mmHg during the posture change (P < 0.05) and less during xiphoid and neck immersion by 7 +/- 3 mmHg (P < 0.05). Total peripheral vascular resistance decreased similarly during the posture change and neck immersion and slightly less during xiphoid immersion (P < 0.05). In conclusion, the hydrostatic stimulation of carotid baroreceptors combined with some additional increase in arterial pulse pressure, which also stimulates aortic baroreceptors, accounts for more than half of the hypotensive response at heart level to a posture change from seated to supine.

Cardiovascular effects of static carotid baroreceptor stimulation during water immersion in humans.

We hypothesized that the more-pronounced hypotensive and bradycardic effects of an antiorthostatic posture change from seated to supine than water immersion are caused by hydrostatic carotid baroreceptor stimulation. Ten seated healthy males underwent five interventions of 15-min each of 1) posture change to supine, 2) seated water immersion to the Xiphoid process (WI), 3) seated neck suction (NS), 4) WI with simultaneous neck suction (-22 mmHg) adjusted to simulate the carotid hydrostatic pressure increase during supine (WI + NS), and 5) seated control. Left atrial diameter increased similarly during supine, WI + NS, and WI and was unchanged during control and NS. Mean arterial pressure (MAP) decreased the most during supine (7 +/- 1 mmHg, P < 0.05) and less during WI + NS (4 +/- 1 mmHg) and NS (3 +/- 1 mmHg). The decrease in heart rate (HR) by 13 +/- 1 beats/min (P < 0.05) and the increase in arterial pulse pressure (PP) by 17 +/- 4 mmHg (P < 0.05) during supine was more pronounced (P < 0.05) than during WI + NS (10 +/- 2 beats/min and 7 +/- 2 mmHg, respectively) and WI (8 +/- 2 beats/min and 6 +/- 1 mmHg, respectively, P < 0.05). Plasma vasopressin decreased only during supine and WI, and plasma norepinephrine, in addition, decreased during WI + NS (P < 0.05). In conclusion, WI + NS is not sufficient to decrease MAP and HR to a similar extent as a 15-min seated to supine posture change. We suggest that not only static carotid baroreceptor stimulation but also the increase in PP combined with low-pressure receptor stimulation is a possible mechanism for the more-pronounced decrease in MAP and HR during the posture change.

Cardiovascular and neuroendocrine responses to left lateral position in non-obese young males.

Previous results from our laboratory indicate that the heart is distended by the left lateral position (LAT) compared to horizontal supine (SUP). We therefore tested the hypothesis that cardiac output is increased by LAT and that mean arterial pressure is maintained unchanged or even decreased through peripheral vasodilatation induced by cardiopulmonary low-pressure receptor stimulation. Twelve non-obese young males were investigated. The location of the mid-aorta between the aortic valves was used as the hydrostatic reference point for the arterial pressure measurements. It was determined by magnetic resonance (n=6) to be 7.0 +/- 0.2 cm below the sternum in SUP (1/3 of anteroposterior chest diameter below the sternum) and 2.5 +/- 0.2 cm below the midsternal level in LAT. Brachial mean (auscultation) and finger mean arterial pressures (infrared photoplethysmography), cardiac output (foreign gas rebreathing), heart rate, and plasma concentrations (n=6) of vasoactive hormones were unchanged by LAT. In conclusion, cardiac output, mean arterial pressures, and vasoactive hormone releases were unaffected by 30 min of LAT. Furthermore, the hydrostatic reference points for arterial pressure measurements is located one third of the antero-posterior chest diameter below the sternum in SUP and 2.5 cm below the midsternal level in LAT in non-obese young males.

Water and sodium balances and their relation to body mass changes in microgravity.

BACKGROUND: Since the very beginning of space physiology research, the deficit in body mass that is often observed after landing has always been interpreted as an indication of the absolute fluid loss early during space missions. However, in contrast to central hypervolemic conditions on Earth, the acute shift of blood volume from the legs to the upper part of the body in astronauts entering microgravity (microG) has neither stimulated diuresis and natriuresis nor resulted in negative water-and sodium-balances. DESIGN: We therefore examined the kinetics of body mass changes in astronauts (n = 3) during their several weeks aboard the space station MIR. A continuous diet monitoring was performed during the first mission (EuroMIR94, 30 days). The second mission (MIR97, 19 days) comprised a 15-day metabolic ward period (including predefined constant energy and sodium intake). Water and sodium balances were calculated and the kinetic of changes in basal concentrations of fluid-balance-related hormones during flight were determined. CONCLUSION: The data suggest firstly that loss of body mass during space flight is rather a consequence of hypocaloric nutrition. Secondly, microG provokes a sodium retaining hormonal status and may lead to sodium storage without an accompanying fluid retention.

Unexpected renal responses in space.

Urine output in astronauts following ingestion of an oral water load was low in space on the Russian space station Mir and less than during simulation by 6 degrees head-down bed rest. This surprising observation shows that the effects of gravity and weightlessness on fluid volume regulation are not well understood and that the head-down bed-rest model does not simulate the effects of weightlessness on renal water handling.

Cardiovascular and neuroendocrine responses to water immersion in compensated heart failure.

The hypothesis was tested that cardiovascular and neuroendocrine (norepinephrine, renin, and vasopressin) responses to central blood volume expansion are blunted in compensated heart failure (HF). Nine HF patients [New York Heart Association class II-III, ejection fraction = 0.28 +/- 0.02 (SE)] and 10 age-matched controls (ejection fraction = 0.68 +/- 0.03) underwent 30 min of thermoneutral (34.7 +/- 0.02 degrees C) water immersion (WI) to the xiphoid process. WI increased (P < 0.05) central venous pressure by 3.7 +/- 0.6 and 3.2 +/- 0.4 mmHg and stroke volume index by 12.2 +/- 2.1 and 7.2 +/- 2.1 ml. beat(-1). m(-2) in controls and HF patients, respectively. During WI, systemic vascular resistance decreased (P < 0.05) similarly by 365 +/- 66 and 582 +/- 227 dyn. s. cm(-5) in controls and HF patients, respectively. Forearm subcutaneous vascular resistance decreased by 19 +/- 7% (P < 0.05) in controls but did not change in HF patients. Heart rate decreased less during WI in HF patients, whereas release of norepinephrine, renin, and vasopressin was suppressed similarly in the two groups. We suggest that reflex control of forearm vascular beds and heart rate is blunted in compensated HF but that baroreflex-mediated systemic vasodilatation and neuroendocrine responses to central blood volume expansion are preserved.

Low LBNP tolerance in men is associated with attenuated activation of the renin-angiotensin system.

Plasma vasoactive hormone concentrations [epinephrine (p(Epi)), norepinephrine (p(NE)), ANG II (p(ANG II)), vasopressin (p(VP)), endothelin-1 (p(ET-1))] and plasma renin activity (p(RA)) were measured periodically and compared during lower body negative pressure (LBNP) to test the hypothesis that responsiveness of the renin-angiotensin system, the latter being one of the most powerful vasoconstrictors in the body, is of major importance for LBNP tolerance. Healthy men on a controlled diet (2,822 cal/day, 2 mmol. kg(-1). day(-1) Na(+)) were exposed to 30 min of LBNP from -15 to -50 mmHg. LBNP was uneventful for seven men [25 +/- 2 yr, high-tolerance (HiTol) group], but eight men (26 +/- 3 yr) reached presyncope after 11 +/- 1 min [P < 0.001, low-tolerance (LoTol) group]. Mean arterial pressure (MAP) did not change measurably, but central venous pressure and left atrial diameter decreased similarly in both groups (5-6 mmHg, by approximately 30%, P < 0.05). Control (0 mmHg LBNP) hormone concentrations were similar between groups, however, p(RA) differed between them (LoTol 0.6 +/- 0.1, HiTol 1.2 +/- 0.1 ng ANG I. ml(-1). h(-1), P < 0.05). LBNP increased (P < 0. 05) p(RA) and p(ANG II), respectively, more in the HiTol group (9.9 +/- 2.2 ng ANG I. ml(-1). h(-1) and 58 +/- 12 pg/ml) than in LoTol subjects (4.3 +/- 0.9 ng ANG I. ml(-1). h(-1) and 28 +/- 6 pg/ml). In contrast, the increase in p(VP) was higher (P < 0.05) in the LoTol than in the HiTol group. The increases (P < 0.05) for p(NE) were nonsignificant between groups, and p(ET-1) remained unchanged. Thus there may be a causal relationship between attenuated activation of p(RA) and p(ANG II) and presyncope, with p(VP) being a possible cofactor. Measurement of resting p(RA) may be of predictive value for those with lower hypotensive tolerance.