Central Volume Expansion Research Articles

Capacitive function of the heart: influence of acute changes in heart volume on mean right atrial pressure.

Net transfer of blood volume into or out of the cardiac chambers should have the same effect on central venous pressure as does transfer of an equal volume of blood to or from peripheral organs (e.g., spleen, or liver). We studied five pentobarbital sodium-anesthetized open-chest pigs (20-23 kg) to determine whether a reduction in the time-averaged volume of blood contained in the heart, induced by rapid atrial pacing, can raise right atrial pressure. A central premise of our study is that the mean value of right atrial pressure is acutely governed by the volume of blood that distends the central veins, and that atrial contractions primarily determine how atrial pressure varies about its mean value. To prevent changes in cardiac output from altering central blood volume and pressure, cardiac output during rapid pacing (2.36 +/- 0.18 l/min) was made to equal the resting output (2.35 +/- 0.16 l/min). This was achieved by selecting a rate of pacing at which the tendency for more frequent cardiac contractions to raise cardiac output was counterbalanced by the decrease in stroke volume induced by rapid pacing. Autonomic reflex mechanisms were attenuated by pharmacological blockade. Mean arterial pressure was minimally affected in the transition from a normal sinus rhythm (89 +/- 6 beats/min) to rapid atrial pacing (165 +/- 7 beats/min) in four pigs. Mean right atrial pressure rose abruptly from 2.8 +/- 0.5 mmHg during normal sinus rhythm to 3.5 +/- 0.5 mmHg (P = 0.015) at the onset of rapid pacing in these four pigs, presumably owing to decreased cardiac blood volume and a reciprocal expansion of central venous volume. In the fifth pig, a reduction in cardiac output induced by tachycardia led to a larger rise in mean right atrial pressure than did a reduction in cardiac output induced by bradycardia, presumably because tachycardia reduces cardiac blood volume whereas bradycardia raises cardiac volume. We conclude that the heart may play an important role in maintaining or raising its own filling pressure when heart rate rises.

RESPONSE TO WATER IMMERSION IN DEHYDRATED OLDER AND YOUNGER SUBJECTS349

The primary signals for thirst emanate from osmoreceptors and volume receptors in the cardiopulmonary region of the circulation. To test the hypothesis that the reported attenuation in thirst with aging is due to a decline in volume receptor sensitivity, we exposed older (70±2 y,n=6) and younger (24±1 y, n=6) subjects to 195 min of water immersion, which shifts blood centrally but does not affect plasma osmolality (Posm). Subjects dehydrated by exercising for 2 h at 36°C in the evening and refrained from fluids overnight prior to immersion in 34°C water (WI) or a seated control in a water perfusion suit(PS) the next morning. Ad libitum water intake was allowed after 15 min of WI or PS. Dehydration decreased plasma volume (PV) by 7.3±1.8% and 10.6±1.8% and increased Posm by 7±1 mosmol·kg-1 H2O and 6±2 mosmol·kg-1 H2O in younger and older subjects, respectively. Thirst ratings were elevated similarly (69±13 mm and 72±11 mm on a line-rating scale) in younger and older subjects. Relative to morning values, 15 min of WI immersion restored PV (5.7±1.0% and 7.8±1.0% in younger and older subjects, respectively) with no change in Posm. During WI, prior to drinking, plasma concentrations of arginine vasopressin(P[AVP]) decreased from 2.75±0.38 pg·ml-1 and 2.17±0.73 pg·ml-1 to 2.09±0.74 pg·ml-1 and 1.35±0.53 pg·ml-1 in younger and older subjects but thirst rating fell in younger subjects only(p<0.05). Fluid intake was markedly reduced in WI compared to PS in younger (7.5±0.5 ml·kg-1 vs 14.3±2.2 ml·kg-1, p<0.05), but not in older subjects (6.7±2.1 ml·kg-1 vs 8.5±3.3 ml·kg-1), allowing us to conclude that the inhibitory influence of central volume expansion on thirst sensitivity and fluid intake is diminished with aging.

Simulated micro-gravity and cortical inhibition: a study of the hemodynamic-brain interaction

The present study was carried out to determine the inhibitory cortical processes induced by changes in hemodynamics. Previous experiments in humans conducted in our laboratory have shown that there is a close relationship between posture and delta and theta EEG activity. The most pronounced effects were obtained during the 6 ° head-down tilt (HDT) position. In space medicine the HDT procedure is very frequently employed to simulate micro-gravity and to determine the neurohormonal counter-regulations evoked by the expansion of central volume. Twenty male subjects spent 23 h in bed in 6 ° HDT and 23 h in 6 ° HUT (head-up tilt) positions during which EEG (frontal, central, parietal, occipital), startle responses, and reaction-times were measured every 2 h (from 10:00 h till 20:00 h). The effects of cardiovascular deconditioning (CD) regularly occurring after HDT were assessed by examining orthostatic tolerance and the physical work capacity (bicycle ergometry). As expected, 23 h HDT led to more pronounced CD than HUT. Spectral power analyses of EEG revealed increases in delta and theta frequency bands similar to those found during HDT in previous EEG studies. In addition, subjects responded more slowly (S1–S2 reaction-time task) during HDT as compared with HUT bedrest. The influence of HDT on startle response, however, was not in keeping with the initial hypothesis (i.e. dampening of reflex activity). The EEG data and the sensorimotor performance indicated that the body fluid shift towards the thoracic cavity induced by HDT resulted in signs of cortical inhibition. In addition to neural mechanisms, other processes must be postulated which are closely related to the counter-regulation evoked by the varying body positions.

Modifications induced by -10 degrees Trendelenburg's posture in sodium tubular handling in patients with essential hypertension.

In essential hypertensive patients "exaggerated natriuresis" is a response to acute volume expansion. However, the underlying mechanisms for this remain to be determined. We studied 19 patients with essential hypertension (HP) and 9 normotensive subjects (NS). In all examined subjects the response to acute central volume expansion, without the plasma compositional change that Trendelenburg's position involves, was evaluated during 90 min (period T) after a similar period of deambulation (period D). Mean blood pressure (MBP), tubular sodium handling by the lithium clearance technique, plasma renin activity (PRA), plasma aldosterone (PA), plasma catecholamines and urine prostaglandine E2 and kallikrein were assessed after D and T. MBP was significantly higher in HP than in NS (p = 0.00001). HP showed "exaggerated natriuresis" after T (fractional excretion of sodium increased from 0.55 +/- 0.1% after D to 1.20 +/- 0.2% after T, p < 0.01). This was because of a decrease in their proximal fractional reabsorption of sodium (from 74.96 +/- 1.8% after D to 62.50 +/- 2.8% after T, p < 0.01). Plasma epinephrine and plasma dopamine after T were significantly lower than in standing position in HP (p < 0.01) but no in NS. The decrease in plasma renin activity after T in HP was 53%, and 32% in NS. There were not any significant differences between groups in the other neurohormonal systems studied. We conclude that the major determinant of "exaggerated natriuresis" in hypertensive patients is a higher stimulation of the cardiopulmonary receptors following Trendelenburg's position and consequently stronger reflex inhibition of sympathetic system activity and renin-angiotensin II activity. The "exaggerated natriuresis" after Trendelenburg's position in HP was an expression of abnormal pressure natriuresis.

Pattern of sodium handling and its consequences in patients with preascitic cirrhosis

Background/Aims: The initial abnormalities in the renal sodium handling in patients with cirrhosis before developing ascites remain unknown. The aim of this study is to further characterize sodium metabolism and the effects of sodium loading in preascitic cirrhosis. Methods: Eight male, preascitic patients with cirrhosis and 6 volunteers had their daily urinary sodium excretion level measured while on a strictly metabolically controlled diet, first consisting of 20 mmol then of 200 mmol sodium per day each for 7 days. Central blood volume, plasma norepinephrine, and atrial natriuretic factor levels were measured during each diet. Results: Preascitic patients with cirrhosis had significantly less daily urinary sodium excretion on both diets. Volume expansion in the patients with cirrhosis was indicated by significantly greater weight gain and higher atrial natriuretic factor levels for each diet. Patients with cirrhosis had central blood volume expansion (1725 ± 54 mL/m 2) compared with controls (1495 ± 81 mL/m 2; P = 0.03) on a low-sodium diet. This increased significantly in the controls (1864 ± 164 mL/m 2; P = 0.04) on a high-sodium diet, associated with suppression of plasma norepinephrine, but not in the patients with cirrhosis (1679 ± 107 mL/m 2; P > 0.05). Conclusions: Failure of further central blood volume expansion in the patients with cirrhosis on high-sodium diet in the presence of significant weight gain suggests maldistribution away from the effective arterial blood volume. This study provides further reasons why preascitic patients with cirrhosis might benefit from sodium restriction.

Release of kaliuretic peptide during immersion-induced central hypervolemia in healthy humans.

Kaliuretic peptide, a new peptide hormone consisting of amino acids 79-98 of the 126 amino acid atrial natriuretic factor (ANF) prohormone, is synthesized in the heart and is a potent stimulator of potassium excretion. The mechanism(s) controlling the release of kaliuretic peptide heretofore has not been defined. Because water immersion to the neck provides an acute central volume expansion identical to that produced by 2 liters of saline but without the plasma compositional change, immersion to the neck (NI) was utilized to assess kaliuretic peptide responses to acute central blood volume expansion in seven seated sodium-replete normal subjects. Since atrial natriuretic factor (ANF; amino acids 99-126 of the prohormone) originates from the amino acids adjacent to kaliuretic peptide in the ANF prohormone but is proteolytically cleaved from the rest of the prohormone before release, measurement of ANF was incorporated into this study to determine if there are differences with respect to release of these two portions of the ANF prohormone. Both kaliuretic peptide and ANF increased promptly with NI, with ANF peaking at 1 hr of immersion, whereas kaliuretic peptide peaked at the 3rd hr of immersion. With cessation of immersion, ANF decreased to preimmersion levels within 0.5 hr while kaliuretic peptide was still significantly (P < 0.05) elevated at 1 hr postimmersion. These findings indicate that kaliuretic peptide and ANF are released simultaneously but that kaliuretic peptide peak circulating concentration and its return to preimmersion values are prolonged compared with ANF. These last findings suggest a slower clearance from the circulation for kaliuretic peptide. The diuretic peak response to NI corresponded in a temporal manner to the peak circulating concentration of kaliuretic peptide, suggesting a possible physiologic role for kaliuretic peptide in modulating volume homeostasis in humans.

The Renin‐Angiotensin‐Aldosterone System and Vasopressin in Early‐Stage Liver Cirrhosis after HBV Infection in Children

SummaryWe evaluated the dynamic response of renin, aldosterone, and vasopressin to intravenous water loading (20 ml 5% glucose/kg b.w.) in 12 children (aged 7–18 years) with postinflammatory liver cirrhosis after hepatitis B virus (HBV) infection. All of the patients had early‐stage liver cirrhosis; according to Child's classification, nine patients had group A; three, group B cirrhosis. A group of 17 children with chronic persistent hepatitis served as the control. The diagnoses were confirmed in all of the patients by liver biopsy. The patients followed a diet containing 3 mmol NaCl/kg/day, maximum 100 mmol per day for 6 days. Water loading was performed in recumbency over ± 45 min. Renin, aldosterone, and vasopressin, assayed by radioimmunoassay (RIA), were determined before, 1 h, and 5 h after starting the water load. Prestudy hormone levels were within normal range in both groups. Renin and aldosterone concentration change patterns were similar in both groups and characterized by suppression of hormone activity caused by central volume expansion and recovery to prestudy levels after 5 h. However, the pattern of change of vasopressin concentrations differed in the control and study groups. In contrast to that of the controls, volume expansion did not suppress vasopressin in the group with liver cirrhosis. We conclude that failure to suppress vasopressin activity after central volume expansion may be one of the early mechanisms responsible for water‐electrolyte imbalance in liver cirrhosis in children.

The Renin-Angiotensin-Aldosterone System and Vasopressin in Early-Stage Liver Cirrhosis after HBV Infection in Children

We evaluated the dynamic response of renin, aldosterone, and vasopressin to intravenous water loading (20 ml 5% glucose/kg b.w.) in 12 children (aged 7-18 years) with postinflammatory liver cirrhosis after hepatitis B virus (HBV) infection. All of the patients had early-stage liver cirrhosis; according to Child's classification, nine patients had group A; three, group B cirrhosis. A group of 17 children with chronic persistent hepatitis served as the control. The diagnoses were confirmed in all of the patients by liver biopsy. The patients followed a diet containing 3 mmol NaCl/kg/day, maximum 100 mmol per day for 6 days. Water loading was performed in recumbency over approximately 45 min. Renin, aldosterone, and vasopressin, assayed by radioimmunoassay (RIA), were determined before, 1 h, and 5 h after starting the water load. Prestudy hormone levels were within normal range in both groups. Renin and aldosterone concentration change patterns were similar in both groups and characterized by suppression of hormone activity caused by central volume expansion and recovery to prestudy levels after 5 h. However, the pattern of change of vasopressin concentrations differed in the control and study groups. In contrast to that of the controls, volume expansion did not suppress vasopressin in the group with liver cirrhosis. We conclude that failure to suppress vasopressin activity after central volume expansion may be one of the early mechanisms responsible for water-electrolyte imbalance in liver cirrhosis in children.

Space sickness and fluid shifts: a hypothesis.

In a sample of 64 first-time Space Shuttle crew members, 9 preflight variables related to fluid, electrolyte, and cardiovascular status were previously found to be significantly related to space sickness. The nine variables are serum uric acid, red cell count, environmental temperature at the launch site, serum phosphate, urine osmolality, serum thyroxine, sitting systolic blood pressure, calculated blood volume, and serum chloride. Using discriminant analysis, these preflight variables were used to correctly classify the 64 astronauts according to their space sickness incidence (NOTSICK or SICK) with 80% success, using two methods of pseudo-crossvalidation. Symptoms of motion sickness may be induced on Earth, either with a sufficiently high level of vestibular stimulation or with less vestibular stimulation after reducing the threshold for motion sickness induction. Some of the nine predictor variables support a fluid shift hypothesis of space sickness etiology by which central volume expansion in weightlessness may lower the threshold required for novel vestibular stimulation to cause space sickness. According to this hypothesis, some astronauts suffer a greater central volume expansion than do others, causing them to have greater physiologic responses to fluid shifts, which, in turn, proportionally reduces their threshold for induction of space sickness. The hypothesis is supported by preflight and postflight echocardiographic comparisons of heart volumes in 19 shuttle astronauts. The postflight left ventricular diastolic volume index was decreased by 34 +/- 3% in the astronauts with MODERATE or SEVERE space sickness, but only 9 +/- 5% (P < .05) in the NONE or MILD group, indicating that an exaggerated physiologic adaptation to fluid shifts is associated with space sickness.

Escape from the sodium-retaining effects of mineralocorticoids: is there a role for dopamine?

To investigate the possible role of dopamine, a catecholamine with natriuretic properties, in modulating the escape from the sodium-retaining effects of mineralocorticoids, we submitted six aldosterone-producing adenoma (APA) patients and six low-renin essential hypertensive patients to acute volume expansion by head-out water immersion with or without dopaminergic blockade by metoclopramide. Water immersion alone induced a marked, comparable natriuresis (P < 0.001) in both hypertensive groups where a slight reduction of already suppressed renin-angiotensin system and a marked stimulation of atrial natriuretic peptide was also observed (P < 0.03 and P < 0.002, respectively). Water immersion plus dopaminergic blockade by metoclopramide did not significantly affect the natriuresis observed during water immersion alone in APA patients; conversely, there was a blunted natriuretic response in low-renin hypertensives during water immersion plus metoclopramide, in comparison with that obtained during water immersion alone (P < 0.006). Furthermore, metoclopramide did prevent the suppression of plasma aldosterone levels produced by central volume expansion alone in low-renin hypertensives, although it did not affect plasma aldosterone levels during water immersion in APA patients. Our data suggest that dopaminergic blockade does not counteract the natriuretic ability of the other hemodynamic and humoral mechanisms involved in the escape phenomenon of APA patients, thus casting serious doubt on the possible role of dopamine in mediating the escape from the sodium-retaining effects of mineralocorticoids.

Vasopressin release and water metabolism in patients with cirrhosis

Water retention is a complication in many patients with cirrhosis, usually attributed to excessive release of arginine vasopressin. To investigate the responsiveness of arginine vasopressin to osmotic and non-osmotic stimuli and its relationship to free water excretion, we studied 19 patients with cirrhosis under three different conditions: 45 min with legs raised to 60 degrees, to expand the central blood volume; infusion of 1000 ml of 0.45% saline solution to reduce plasma osmolality; and rapid injection of 50 ml of 2 M NaCl to increase plasma osmolality. Both expansion of central blood volume and decrease of plasma osmolality significantly reduced plasma vasopressin levels (from 2.1 +/- 0.6 to 1.39 +/- 0.3 pg/ml, p < 0.04; and from 1.09 +/- 0.25 to 0.41 +/- 0.13 pg/ml, p < 0.0001). The changes in free water excretion differentiated two subgroups of patients during each test: excretors and non-excretors. In the excretors, increased free water excretion was associated with suppressed vasopressin levels (below 0.5 pg/ml) and normal renal function. In the non-excretors, inability to improve free water excretion was associated with high vasopressin levels or with reduced distal delivery of the glomerular filtrate, except in some cases where vasopressin levels had fallen below 0.5 pg/ml and renal function was normal. For these cases the presence of other vasopressin-independent antidiuretic mechanisms is conceivable. The injection of hypertonic saline solution caused significant rises in plasma osmolality (from 287 +/- 1.9 to 292 +/- 1.6 mmol/kg, p < 0.05) and in plasma vasopressin levels (from 1.13 +/- 0.29 to 2.86 +/- 0.52 pg/ml, p < 0.05). These results suggest that vasopressin release in patients with cirrhosis is normally responsive to osmotic and non-osmotic stimuli, although our results show a lower theoretical osmolar threshold for suppression of vasopressin release in non-excretors than in excretors (276 vs 284 mmol/kg).

Gravitational stress and volume regulation.

During the past 3 decades, groundbased experiments have been performed in order to investigate the effects of increased and decreased gravitational stress, respectively, on the renal response in humans. Experiments that simulate an increase in gravitational load (+Gz) to the subjects (centrifugation, passive head-up titlt [HUT] or lower body negative pressure [LBNP] have clearly demonstrated a decrease in renal sodium and water excretion. Simultaneously, increases in plasma levels of arginine vasopressin (AVP), renin activity (PRA), aldosterone (PA), norepinephrine (NE) and decreases in ANP have been observed. Additionally, experiments that have utilized immersion of seated subjects to simulate a decreased gravitational stress (approximately 0 Gz) have demonstrated that renal water and sodium excretion increases by 100-400% and that plasma AVP, PRA, PA, and NE concentrations are reduced and ANP levels increased. Alternative experimental models conducted to simulate the effects of weightlessness in humans such as head-down tilt (HDT) and lower body positive pressure (LBPP) have yielded less consistent results than those of water immersion (WI) with respect to renal function. However, compared to a seated control HDT clearly induces an increased rate of renal fluid and sodium excretion. The demonstration that central volume expansion during WI is accompanied by an increase in renal fluid and electrolyte excretion and that central hypovolaemia during centrifugation, HUT, and LBNP is accompanied by the opposite effects indicate that changes in central blood volume is an important determinant of the renal functional changes. Results of experiments in humans during weightlessness in space are inconsistent and difficult to interpret. However, they have indicated that a cephalad redistribution of blood and fluid occurs and that this is accompanied by a decrease in total body fluid. Experimental models that, respectively, increase and decrease the gravitational stress in humans constitute promising tools in the investigation of the physiology and pathophysiology of volume regulation.

A New Diagnostic Test for Primary Aldosteronism

Isotonic-isooncotic central volume expansion by head-out water immersion was induced in six aldosterone-producing adenoma subjects and in six patients with idiopathic hyperaldosteronism. Plasma renin activity and plasma aldosterone levels did not significantly change during water immersion while serum cortisol was significantly suppressed (P less than .001) and the aldosterone-cortisol ratio increased (P less than .02) in aldosterone-producing adenoma patients. Water immersion also revealed the failure of plasma aldosterone levels to decrease below 10 ng/dL in these subjects, thus confirming previous results obtained during isotonic saline infusion. Otherwise, plasma renin activity and plasma aldosterone were significantly reduced (P less than .05 and P less than .01 respectively) by water immersion and plasma aldosterone invariably fell below 10 ng/dL in patients with idiopathic aldosteronism. In view of the diagnostic reliability of such a suppression test we conclude that water immersion is suitable for discriminating between the two forms of primary aldosteronism. We therefore suggest its use for assessing renin-aldosterone responsiveness in primary aldosteronism.

Renal response to 7 days of lower body positive pressure in squirrel monkeys

The purpose of this study was to characterize the renal response to central volume expansion using lower body positive pressure (LBPP) in the adult male squirrel monkey (Saimiri sciureus). Urinary excretion of sodium, potassium, and water and plasma aldosterone concentrations were measured during a control day, 7 days of LBPP, and a recovery day. Time control experiments in the same animals included chair sitting without exposure to LBPP. Seven monkeys (600-1,000 g) were trained to sit in a specially designed metabolism chair before chronic implantation of arterial and venous catheters to facilitate maintenance infusion of saline, monitoring of vascular pressures, and blood sampling; urine was collected via a condomlike tube. A cephalad shift in body fluid was induced by applying 20 mmHg of air pressure from the waist down. Urine volume and sodium excretion were increased significantly (28 to 52 ml/day and 0.4 to 3.5 meq/day, respectively) during the initial 24 h of LBPP with most of this response occurring in the first 6-12 h. From the 2nd to the 7th day of LBPP, urinary excretion rates for sodium and water were not different from chair-sitting controls. Water and sodium balance significantly decreased from +15 to -12 ml/day and from +1.1 to -2.2 meq/day, respectively, from the control to the first day of LBPP. This change in balance was not observed in the time-control group. Removal of the stimulus resulted in a modest conservation of sodium and water. The renal responses were not associated with any changes in plasma aldosterone levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased Release of the N-Terminal and C-Terminal Portions of the Atrial Natriuretic Factor Prohormone during Immersion-Induced Central Hypervolemia in Cirrhotic Humans

The role of peptides from the N-terminus and C-terminus of the 126 amino acid (a.a.) atrial natriuretic factors (ANF) prohormone in modulating renal sodium and water handling in cirrhotic patients has not been defined. Eight cirrhotic individuals were evaluated; their mean basal circulating concentration of the C-terminus (a.a. 99-126; i.e., ANF) was 25 +/- 2 fmol/ml, not different from the 22 +/- 1 fmol/ml value found in 54 normal volunteers. On the other hand, the basal circulating concentrations of the whole N-terminus (a.a. 1-98) and the midportion of the N-terminus (namely a.a. 31-67; pro ANF 31-67) of the ANF prohormone in these cirrhotic subjects of 704 +/- 52 and 654 +/- 83 fmol/ml were significantly elevated (p less than 0.05; ANOVA) in comparison to control values (531 +/- 25, 317 +/- 22 fmol/ml, respectively). Following equilibration on a 10 mmol/day sodium diet, the responsiveness of the N-terminus and C-terminus of ANF prohormone to 3 h of water immersion, which induces marked acute central volume expansion, was evaluated in these 8 seated cirrhotic patients. There was a prompt increase in the circulating concentrations of immunoreactive (ir) pro ANF 1-98 (whole N-terminus), ir pro ANF 31-67, and ir ANF (C-terminus) within 15 min of immersion (p less than 0.05; ANOVA) compared to their preimmersion values. The response of circulating ir pro ANF 1-98, pro ANF 31-67, and ANF concentrations in these 8 cirrhotic subjects to immersion was significantly greater (p less than 0.05; ANOVA) than that of 7 healthy volunteers undergoing an identical 3-hour immersion study. With cessation of immersion, the C-terminus decreased within 30 min to a concentration not significantly different from preimmersion values, whereas the N-terminus and pro ANF 31-67 remained significantly elevated after 1 h.

Exaggerated ANF response to exercise in middle-aged vs. young runners

Hormonal, electrolyte, and renal responses were measured before, during, and after a marathon (42.2 km) in 14 runners: 8 young (Y) (mean age 27.8 yr) and 6 middle aged (MA) (mean aged 46.7 yr). No differences between groups in prerun values for heart rate (HR), plasma osmolality (OSM), antidiuretic hormone (ADH), aldosterone (ALDO), atrial natriuretic factor (ANF), or plasma renin activity (PRA) were found. Renal and urinary measurements were also similar between groups before the marathon. After 10 km of running, both groups had significant increases in HR, ALDO, ANF, and PRA, while OSM, Na+, and ADH remained unchanged from prerun values. The increase in plasma ANF concentrations at this point was significantly greater in the MA subjects compared with the Y (mean increase 104.1 vs. 42.8 pg/ml, respectively; P less than 0.01). Immediate postmarathon values for OSM, ADH, and Na+ were significantly higher than initial values in both groups, while HR, PRA, and ALDO continued to increase above the elevated levels found at 10 km. ANF values immediately postmarathon remained higher than prerun concentrations but were significantly reduced from those obtained at 10 km. In contrast, HR continued to rise until the completion of the run. These data are consistent with recent reports of an exaggerated ANF response in older subjects in response to central blood volume expansion.

Atrial natriuretic factor modulates whole kidney tubuloglomerular feedback

Increases in sodium delivery to the distal nephron reduce glomerular filtration rate (GFR) via tubuloglomerular feedback (TGF). Central volume expansion and pharmacological concentrations of atrial natriuretic factor (ANF) are known to attenuate this response. To test the hypothesis that whole kidney TGF is attenuated by pathophysiological concentrations of ANF, hypertonic saline was given intrarenally in five dogs receiving an intravenous infusion of synthetic ANF at 20 ng.kg-1.min-1. To examine whole kidney TGF responses in heart failure, six additional dogs with acute congestive heart failure induced by rapid ventricular pacing also received intrarenal hypertonic saline. Seven sham-paced dogs served as controls. An isolated increase in circulating ANF from 26 +/- 3 to 342 +/- 23 pg/ml abolished the whole kidney GFR response to hypertonic saline. In acute congestive heart failure, the GFR response to hypertonic saline was not attenuated despite acute central volume overload and similar increases in circulating ANF. This intact response to hypertonic saline in acute congestive heart failure may contribute to the renal sodium retention characteristic of congestive heart failure.

A New Radioimmunoassay for Human Alpha Atrial Natriuretic Peptide and Its Physiological Validation

A new sensitive, specific radioimmunoassay for human alpha atrial natriuretic peptide (hANP) and a novel extraction method for hANP have been developed. Antiserum to hANP (Keq = 1.923 x 10(11) l/mol) showed no cross-reactivity with related analogues. Displacement of 50% bound 125I-hANP occurred at 4.7 +/- 0.1 fmol/tube (n = 15). The limit of detection of plasma hANP after extraction of 2 ml plasma with Florisil was 1.2 pmol hANP/litre plasma. The recovery of synthetic hANP from plasma over the range 6.5-162.5 pmol/l was 71.2 +/- 1.9%. Inter- and intra-assay coefficients of variation were 13.1% and 10.1% respectively. Extracted plasma was stored at -80 degrees C without loss in immunoreactivity. The radioimmunoassay was physiologically validated in man by measuring plasma hANP following central volume expansion - (a) plasma hANP rose from 2.5 +/- 0.5 to 4.1 +/- 0.6 pmol/l in 9 normal volunteers after postural change from seated to lying (b) infusion of normal saline (2 litre/2 hour) increased hANP from 1.6 to 4.3 pmol/l (n = 2). Infusion of hANP (2 pmol/kg/min) increased plasma hANP to 19.9 +/- 3.4 pmol/l (n = 6).

Atrial natriuretic factor (ANF 103–126) enhances volume‐ and pressor‐induced heart rate response in the conscious rat

The reduction in blood pressure due to ANF(103-126) fails to elicit reflex cardioacceleration in the conscious rat. To examine baroreflex sensitivity, the effect of ANF(103-126) on the heart period (HP) response to rapid central volume expansion and to alterations in mean arterial pressure (MAP) induced by bolus injections of phenylephrine and sodium nitroprusside was assessed. ANF(103-126) significantly augmented the bradycardic response induced by acute volume expansion from 426 +/- 21 to 391 +/- 23 beats min-1 versus 421 +/- 23 to 405 +/- 24 without ANF(103-126). Baroreflex sensitivity was defined by the ratio of the change in heart period to the maximal change in mean arterial pressure. The dose of ANF(103-126) utilized did not affect basal heart rate or the magnitude of the mean arterial pressure response to phenylephrine but did significantly enhance the nitroprusside-induced decrease in mean arterial pressure. Baroreceptor sensitivity to phenylephrine was significantly increased by ANF(103-126): 0.997 +/- 0.07 (ms mmHg-1) during ANF(103-126) vs 0.613 +/- 0.08 during vehicle. The total duration of the heart rate response to phenylephrine was also prolonged. In contrast, ANF(103-126) did not alter the baroreceptor sensitivity (1.45 +/- 0.3 vs 1.43 +/- 0.2 ms mmHg-1) or duration of heart rate response to nitroprusside. In the conscious rat, ANF(103-126) modifies the heart rate response to changes in mean arterial pressure and acute central volume expansion. This action appears to be dependent on stimulation of cardiac vagal afferents.

Increased Release of the N-Terminal and C-Terminal Portions of the Prohormone of Atrial Natriuretic Factor During Immersion-Induced Central Hypervolemia in Normal Humans

The role of peptides from the N terminus and C terminus of the 126 amino acid atrial natriuretic factor (ANF) prohormone in modulating renal sodium and water handling has not been defined. Since water immersion to the neck (NI) provides an acute central volume expansion identical to that produced by 2 liters of saline but without plasma compositional change, immersion to the neck was used to assess the N-terminal and C-terminal portions of the ANF prohormone response to acute central blood volume expansion in seven seated sodium-replete normal subjects. Both the C terminus, which contains amino acids 99-126 and is identical to ANF, and the whole N terminus (i.e., amino acids 1-98) increased promptly with NI and peaked after 1 hr of immersion. A Mr 3900 peptide from the midportion of the N terminus consistent with amino acids 31-67 (i.e., pro-ANF-31-67) also increased with NI and followed a pattern of increasing circulating concentration nearly identical to that of the whole N terminus of the prohormone, except that its maximal concentration was at the second hour of the 3 hr of NI. With cessation of immersion, ANF decreased to preimmersion levels within 1 hr whereas the N terminus and pro-ANF-31-67, although their circulating concentrations were decreasing, were still significantly elevated at 1 hr. These findings suggest that the increase in plasma ANF, the N terminus of the ANF prohormone, and pro-ANF-31-67 from the midportion of the N terminus, with natriuretic properties similar to ANF, contribute to the natriuretic response to NI, implying a physiologic role for these atrial peptides in modulating volume homeostasis in humans.