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PubMed2004

Induction of c-fos in forebrain circumventricular organs after renal artery stenosis.

Experiments were done in the anaesthetized rat to determine the effect of activation of renal receptors following renal arterial occlusion (RAO) on the induction of c-fos in neurons of the lamina terminalis in the forebrain. Following RAO, fos labeled neurons were found in both the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT). Transection of the renal nerves ipsilateral to RAO reduced ( approximately 61%) the number of fos labeled neurons in the SFO and prevented the fos labeling in the OVLT. Similarly, administration of the angiotensin II converting enzyme inhibitor enalapril maleate prior to RAO also reduced ( approximately 27%) the number of fos labeled neurons in the SFO to RAO. However, the number of fos labeled neurons was not altered in the OVLT. The number of fos labeled neurons in the SFO of the intact animals after RAO was found to be greater than the algebraic sum of the number of fos labeled neurons in the renal nerve transected and enalapril treated animals. These results suggest that neurons in the SFO are activated by at least two different mechanisms following renal artery occlusion; those involving the activation of afferent renal nerves and those due to changes in circulating levels of angiotensin II. In addition, afferent renal nerve inputs combined with the effect of increased circulating levels of angiotensin II produce a greater activation of the SFO than either input alone. On the other hand, the OVLT appears to be selectively activated by afferent renal nerve inputs following RAO. Taken together, these data suggest that neural inputs from the kidney may play an important role in controlling body fluid balance and arterial pressure (AP) by influencing the activity of forebrain circumventricular organs neurons that function in the detection of blood borne signals associated with changes in extracellular fluid volume.

Angiotensin II↗
PubMed2004

Direct projections from caudal ventrolateral medullary depressor sites to the subfornical organ.

Experiments were performed in the male Wistar rat to investigate the projections from cardiovascular responsive sites in the ventrolateral medulla (VLM) to the subfornical organ (SFO). Unilateral iontophoretic injections of Phaseolus vulgaris leucoagglutinin (PHA-L) were made into either caudal VLM (CVLM) sites at which microinjection of l-glutamate (10 nl; 0.25 M) elicited decreases in mean arterial pressure or into rostral VLM (RVLM) sites at which l-glutamate microinjection elicited increases in arterial pressure. After a survival period of 7-10 days, transverse sections of the forebrain and brainstem were processed for PHA-L immunoreactivity. After injections of PHA-L into the CVLM, axonal and presumptive terminal labeling was found bilaterally throughout the rostrocaudal extent of the SFO, although most of the projections were observed within the rostral half of the nucleus. Within the SFO, labeling was found primarily in the lateral aspects of the nucleus, often in close proximity to blood vessels. In addition, CVLM injections resulted in labeling within the organum vasculosum of the laminae terminalis (OVLT) and within the ventral and dorsal components of the median preoptic nucleus (MnPO) bilaterally, but with an ipsilateral predominance. In contrast, PHA-L injections into the RVLM did not result in axonal labeling in the SFO or OVLT, although a few labeled axons were found to course through the region of the ventral component of MnPO. These data have demonstrated that neurons within the cardiovascular responsive region of the CVLM send direct axonal projections to the SFO and other structures of the laminae terminalis, and suggest that the CVLM may function in the modulation of the activity of neurons of circumventricular organs to intra- and extracellular signals of body fluid balance.

Animals↗
PubMed2004

Development of AT(1) and AT(2) receptors in the ovine fetal brain.

This study determined the development of AT(1) and AT(2) receptors in the ovine fetal brain from preterm to term by utilizing Western blot for the receptor expression at the protein level, RT-PCR for the receptor mRNA, and immunostaining for the specific receptor immunoreactivity. The results demonstrated that AT(1) and AT(2) receptors developed in an increasing pattern from preterm to term gestational periods in the fetal sheep brain. Both AT(1) and AT(2) receptors have appeared in the major structures in the angiotensin-related central cardiovascular and body fluid controlling pathways at the 0.7 of the gestational age. Importantly, AT(1) receptors have been discovered in the supraoptic nuclei in the fetal hypothalamus, and in the lateral parabrachial nuclei and the ventrolateral medulla in the fetal hindbrain. This provides evidence of the anatomical existence of the angiotensin receptors in the brain areas that are critical for cardiovascular and fluid regulatory functions in utero. In addition, although the results demonstrated the predominance of AT(2) receptors in several regions such as the cerebellum in the ovine fetal brain, dominant occupation of AT(1) receptors in the hypothalamus have appeared early in the life of sheep animals before birth. Together, the data support the hypothesis that the central angiotensin receptors are well developed and established in the last third trimester of gestation. The brain receptors provide a pharmacological basis for the action of angiotensin in the maintenance of in utero fetal physiological functions, including cardiovascular and body fluid balance.

Angiotensins↗
PubMed2004

Expression of aquaporin 1 in human cardiac and skeletal muscle.

Aquaporins (AQPs) are a family of water channel proteins that assist in maintenance of the cellular osmotic environment and whole body fluid balance. Specialized organ-specific AQPs are important in physiologic and pathologic processes but little is known about AQPs in the human heart. AQP1 has been identified in rodent heart. We investigated the presence and localization of AQP1 in human heart and skeletal muscle using immunohistochemistry and confocal microscopy, western blot and reverse transcriptase-polymerase chain reaction. There was abundant AQP1 present in both cardiac and skeletal muscle. Immunohistochemistry revealed co-localization of AQP1 with vinculin, a t-tubule marker, and caveolin-3. No novel sequences bearing an NPA box motif common to other AQPs were identified in human heart using degenerative PCR analysis. We conclude that AQP1 is present in the human heart. AQP1 co-localizes with t-tubular and caveolar proteins. Cardiac AQPs may have a role during osmotic stresses including ischemia/reperfusion and cardiopulmonary bypass.

Adult↗
PubMed1997

Fos induction in central structures after afferent renal nerve stimulation.

Experiments were done in the conscious and unrestrained rat to identify central structures activated by electrical stimulation of afferent renal nerves (ARN) using the immunohistochemical detection of Fos-like proteins. Fos-labelled neurons were found in a number of forebrain and brainstem structures bilaterally, but with a contralateral predominance. Additionally, Fos-labelled neurons were found in the lower thoracolumbar spinal cord predominantly ipsilateral to the side of ARN stimulation. Within the forebrain, neurons containing Fos-like immunoreactivity after ARN stimulation were primarily found along the outer edge of the rostral organum vasculosum of the laminae terminalis, in the medial regions of the subfornical organ, in the median preoptic nucleus, in the ventral subdivision of the bed nucleus of the stria terminalis, along the lateral part of the central nucleus of the amygdala, throughout the deeper layers of the dysgranular insular cortex, in the parvocellular component of the paraventricular nucleus of the hypothalamus (PVH), and in the paraventricular nucleus of the thalamus. Additionally, a smaller number of Fos-labelled neurons was observed in the supraoptic nucleus, in the magnocellular component of the PVH and along the lateral border of the arcuate nucleus. Within the brainstem, Fos-labelled neurons were found predominantly in the commissural and medial subnuclei of the nucleus of the solitary tract and in the external subnucleus of the lateral parabrachial nucleus. A smaller number were observed near the caudal pole of the locus coeruleus, and scattered throughout the ventrolateral medullary and pontine reticular formation in the regions known to contain the A1, C1 and A5 catecholamine cell groups. The final area observed to contain Fos-labelled neurons in the central nervous system was the thoracolumbar spinal cord (T9-L1) which contained cells in laminae I-V of the dorsal horn ipsilateral to side of stimulation and in the intermediolateral cell column at the same levels bilaterally, but with an ipsilateral predominance. Few, if any Fos-labelled neurons were observed in the same structures of control animals in which the ARN were stimulated, but the renal nerves proximal to the site of stimulation were transected, or in the sham operated animals. These data indicate that ARN information originating in renal receptors is conveyed to a number of central areas known to be involved in the regulation of body fluid balance and arterial pressure, and suggest that this afferent information is an important component of central mechanisms regulating these homeostatic functions.

Afferent Pathways↗
PubMed1998

Comparison of the acute effects of a selective endothelin ETA and a mixed ETA/ETB receptor antagonist in heart failure.

OBJECTIVE: Both the selective endothelin (ET) ETA receptor and mixed ETA/ETB receptor antagonists improve haemodynamics in patients and experimental models with congestive heart failure (CHF) and reduce the mortality in CHF rats. However, it remains unclear which of these antagonists is superior in the treatment of CHF. In addition, there is little information as to whether these ET receptor antagonists contribute to the neuroendocrine regulation and body fluid balance. We therefore investigated the cardiorenal and neurohumoral benefits of selective ETA receptor and mixed ETA/ETB receptor antagonists in CHF. METHODS: We administered acutely either the selective ETA receptor antagonist FR139317 (FR, n = 6, 1 and 10 mg/kg) or the mixed ETA/ETB receptor antagonist TAK-044 (TAK, n = 6, 1 and 3 mg/kg) to conscious dogs with CHF induced by rapid right ventricular pacing for ten days. RESULTS: Both FR and TAK decreased the cardiac pressures and the plasma atrial natriuretic peptide level and increased the cardiac output and urinary sodium excretion. FR increased the urine flow rate in association with an increased glomerular filtration rate and renal plasma flow, while TAK reduced the plasma aldosterone level. Neither antagonist increased the plasma renin activity or norepinephrine levels. CONCLUSIONS: These ETA/ETB antagonist. However, the long-term administration of a mixed ETA/ETB receptor antagonist would improve not only the haemodynamics but also prevent fluid retention by suppressing secretion of aldosterone during the treatment of chronic CHF.

Aldosterone↗
PubMed2000

Taste preference and acceptance in thirsty and rehydrated [correction of dehydrated] rats.

Experiments were designed to determine whether water deprivation affects taste preferences and/or taste acceptance. In experiment 1, both five- and two-bottle preference tests were performed in normally hydrated rats to permit the selection of five groups of rats showing the same taste preference for one of four prototypical tastes. Subsequently, in the same groups of rats, taste preferences were determined by a two-bottle test (experiment 2), and taste acceptance by a one-bottle test (experiment 3), following 12, 24, 36, and 48 h of water deprivation. After both 12 and 24 h of dehydration, during the first 10 min of the tests of experiment 2, all rats ingested greater volumes of either NaCl or sucrose solution than water, but more water than either HCl or quinine solution, and the differences were very significant (P<.0001). After 36 or 48 h of dehydration, the differences became very small and, in some cases, the P-values were at the lowest or borderline level of the significance, suggesting that dehydrated rats poorly discriminate the nature of the fluid drunk. During the 11-60 min interval, all rats preferred either sucrose or NaCl to water, but water to either HCl or quinine. Experiment 3 was performed to ascertain whether the need for fluid might overcome the palatability of solutions. All rats, dehydrated for 36 or 48 h, after 10 min of exposure, drank equal amounts of fluid, independent of its palatability. During the 11-20 and 21-60 min interval, the fluid intake of rats changed in accordance with the palatability of the solution available. In conclusion, severe thirst in rats may override the palatability of the solutions, and the thirst drive may be so strong that they do not reject fluids because body fluid balance would be severely compromised.

Animals↗
PubMed2000

Appearance of central dipsogenic mechanisms induced by dehydration in near-term rat fetus.

Cellular dehydration of central osmoreceptors evokes an integration of behavioral (i.e. drinking) and endocrinologic (i.e. arginine vasopressin secretion) responses to maintain body fluid balance. These osmoregulatory mechanisms have been intensely investigated in adult models. However, there has been limited research of the fetal development of neural mechanisms regulating responses to dehydration. Although behavioral and neuroendocrine responses to dehydration have been demonstrated in utero in precocial species (e.g. ovine), there has been no study to date demonstrating that these responses develop before the neonatal period of altricial species (e.g. rat). This study is the first to use the near-term rat fetus to investigate the effects of maternal subcutaneous hypertonic (2 M NaCl) or isotonic (0.15 M NaCl) saline injection on fetal plasma osmolality and brain FOS-immunoreactivity (FOS-ir). Maternal subcutaneous hypertonic saline significantly increased maternal and fetal plasma osmolality to similar levels (328+/-6 and 326+/-6 mosM/kg, respectively). In response to plasma hypertonicity, maternal and fetal brain FOS-ir increased significantly in the regions including the lamina terminalis, and the supraoptic and paraventricular nuclei (SON and PVN) of the hypothalamus. Together, these data indicate that central mechanisms for dipsogenic and arginine vasopressin secretory responses to hypertonicity are present and responsive in the fetal rat brain at near-term gestation. However, differences between fetal and maternal FOS-ir mapping suggest that fetal osmoreceptor development is not yet completed near term.

Animals↗
PubMed2000

Osmotic regulation of neuronal activity: a new role for taurine and glial cells in a hypothalamic neuroendocrine structure.

Maintenance of osmotic pressure is a primary regulatory process essential for normal cell function. The osmolarity of extracellular fluids is regulated by modifying the intake and excretion of salts and water. A major component of this regulatory process is the neuroendocrine hypothalamo-neurohypophysial system, which consists of neurons located in the paraventricular and supraoptic nuclei. These neurons synthesize the neurohormones vasopressin and oxytocin and release them in the blood circulation. We here review the mechanisms responsible for the osmoregulation of the activity of these neurons. Notably, the osmosensitivity of the supraoptic nucleus is described including the recent data that suggests an important participation of taurine in the transmission of the osmotic information. Taurine is an amino acid mainly known for its involvement in cell volume regulation, as it is one of the major inorganic osmolytes used by cells to compensate for changes in extracellular osmolarity. In the supraoptic nucleus, taurine is highly concentrated in astrocytes, and released in an osmodependent manner through volume-sensitive anion channels. Via its agonist action on neuronal glycine receptors, taurine is likely to contribute to the inhibition of neuronal activity induced by hypotonic stimuli. This inhibitory influence would complement the intrinsic osmosensitivity of supraoptic neurons, mediated by excitatory mechanoreceptors activated under hypertonic conditions. These observations extend the role of taurine from the regulation of cell volume to that of the whole body fluid balance. They also point to a new role of supraoptic glial cells as active components in a neuroendocrine regulatory loop.

Animals↗
PubMed2003

GABAergic modulation of noradrenaline release in the median preoptic nucleus area in the rat.

Microdialysis was employed to investigate whether gamma-aminobutyric acid (GABA) receptor mechanisms are involved in the regulation of noradrenaline (NA) release in the median preoptic nucleus (MnPO) in awake, freely moving rats. Perfusion with the GABA receptor antagonists as well as agonists was performed in the region of the MnPO through a microdialysis probe and dialysate levels of NA were measured. Perfusion with either bicuculline (10 and 50 microM), a GABA(A) receptor antagonist, or phaclofen (10 and 50 microM), a GABA(B) receptor antagonist, enhanced the release of NA in the MnPO area. Higher-dose perfusion with the GABA(A) agonist muscimol (50 microM) or the GABA(B) agonist baclofen (250 microM) decreased dialysate NA in the MnPO area. An iso-osmotic reduction of fluid volume following subcutaneous treatment with polyethylene glycol (PEG, 30%, 5 ml) significantly increased the NA level in the MnPO area. The increased levels of NA caused by the PEG treatment were attenuated by perfusion with muscimol (10 microM), but not by baclofen (50 microM). These results show the participation of both GABA(A) and GABA(B) receptors in the modulation of the release of NA in the MnPO area, and imply that the GABA(A) receptor mechanism may play an important role in the noradrenergic regulatory system of body fluid balance.

Animals↗
PubMed2003

Osmotic stimuli increase brain-derived neurotrophic factor mRNA level in the rat subfornical organ.

The effects of water deprivation and chronic salt loading on the expression of the brain-derived neurotrophic factor (BDNF) gene were examined in the rat subfornical organ (SFO), using immunohistochemistry for BDNF and in situ hybridization histochemistry. Increased BDNF-like immunoreactivity was observed in the SFO after water deprivation for 4 days. Water deprivation for 24 h and 2 and 4 days and salt loading for 7 days caused a significant increase in the BDNF gene transcripts in the SFO, compared with euhydrated rats. These results suggest that BDNF in the SFO may be involved in the regulatory mechanisms of body fluid balance.

Animals↗
PubMed1997

Baroreceptor regulation of salt intake.

Baroreceptor input plays a critical role in body fluid balance and the endocrine response to NaCl consumption [25]. Experiments were performed to characterize the alterations in salt intake that are seen after baroreceptor denervation. Using chronically baroreceptor denervated (SAD) or control (CON) male Sprague-Dawley rats, we determined: 1) concentration-dependent consumption of NaCl, 2) time course of saline intake, 3) effect of food access on saline intake, 4) intake of sucrose vs. saline, and 5) water vs. saline intake using a choice paradigm. In protocols 1-4 the rats were given a single bottle containing saline or sucrose for a 2-h period during the early dark period. A comparison of the intake of varying concentrations of NaCl (0.3 to 2.0% NaCl, six concentrations) demonstrated that the SAD consumed significantly less NaCl than the CON (from 0.9 to 2% NaCl), Saline Intake in SAD was 14-56% of the CON (significant group, salt concentration and interaction effects). Regression analysis demonstrated that in the SAD there was an inverse relationship between concentration and the amount of NaCl consumed (p < 0.02), an effect not seen in the CON. There were also differences in the pattern of saline intake with the CON showing the highest consumption in the early dark period with a gradual decrease as compared to the SAD, which demonstrated a uniformly lower pattern of consumption. The reduction in intake in the SAD appeared to be specific for NaCl because there was no difference in water or sucrose intake. The deficit could not be attributed to alterations in food intake, nor was there any difference in the amount of water consumed after the saline challenge.

Animals↗
PubMed2003

Mathematical model of renal elimination of fluid and small ions during hyper- and hypovolemic conditions.

This study is concerned with the formulation of a 'kidney module' linked to the plasma compartment of a larger mathematical model previously developed. Combined, these models can be used to predict, amongst other things, fluid and small ion excretion rates by the kidney; information that should prove useful in evaluating values and trends related to whole-body fluid balance for different clinical conditions to establish fluid administration protocols and for educational purposes. The renal module assumes first-order, negative-feedback responses of the kidney to changes in plasma volume and/or plasma sodium content from their normal physiological set points. Direct hormonal influences are not explicitly formulated in this empiric model. The model also considers that the renal excretion rates of small ions other than sodium are proportional to the excretion rate of sodium. As part of the model development two aspects are emphasized (1): the estimation of parameters related to the renal elimination of fluid and small ions, and (2) model validation via comparisons between the model predictions and selected experimental data. For validation, model predictions of the renal dynamics are compared with new experimental data for two cases: plasma overload resulting from external fluid infusion (e.g. infusions of iso-osmolar solutions and/or hypertonic/hyperoncotic saline solutions), and untreated hypo volemic conditions that result from the external loss of blood. The present study demonstrates that the empiric kidney module presented above can provide good short-term predictions with respect to all renal outputs considered here. Physiological implications of the model are also presented.

Algorithms↗
PubMed1980

Characterization of the natriuretic activity in the plasma of hypervolaemic rats.

1. Plasma from hypervolaemic rats was fractionated on a G-200 Sephadex column. In addition to three different protein peaks, a fourth non-protein fraction was obtained. Each of the four peaks was desalted, freeze-dried, reconsituted and injected into normal anaesthetized rats. Significant natriuretic responses resulted, from injection, of the middle protein peak and of the small-molecular-weight peak. It was concluded that a natriuretic humoral factor was present in the blood of hypervolaemic rats, and that this factor was of low molecular weight but normally occurred bound to plasma protein. 2. The renal response to injection of non-protein fraction, obtained from either hypervolaemic donors or from iso- or hypo-volaemic donors, was compared in two groups of bioassay rats to test whether the natriuretic factor was present only in plasma of the blood-volume-expanded animals. Both types of reconstituted fraction caused diuresis, natriuresis and kaliuresis in bioassay animals. Only the natriuretic response was statistically greater when the fraction obtained from hypervolaemic plasma was used. In addition to non-specific increase in fluid and ion excretion, possibly due to the extraction and/or methodological procedures, these results demonstrate that blood-volume expansion releases a humoral natriuretic factor into plasma. Since there were no increases in filtration rate, the factor specifically inhibited tubular sodium reabsorption. 3. To determine the maximum possible effect of the non-protein factor, the dose given to bioassay rats was tripled. There was no further increase in sodium excretion, indicating that the effect was quantitatively limited and suggesting that the physiological importance of natriuretic hormone lies in long-term regulation of body-fluid balance.

Animals↗
PubMed2002

Chronic effects of an endothelin-converting enzyme inhibitor on cardiorenal and hormonal function in heart failure.

Endothelin (ET)-converting enzyme (ECE) is a rate-limiting step in ET-1 generation, and its expression and activity are increased significantly with the development of congestive heart failure (CHF). The selective enzymic inhibition of ET-1 formation thus seems to be a very important target in the prevention of CHF. We evaluated the chronic effects of a specific ECE inhibitor, FR901533 (0.3 mg x kg(-1) x h(-1), n=5) on cardiac, hormonal, and body fluid balance in dogs with CHF induced by rapid right ventricular pacing (270 beats/min, 22 days). Vehicle dogs were given placebo (n=5). Despite no significant difference in blood pressure, FR901533 decreased pulmonary capillary wedge pressure and increased cardiac output compared with the vehicle. FR901533 prevented the reduction of urine flow rate and urinary sodium excretion in association with an increase in the glomerular filtration rate and renal plasma flow compared with the vehicle. FR901533 also suppressed significantly the elevation of plasma atrial natriuretic peptide and aldosterone levels which is an established prognostic factor in CHF. These results indicate that the role of ECE in CHF is important and that chronic ECE inhibition could possess therapeutic potential in the treatment of CHF not only on haemodynamics but also in the prevention of fluid retention.

Aldosterone↗
PubMed2002

Chronic administration of phosphodiesterase type 5 inhibitor suppresses renal production of endothelin-1 in dogs with congestive heart failure.

Endothelin-1 (ET-1) and atrial natriuretic peptide (ANP) play important roles in the regulation of body fluid balance in congestive heart failure (CHF). Renal production of ET-1 increases in CHF and it is a significant independent predictor of sodium excretion. ANP inhibits the ET system through cGMP, a second messenger of ANP. However, in severe CHF, plasma cGMP levels reached a plateau despite the activation of ANP secretion. Thus, ANP does not seem to sufficiently oppose exaggerated ET-1 actions in severe CHF, partially due to the accelerated degradation of cGMP, through phosphodiesterase type 5 (PDE5). We examined the chronic effects of a PDE5 inhibitor, T-1032 (1 mg/kg per day, n=5), on renal function and renal production of ET-1 in dogs with CHF induced by rapid ventricular pacing (270 beats/min). Vehicle dogs were given a placebo (n=5) and normal dogs (n=5) served as normal controls without pacing. In this experimentally produced CHF, plasma levels of ET-1, ANP and cGMP were elevated and renal production of cGMP was increased compared with the normal group, associated with increases in renal expression of preproET-1 mRNA and the number of ET-1-positive cells in glomeruli. In the T-1032 group, systemic and renal production of cGMP were further increased compared with the vehicle group despite no significant difference in plasma ANP levels between the two groups. Subsequently, the agent significantly improved urine flow rate, sodium excretion rate and glomerular filtration rate (GFR) associated with reductions in renal expression of preproET-1 mRNA and the number of ET-1-positive cells compared with the vehicle group. Moreover, there was a significant negative correlation between the number of ET-1-positive cells and GFR (r=-0.802 and P<0.001 respectively). Our results indicate that chronic PDE5 inhibition ameliorates the antagonistic relationship between renal ANP and ET-1 through the cGMP pathway, subsequently preventing renal dysfunction during the progression of CHF.

Animals↗
PubMed1998

Changes in peak oxygen uptake and plasma volume in fit and unfit subjects following exposure to a simulation of microgravity.

To test the hypothesis that the magnitude of reduction in plasma volume and work capacity following exposure to simulated microgravity is dependent on the initial level of aerobic fitness, peak oxygen uptake (VO2peak) was measured in a group of physically fit subjects and compared with VO2peak in a group of relatively unfit subjects before and after 10 days of continuous 6 degrees head-down tilt (HDT). Ten fit subjects (40 +/- 2 year) with mean +/- SE VO2peak = 48.9 +/- 1.7 mL kg-1 min-1 were matched for age, height, and lean body weight with 10 unfit subjects (VO2peak = 37.7 +/- 1.6 mL kg-1 min-1). Before and after HDT, plasma, blood, and red cell volumes and body composition were measured and all subjects underwent a graded supine cycle ergometer test to determine VO2peak period needed. Reduced VO2peak in fit subjects (-16.2%) was greater than that of unfit subjects (-6.1%). Similarly, reductions in plasma (-18.3%) and blood volumes (-16.0%) in fit subjects were larger than those of unfit subjects (blood volume = -5.6%; plasma volume = -6.6%). Reduced plasma volume was associated with greater negative body fluid balance during the initial 24 h of HDT in the fit group (912 +/- 154 mL) compared with unfit subjects (453 +/- 200 mL). The percentage change for VO2peak correlated with percentage change in plasma volume (r = +0.79). Following exposure to simulated microgravity, fit subjects demonstrated larger reductions in VO2peak than unfit subjects which was associated with larger reductions in plasma and blood volume. These data suggest that the magnitude of physical deconditioning induced by exposure to microgravity without intervention of countermeasures was influenced by the initial fitness of the subjects.

Adult↗
PubMed2000

Influence of asimadoline, a new kappa-opioid receptor agonist, on tubular water absorption and vasopressin secretion in man.

AIMS: The purpose of the study was to investigate the effects of asimadoline, a new kappa-opioid agonist, on renal function and on hormones related to body fluid balance as well as its tolerability in healthy subjects. METHODS: In a placebo-controlled, randomised, double-blind crossover design we studied the effects of single oral doses of 1, 5, and 10 mg of asimadoline, in 24 healthy volunteers. Two hour control urine collections were followed by 2 h postdose urine collections and subsequently 2.5% saline was given i.v. at a rate of 0.3 ml min(-1) kg(-1) during another 2 h urine collection. Blood was obtained hourly. Arginine-vasopressin (AVP), atrial natriuretic peptide (alpha-hANP), endothelin (ET-1) and cAMP were determined by r.i.a. or ELISA. RESULTS: GC-MS measurements revealed Cmax values of asimadoline in plasma ranging from 18 ng ml(-1) at the 1 mg dose, 91 ng ml(-1) at the 5 mg dose, to 214 ng ml(-1) at the 10 mg dose after an average of 1.1-1.4 h. Without effects on blood pressure, heart rate, GFR or urine electrolyte excretion, urine volume increased after 1-2 h after administration of 5 and 10 mg asimadoline from 3.3+/-1.3 to 5.6+/-1.4 (P<0.05) and from 3.2 +/-1.6 to 5.5+/-2.2 ml min(-1) (P<0.01), respectively. CH2O rose from 0.2+/-1.5 to 2.0+/-1.6 (P<0.05) and from 0.6+/-1.6 to 3.0+/-1.6 ml min(-1) (P<0.01). Urinary excretion of AVP was suppressed only with the 10 mg dose from 46+/-23 to 25+/-15 fmol min(-1) (P<0.05) without and from 410+/-206 to 181+/-125 fmol min(-1) (P<0.05) with stimulation by 2.5% saline. Plasma AVP was suppressed only by the 10 mg dose of asimadoline in six of eight subjects during the 2.5% saline infusion. Changes in the alpha-hANP or ET-1 systems were not affected by asimadoline. CONCLUSIONS: Asimadoline is diuretic in man after single doses of 5 or 10 mg probably through a direct effect at the renal tubular level. Suppression of AVP secretion was observed only at the highest dose level of 10 mg of asimadoline.

Acetamides↗