Characterization of a non-human primate model for the study of testicular peritubular cells-comparison with human testicular peritubular cells.

STUDY QUESTION: Are monkey testicular peritubular cells (MKTPCs) from the common marmoset monkey (Callithrix jacchus) a suitable translational model for the study of human testicular peritubular cells (HTPCs)? SUMMARY ANSWER: MKTPCs can be isolated and propagated in vitro, retain characteristic markers for testicular peritubular cells and their proteome strongly (correlation coefficient of 0.78) overlaps with the proteome of HTPCs. WHAT IS KNOWN ALREADY: Smooth-muscle-like peritubular cells form the wall of seminiferous tubules, transport sperm, are immunologically active, secrete a plethora of factors and may contribute to the spermatogonial stem cell niche. Mechanistic studies are hampered by heterogeneity of human samples. STUDY DESIGN, SIZE, DURATION: We established a culture method for MKTPCs and characterized these cells from six young adult animals (2-3 years). To examine whether they qualify as a translational model we also examined HTPCs from seven men and compared the proteomes of both groups. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used explant cultures to obtain MKTPCs, which express smooth muscle markers (calponin (CNN1), smooth muscle actin (ACTA2)), lack FSH-receptors (FSHR) and LH-receptors (LHCGR), but possess androgen receptors (AR). MKTPCs can be passaged at least up to eight times, without discernable phenotypic changes. Mass-spectrometry-based analyses of the MKTPC and HTPC proteomes were performed. MAIN RESULTS AND THE ROLE OF CHANCE: We established a method for isolation and cultivation of MKTPCs, and provide a comprehensive analysis of their protein repertoire. The results let us conclude that MKTPCs are suitable as a non-human primate model to study peritubular cell functions. LARGE SCALE DATA: List of identified proteins in MKTPCs by liquid chromatography-tandem mass spectrometry is accessible at the ProteomeXchange (identifier PXD009394). LIMITATIONS, REASON FOR CAUTION: This is an in vitro cellular non-human primate model used to provide a window into the role of these cells in the human testis. WIDER IMPLICATIONS OF THE FINDINGS: Previous studies with HTPCs from patients revealed a degree of heterogeneity, possibly due to age, lifestyle and medical history of the individual human donors. We anticipate that the new translational model, derived from young healthy non-human primates, may allow us to circumvent these issues and may lead to a better understanding of the role of peritubular cells. STUDY FUNDING AND COMPETION OF INTEREST(S): This work was supported by grants from the Deutsche Forschungsgemeinschaft (MA 1080/27-1; AR 362/9-1; BE 2296/8-1). The authors declare no competing financial interests.

Primordial germ cell development in the marmoset monkey as revealed by pluripotency factor expression: suggestion of a novel model of embryonic germ cell translocation.

Primordial germ cells (PGCs) are the embryonic progenitors of sperm and egg cells. Mammalian PGCs are thought to actively migrate from the yolk sac endoderm over long distances across the embryo to reach the somatic genital ridges. The general principles of mammalian PGC development were discovered in mice. In contrast, little is known about PGC development in primates due to extremely limited access to primate embryos. Here, we analyzed 12 well preserved marmoset monkey (Callithrix jacchus) embryos covering the phase from PGC emergence in the endoderm to the formation of the sexually differentiated gonad (embryonic day (E) 50 to E95). We show using immunohistochemistry that the pluripotency factors OCT4A and NANOG specifically mark PGCs throughout the period studied. In contrast, SALL4 and LIN28 were first expressed ubiquitously and only later down-regulated in somatic tissues. We further show, for the first time, that PGCs are located in the endoderm in E50 embryos in close spatial proximity to the prospective genital ridge, making a long-range migration of PGCs dispensable. At E65, PGCs are already present in the primitive gonad, while significantly later embryonic stages still exhibit PGCs at their original endodermal site, revealing a wide spatio-temporal window of PGC distribution. Our findings challenge the 'dogma' of active long-range PGC migration from the endoderm to the gonads. We therefore favor an alternative model based primarily on passive translocation of PGCs from the mesenchyme that surrounds the gut to the prospective gonad through the intercalar expansion of mesenchymal tissue which contains the PGCs. In summary, we (i) show differential pluripotency factor expression during primate embryo development and (ii) provide a schematic model for embryonic PGC translocation.

The neonatal marmoset monkey ovary is very primitive exhibiting many oogonia.

Oogonia are characterized by diploidy and mitotic proliferation. Human and mouse oogonia express several factors such as OCT4, which are characteristic of pluripotent cells. In human, almost all oogonia enter meiosis between weeks 9 and 22 of prenatal development or undergo mitotic arrest and subsequent elimination from the ovary. As a consequence, neonatal human ovaries generally lack oogonia. The same was found in neonatal ovaries of the rhesus monkey, a representative of the old world monkeys (Catarrhini). By contrast, proliferating oogonia were found in adult prosimians (now called Strepsirrhini), which is a group of 'lower' primates. The common marmoset monkey (Callithrix jacchus) belongs to the new world monkeys (Platyrrhini) and is increasingly used in reproductive biology and stem cell research. However, ovarian development in the marmoset monkey has not been widely investigated. Herein, we show that the neonatal marmoset ovary has an extremely immature histological appearance compared with the human ovary. It contains numerous oogonia expressing the pluripotency factors OCT4A, SALL4, and LIN28A (LIN28). The pluripotency factor-positive germ cells also express the proliferation marker MKI67 (Ki-67), which has previously been shown in the human ovary to be restricted to premeiotic germ cells. Together, the data demonstrate the primitiveness of the neonatal marmoset ovary compared with human. This study may introduce the marmoset monkey as a non-human primate model to experimentally study the aspects of primate primitive gonad development, follicle assembly, and germ cell biology in vivo.

The pluripotency factor LIN28 in monkey and human testes: a marker for spermatogonial stem cells?

Mammalian spermatogenesis is maintained by spermatogonial stem cells (SSCs). However, since evidentiary assays and unequivocal markers are still missing in non-human primates (NHPs) and man, the identity of primate SSCs is unknown. In contrast, in mice, germ cell transplantation studies have functionally demonstrated the presence of SSCs. LIN28 is an RNA-binding pluripotent stem cell factor, which is also strongly expressed in undifferentiated mouse spermatogonia. By contrast, two recent reports indicated that LIN28 is completely absent from adult human testes. Here, we analyzed LIN28 expression in marmoset monkey (Callithrix jacchus) and human testes during development and adulthood and compared it with that in mice. In the marmoset, LIN28 was strongly expressed in migratory primordial germ cells and gonocytes. Strikingly, we found a rare LIN28-positive subpopulation of spermatogonia also in adult marmoset testis. This was corroborated by western blotting and quantitative RT-PCR. Importantly, in contrast to previous publications, we found LIN28-positive spermatogonia also in normal adult human and additional adult NHP testes. Some seasonal breeders exhibit a degenerated (involuted) germinal epithelium consisting only of Sertoli cells and SSCs during their non-breeding season. The latter re-initiate spermatogenesis prior to the next breeding-season. Fully involuted testes from a seasonal hamster and NHP (Lemur catta) exhibited numerous LIN28-positive spermatogonia, indicating an SSC identity of the labeled cells. We conclude that LIN28 is differentially expressed in mouse and NHP spermatogonia and might be a marker for a rare SSC population in NHPs and man. Further characterization of the LIN28-positive population is required.

AZFa Y gene, DDX3Y, evolved novel testis transcript variants in primates with proximal 3´UTR polyadenylation for germ cell specific translation.

Translational control is a major level of gene expression regulation in the male germ line. DDX3Y located in the AZFa region of the human Y chromosome encodes a conserved RNA helicase important for translational control at the G1-S phase of the cell cycle. In human, DDX3Y protein is expressed only in premeiotic male germ cells. In primates, DDX3Y evolved a second promoter producing novel testis-specific transcripts. Here, we show primate species-specific use of alternative polyadenylation (APA) sites for these testis-specific DDX3Y transcript variants. They have evolved subsequently in the 3´UTRs of the primates´ DDX3Y transcripts. Whereas a distal APA site (PAS4) is still used for polyadenylation of most DDX3Y testis transcripts in Callithrix jacchus; two proximal APAs (PAS1; PAS2) are used predominantly in Macaca mulatta, in Pan trogloydates and in human. This shift corresponds with a significant increase of DDX3Y protein expression in the macaque testis tissue. In chimpanzee and human, shift to predominant use of the most proximal APA site (PAS1) is associated with translation of these DDX3Y transcripts in only premeiotic male germ cells. We therefore assume evolution of a positive selection process for functional DDX3Y testis transcripts in these primates which increase their stability and translation efficiency to promote its cell cycle balancing function in the human male germ line.

Quantitative measurement of udder oedema in dairy cows using ultrasound to monitor the effectiveness of diuretic treatment with furosemide.

INTRODUCTION: The aim of this study was to record the course of peripartal udder oedema with ultrasonography in dairy cows and to investigate the therapeutic effects of diuretic furosemide. For this purpose, a device with a force sensor for the ultrasound probe was developed, which ensured the generation of data under similar pressure conditions and thereby repeatable and comparable results. In a pretrial with ten cows, ultrasonographic measurements were performed daily at four locations per udder quarter beginning 14 days ante partum until 14 d post partum. The main study included 50 dairy cows. The experimental group (n=25) received 500 mg furosemide intramuscularly on the day of calving, as well as on the first and second day post partum. The control group (n=25) was treated with 10 mL 0,9 % sodium chloride solution (NaCl) at the same timepoints. The experimental period was extended from 21 days ante partum until 21 days post partum and included 15 ultrasonographic measurements at three-day intervals. The measurements were performed at the teat base, which turned out to be the most suitable location in the pretrial. Quarter milk samples were collected on the day of calving, 7 and 14 days post partum. The average thickness of the udder oedema between the group treated with furosemide and the control group did not differ. In conclusion, a method for the ultrasonographic measurement of udder oedema under comparable applied forces was established. The teat base turned out to be a suitable location to monitor the characteristic temporal course of udder oedema. In the present study, treatment with furosemide did not have a measurable, positive effect on the severity of the udder oedema post partum in the study animals. Finally, further studies with a higher sample size are necessary to confirm this relationship.

INTRODUCTION: Le but de la présente étude était d'enregistrer l'évolution de l'œdème de la mamelle périnatal par échographie chez les vaches laitières et d'étudier les effets thérapeutiques du diurétique furosémide. À cette fin, un appareil avec un capteur de force pour la sonde à ultrasons a été développé, ce qui a assuré la génération de données dans des conditions de pression similaires et ainsi des résultats reproductibles et comparables. Dans un essai préliminaire avec dix vaches, des mesures échographiques ont été effectuées quotidiennement à quatre endroits par quartier à partir de 14 jours ante partum jusqu'à 14 jours post partum. L'étude principale portait sur 50 vaches laitières. Le groupe expérimental (n=25) a reçu 500 mg de furosémide par voie intramusculaire le jour du vêlage ainsi que les premier et deuxième jours post-partum. Le groupe témoin (n = 25) a été traité avec 10 ml de solution de chlorure de sodium à 0,9 % (NaCl) aux mêmes moments. La période expérimentale a été étendue de 21 jours ante partum jusqu'à 21 jours post partum et comprenait 15 mesures échographiques à trois jours d'intervalle. Les mesures ont été effectuées à la base du trayon, qui s'est avérée être l'emplacement le plus approprié dans la phase préliminaire. Des échantillons de lait de chaque quartier ont été prélevés le jour du vêlage, 7 et 14 jours post-partum. L'épaisseur moyenne de l'œdème de la mamelle entre le groupe traité au furosémide et le groupe témoin ne différait pas. En conclusion, une méthode de mesure échographique de l'œdème de la mamelle sous des forces appliquées comparables a été établie. La base du trayon s'est avérée être un endroit approprié pour surveiller l'évolution temporelle caractéristique de l'œdème de la mamelle. Dans la présente étude, le traitement au furosémide n'a pas eu d'effet positif mesurable sur la gravité de l'œdème de la mamelle post-partum chez les animaux de l'étude. Enfin, d'autres études avec une taille d'échantillon plus élevée sont nécessaires pour confirmer cette relation.

Water immersion is associated with an increase in aquaporin-2 excretion in healthy volunteers.

Here, we report the alterations in renal water handling in healthy volunteers during a 6 h thermoneutral water immersion at 34 to 36 degrees C. We found that water immersion is associated with a reversible increase in total urinary AQP2 excretion.

Pilot study on omega-3 fatty acids in type I diabetes mellitus.

Patients with diabetes mellitus are prone to develop vascular complications. Because omega-3 polyunsaturated fatty acid (omega 3FA) intake has a potential protective effect on cardiovascular disease, we studied the influence of omega 3FA supplementation (5.4 g eicosapentaenoic acid and 2.3 g docosahexaenoic acid daily) for 4 wk in 13 well-controlled type I (insulin-dependent) diabetic subjects on a vascular risk profile. Each subject served as his/her own control in a pre- and post-omega 3FA-intake phase. In plasma and platelets, phospholipids eicosapentaenoic acid and docosahexaenoic acid increased at the expense of arachidonic acid and linoleic acid. There was no significant change in blood pressure and glycosylated proteins. Only small changes were noted in blood glucose levels and insulin dose. Side effects were not noted. Triglycerides decreased significantly in the first 14 days, and total cholesterol increased slightly, probably because of an elevation of high-density lipoprotein cholesterol, although low-density lipoprotein cholesterol remained unchanged. Platelet aggregation induced by low doses of ADP and collagen, which was higher in diabetic than nondiabetic subjects, decreased during omega 3FA intake to levels of healthy control subjects. Thromboxane production after ADP- and collagen-induced platelet aggregation decreased significantly. Thromboxane liberation during clotting of whole blood and urinary excretion of thromboxane were markedly lowered during omega 3FA supplementation. The results show that even short-term intake of omega 3FAs leads to beneficial changes of vascular risk factors without significant changes in glucose homeostasis.

Differential expression of functional guanylyl cyclases in melanocytes: absence of nitric-oxide-sensitive isoform in metastatic cells.

Nitric oxide (NO) is a reactive endogenous molecule with multiple functions and its cellular signaling activity is mainly mediated by activation of the soluble isoform of guanylyl cyclase, a heterodimeric (alpha/beta) hemeprotein. The expression of the NO-sensitive soluble isoform of guanylyl cyclase was studied in various cultured melanocytic cells by measuring the accumulation of guanosine 3',5'-cyclic monophosphate in the presence and absence of NO donors. Here we report that 3-morpholino-sydnonimine, a donor of NO redox species, and (Z)-1-[2- (2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate, a direct NO donor, induced a 20-fold increase in intracellular guanosine 3',5'-cyclic monophosphate in nonmetastatic melanoma cells and normal melanocytes in culture that could be related to cellular melanin content in a concentration-dependent manner. The increased intracellular guanosine 3',5'-cyclic monophosphate was due to stimulation of the activity of soluble guanylyl cyclase as such increase was completely abolished by using a specific inhibitor of soluble guanylyl cyclase. The involvement of functional soluble guanylyl cyclase was further confirmed by the presence of alpha1 and beta1 subunits in these cells at both mRNA and protein levels. In contrast, none of the NO donors induced guanosine 3',5'-cyclic monophosphate production in metastatic melanoma cells, which could be attributed to the absence of the beta1 subunit that is essential for catalytic activity of the soluble isoform of guanylyl cyclase. Metastatic melanoma cells produced higher levels of intracellular guanosine 3',5'-cyclic monophosphate in response to natriuretic peptides than other cell types, however, due to upregulation of membrane-bound guanylyl cyclase activities, but they are less pigmented or unpigmented. The present finding suggests that NO signaling in association with melanogenesis is dependent on the soluble isoform of guanylyl cyclase, whereas absence of soluble guanylyl cyclase but the presence of membrane-bound guanylyl cyclase correlates with the metastatic behavior of melanoma cells.

Lactose does not enhance calcium bioavailability in lactose-tolerant, healthy adults.

BACKGROUND: There is evidence from animal studies that lactose has a beneficial effect on intestinal calcium absorption. However, data concerning the effect of lactose on calcium absorption in lactose-tolerant adults are inconclusive. OBJECTIVE: Our objective was to investigate the effect of lactose on calcium bioavailability in humans by the use of a stable-strontium test under controlled metabolic conditions. DESIGN: Eleven healthy, lactose-tolerant subjects (8 women, 3 men) randomly received a bolus of 2.27 mmol strontium alone (load A), the bolus with 35 g lactose (load B), or the bolus with 17.5 g glucose and 17.5 g galactose (load C). Blood samples were drawn at 0, 15, 30, 60, 90, 180, 240, and 300 min. Urine specimens were collected during the time intervals -2 to 0, 0-2, 2-4, 4-6, and 6-24 h. RESULTS: Pharmacokinetic parameters of strontium bioavailability were comparable for all 3 loads. In detail, fractional absorption at 240 min for loads A, B, and C was 12.1 +/- 0.7%, 13.0 +/- 1.1%, and 12.2 +/- 0.7%, respectively. Areas under the curve for 0-240 min were 70.8 +/- 6.3, 69.6 +/- 3.5, and 65.8 +/- 5.1 micromol*h/L for loads A, B, and C, respectively (NS). Moreover, fractional strontium excretion values of 5.1 +/- 0.8% (load A), 5.8 +/- 0.4% (load B), and 5.2 +/- 0.8% (load C) were not significantly different. CONCLUSIONS: Lactose does not have a beneficial effect on calcium bioavailability in lactose-tolerant adults.

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.

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.

Body mass changes, energy, and protein metabolism in space.

Most astronauts lose body mass during their stay in microgravity. The early hypothesis, which attributed this phenomenon to an increase in diuresis and natriuresis after entering microgravity, is now untenable. Although a fluid shift from the lower to the upper body occurs, it does not lead to a marked fluid loss in the first 2 days of space flight. The continuous day-by-day body mass measurement during the Euromir 94 mission showed that there was a gradual reduction over the entire mission instead of a rapid loss of 2 to 3 kg at the beginning of a mission. The daily energy intake during this mission and the negative energy balances found in the Skylab and LMS-Mission show that lowered body mass is very likely caused by an insufficient energy consumption and its accompanying effects. These include the metabolization of endogenous energy stores, ie, glycogen, protein, and fat. Mobilization of glycogen and protein buffers will also cause the water that is bound to both to be lost. Thus, a gradual decrease in body mass and a concomitant reduction in total body fluid occurs without a significant increase in urine flow or natriuresis. In conclusion, the body mass loss in microgravity is likely a result of undernutrition instead of diuresis and natriuresis caused by the fluid shift.

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.

Involvement of the renal natriuretic peptide urodilatin in body fluid regulation.

Urodilatin, a 32-aminoacid peptide, is expressed in distal tubular cells of the human kidney and presumably released into the luminal part of the nephron to exert its effect via activation of membrane-bound guanylyl cyclases (type A) at the medullary collecting duct. Thereby, the tubular reabsorption of sodium is inhibited and natriuresis is stimulated. The peptide is derived from the same gene and propeptide as the atrial natriuretic peptide (ANP), a more N-terminal cleavage in the human kidney than in other body tissues may be responsible for the existence of this renal natriuretic peptide and its increased stability in the extreme environment of the kidney and primary urine. The results of a sequence of human and animal physiology experiments has suggested that the renal natriuretic peptide, rather than its cardiac analog ANP, may play an essential role in mediating urinary sodium excretion. First observations are made suggesting a contribution of the renal natriuretic peptide also to disturbed sodium handling under pathophysiological conditions.

Effect of water immersion on renal natriuretic peptide (urodilatin) excretion in humans.

We examined 1) the effect of thermoneutral (34.5 +/- 0.5 degrees C) water immersion to the neck (WI) in humans on the temporal profile of renal urodilatin [atrial natriuretic peptide- (ANP) (95-126)] excretion and 2) the relationship between urodilatin and urinary fluid (V) and sodium (UNaV) excretion. Eight normal subjects underwent 12 h of WI, and another group of eight were studied during seated control conditions. The subjects ingested 200 ml of tap water hourly. WI induced an increase in renal urodilatin and guanosine 3',5'-cyclic monophosphate (cGMP) excretion, V, and UNaV. After peak values were attained between the 2nd and 5th h of WI, urodilatin and cGMP excretion, V, and UNaV returned toward preimmersion and control levels. At the 12th h of WI, urodilatin and cGMP excretion and V were indistinguishable from preimmersion values but were significantly elevated compared with the control values. UNaV was maintained elevated compared with both preimmersion and control values. During WI, positive and statistically significant linear correlations could be established between V and renal urodilatin excretion in six subjects and between UNaV and urodilatin excretion in four subjects. We conclude that WI induces an increase in the rate of renal urodilatin excretion, attaining a peak value at the 3rd h followed by an attenuation toward preimmersion and control levels. Furthermore, urodilatin might participate as one of several mechanisms of the natriuresis and diuresis of WI in humans.

Renal and endocrine responses in humans to isotonic saline infusion during microgravity.

It was the purpose of this study to investigate how the endocrine and renal mechanisms of fluid volume control in humans (n = 4) adapt to microgravity by applying an intravenous isotonic saline infusion. The acute ground-based supine (Sup) and seated (Seat) positions were chosen as references. During microgravity, renal sodium excretion (UNaV) was doubled during the second and third hours after infusion compared with during Seat (P < 0.05) but blunted during the first hour after infusion compared with during Sup, leading to a reduction in cumulative UNaV (59 +/- 15 vs. 108 +/- 12 mmol/5 h; P < 0.05). Plasma norepinephrine (NE) attained the highest value 3 h after infusion during microgravity (31 +/- 5 x 10(-2) ng/ml vs. 19 +/- 1 and 13 +/- 3 x 10(-2) ng/ml for Seat and Sup, respectively; P < 0.05). Inflight levels of plasma renin and aldosterone were very similar to levels during Seat. In conclusion, 1) the microgravity-adapted renal responses to infusion reflected a condition in between that of ground-based Seat and Sup, respectively, and 2) the plasma levels of NE, renin, and aldosterone were elevated inflight and not related to the changes in UNaV and urinary flow rate. These observations are in contrast to results of ground-based simulation experiments and might partly have been caused by a prior inflight reduction in extracellular fluid volume. The high levels of NE during microgravity warrant further investigation.

Effect of water temperature on diuresis-natriuresis: AVP, ANP, and urodilatin during immersion in men.

Effects of water temperature on diuresis, natriuresis, and associated endocrine responses during head-out immersion were studied in eight men (23.4 +/- 0.3 yr) during four 5-h experimental conditions: air control at 28 degrees C and immersion at 34.5 degrees C [thermoneutral (Tnt)], 36 degrees C [above Tnt (aTnt)], and 32 degrees C [below Tnt (bTnt)]. Esophageal temperature decreased by approximately 0.4 degrees C in bTnt and increased by approximately 0.5 degrees C in aTnt. Cardiac output increased by approximately 80% in aTnt and approximately 40% in bTnt while thoracic impedance, an index of central blood pooling, decreased by 7.5 omega in bTnt (NS vs. Tnt) and 8.8 omega in aTnt (P < 0.05 vs. Tnt and bTnt). Total peripheral resistance decreased at all temperatures (50% in aTnt, 20% in bTnt). Urine flow and Na+ excretion increased by sixfold in bTnt and Tnt but by only threefold in aTnt. Creatinine clearance was unchanged while osmolal clearance (but not free water clearance) increased two-fold with all immersions. Plasma atrial natriuretic peptide (ANP), urinary urodilatin, and urinary guanosine 3',5'-cyclic monophosphate increased while plasma renin activity, aldosterone, and arginine vasopressin (AVP) decreased similarly at all temperatures. bTnt did not potentiate diuresis by selective attenuation of AVP. The overall natriuretic response exhibited a higher correlation with urodilatin (r = 0.45, P < 0.001) than with ANP (r = 0.26, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)