Endogenous alpha-atrial natriuretic peptide (ANP) in plasma is elevated in various hypervolaemic conditions. Possible relationships between circulating immunoreactive ANP and cardiovascular and splanchnic haemodynamics were therefore studied in patients with cirrhosis (n = 16) and controls (n = 12). Arterial plasma concentration of ANP in supine patients was (mean +/- SEM) 33 +/- 4 vs 41 +/- 10 pg/ml (9.9 +/- 1.2 vs 12.3 +/- 3.0 fmol/l) in controls (n.s.), and there was a weak direct correlation with right atrial pressure (r = 0.36, P = 0.05). There was no relationship with the presence of ascites or diuretic treatment. Central blood volume (CBV, i.e. the blood volume in the heart cavities, lungs, and aorta), determined from the mean transit time of 125I-labelled of 125I-labelled albumin and cardiac output, was significantly reduced in cirrhotics compared to controls (1.45 +/- 0.12 vs. 1.83 +/- 0.10 l, P less than 0.02) and inversely correlated with portal pressure (r = 0.42, P less than 0.05), whereas total plasma volume was somewhat increased (3.51 +/- 0.2 vs. 3.19 +/- 0.2, 0.05 less than P less than 0.1). A high arterio-venous extraction of ANP was found in the splanchnic system (extraction ratio 0.44 vs 0.28), kidney (0.45 vs 0.54), lower limb (0.53 vs 0.40), and forearm (0.27 vs 0.18) in patients and controls, respectively (n.s.). Our results suggest that the lack of elevation of circulating ANP in cirrhosis, even in the presence of actual fluid retention, may be explained by central hypovolaemia in these patients. Turnover and degradation of ANP is rapid and normal, as evaluated from the tissue extraction ratios.

BACKGROUND:Based on maximisation of cardiac stroke volume (SV), peri-operative individualised goal-directed fluid therapy improves patient outcome. It remains, however, unknown how fluid therapy by this strategy relates to filling of the heart during supine rest as reference for the anaesthetised patient and whether the heart becomes distended. To answer these questions, this study related SV to the diastolic filling of the heart while varying central blood volume (CBV) between hypo- and hyper-volaemia, simulating bleeding, and fluid loading, respectively, when exposing healthy human subjects to head-up (HUT) and head-down tilt (HDT).METHODS:Twelve healthy volunteers underwent graded tilt from 20 degrees HDT to 30 degrees HUT. The end-diastolic dimensions of the heart were assessed by transthoracic echocardiography with independent evaluation of SV by Modelflow. The CBV was monitored by thoracic electrical admittance, central venous oxygenation and pressure, and arterial plasma atrial natriuretic peptide. Also, muscle and brain oxygenation were assessed by near infrared spectroscopy (n=7).RESULTS:The HUT reduced the mentioned indices of CBV, the end-diastolic dimensions of the heart, and SV. Conversely, HDT-enhanced tissue oxygenation and the diastolic filling of the heart, but not SV.CONCLUSIONS:In healthy supine humans, the heart is provided with a volume that is sufficient to secure a maximal SV without distending the heart. The implication for individualised goal-directed fluid therapy is that when a maximal SV is established for patients, cardiac pre-load is comparable to that of supine healthy subjects.

During arm exercise (A), mean arterial pressure (MAP) is higher than during leg exercise (L). We evaluated the effect of central blood volume on the MAP response to exercise by determining plasma atrial natriuretic peptide (ANP) during moderate upright and supine A, L and combined arm and leg exercise (A + L) in 11 male subjects. In the upright position, MAP was higher during A than at rest (102 +/- 6 versus 89 +/- 6 mmHg; mean +/- s.d.) and during L (95 +/- 7 mmHg; P < 0.05), but similar to that during A + L (100 +/- 6 mmHg). There was no significant change in plasma ANP during A, while plasma ANP was higher during L and A + L (42.7 +/- 12.2 and 43.3 +/- 17.1 pg ml(-1), respectively) than at rest (34.6 +/- 14.3 pg ml(-1), P < 0.001). In the supine position, MAP was also higher during A than at rest (100 +/- 7 versus 86 +/- 5 mmHg) and during L (92 +/- 5 mmHg; P < 0.01) but similar to that during A + L (102 +/- 6 mmHg). During supine A, plasma ANP was higher than at rest and during L but lower than during A + L (73.1 +/- 22.5 versus 47.2 +/- 15.9, 67.4 +/- 18.3 and 78.1 +/- 25.0 pg ml(-1), respectively; P < 0.05). Thus, upright A was the exercise mode that did not enhance plasma ANP, suggesting that central blood volume did not increase. The results suggest that the similar blood pressure response to A and to A + L may relate to the enhanced central blood volume following the addition of leg to arm exercise.

Orexin-A is an orexigenic peptide expressed mainly in the hypothalamus. Orexin-A increases and anti-orexin-A antibodies decrease food intake. However, the exact mechanism by which orexin-A exerts its orexigenic action is not fully elucidated. The histaminergic system is known to play a role in feeding behavior and we hypothesized that it could be involved in the orexigenic effect of orexin-A. To study this, we used histamine knockout animals and pharmacological blockade of the histaminergic system and studied the effect of orexin-A on feeding behavior and gene expression of neuropeptide Y (NPY). Orexin-A was administered intracerebroventricularly and food intake measured in wild-type, histamine H1-receptor knockout or histidine decarboxylase knockout mice. Additionally, we administered orexin-A to wild-type mice with pharmacologically blocked H1-receptors or pharmacologically stimulated autoinhibitory H3-receptors. By quantitative real-time PCR we measured the effect of orexin-A on NPY mRNA expression in wild-type and knockout mice. Orexin-A dose-dependently stimulated food intake when administered to wild-type mice in doses up to 0.03 µg. Orexin-A in a dose of 0.01 µg increased food intake 10-fold in wild-type mice, whereas no increase in food intake was seen in either knockout mice or pharmacologically manipulated mice. Orexin-A increased NPY mRNA 4-fold in wild-type mice, whereas no change was observed in knockout mice. We conclude that the orexigenic effect of orexin-A is dependent on an intact histaminergic neuronal system and seems to involve an H1-receptor mechanism.

BACKGROUND:Hypovolaemia may be considered to represent a volume-restricted cardiac output (CO), but CO varies inversely with the haemoglobin concentration (Hb) and a maximal mixed venous oxygen saturation (SvO2) may be a better target for volume administration than a maximal CO.METHODS:In 10 anaesthetized pigs, volume loading with 6% hydroxyethyl starch was performed to obtain a maximal SvO2 followed by normovolaemic haemodilution with 6% hydroxyethyl starch.RESULTS:Volume loading increased SvO2 from 55.0+/-5.2% to 64.8+/-9.0% (mean+/-SD) associated with an increase in CO (2.3+/-0.4 to 3.5+/-0.9 l/min) and central venous oxygen saturation (ScvO2; 68.2+/-9.3% to 79.4+/-7.2%; P<0.05). Heart rate (HR), mean arterial (MAP), central venous (CVP), pulmonary arterial mean (PAMP), and occlusion pressures (PAOP) increased as well (P<0.05). In contrast, during progressive haemodilution, SvO2 and ScvO2 remained statistically unchanged until the haemoglobin concentration had decreased from 5.5+/-0.4 to 2.9+/-0.2 mM, while CO and HR increased at a haemoglobin value of 4.4+/-0.4 and 4.0+/-0.4 mM and CVP and PAOP decreased at a haemoglobin of 4.0+/-0.4 and 2.9+/-0.2 mM, respectively (P<0.05) leaving MAP unaffected.CONCLUSION:This study found that volume loading increased cardiac output and mixed and central venous oxygen saturations in parallel, but during normovolaemic haemodilution an increase in cardiac output left mixed and central venous oxygen saturations statistically unchanged until haemoglobin concentration was reduced by approximately 50%. Accordingly, volume therapy should be directed to maintain a high venous oxygen saturation rather than a change in cardiac output.

Strenuous exercise increases the cerebral uptake of carbohydrate out of proportion to that of oxygen, but it is unknown whether such enhanced carbohydrate uptake is influenced by the marked endocrine response to exercise. During exhaustive exercise this study evaluated the a–v differences across the brain (a–v diff) of hormones that could influence its carbohydrate uptake (n= 9). In addition, neuroendocrine activity and a potential uptake of hormones via the cerebrospinal fluid (CSF) were assessed by lumbar puncture postexercise and at rest (n= 6). Exercise increased the arterial concentration of noradrenaline and adrenaline, but there was no cerebral uptake. However, following exercise CSF noradrenaline was 1.4 (0.73–5.5) nmol l−1, and higher than at rest, 0.3 (0.19–1.84) nmol l−1 (P < 0.05), whereas adrenaline could not be detected. Exercise increased both the arterial concentration of NH4+ and its a–v diff, which increased from 1 (–12 to 5) to 17 (5–41) μmol l−1 (P < 0.05), while the CSF NH4+ was reduced to 7 (0–10) versus 11 (7–16) μmol l−1 (P < 0.05). There was no release from, or accumulation in the brain of interleukin (IL)‐6, tumour necrosis factor (TNF‐α), heatshock protein (HSP72), insulin, or insulin‐like growth factor (IGF)‐I. The findings indicate that for maximal exercise, the concentration of noradrenaline is increased within the brain, whereas blood borne hormones and cytokines are seemingly unimportant. The results support the notion that the exercise‐induced changes in brain metabolism are controlled by factors intrinsic to the brain.

Prostaglandins and histamine in the hypothalamus are involved in the regulation of oxytocin and vasopressin secretion, and appear to be involved in the mediation of pituitary hormone responses to immunochallenges. Therefore, we investigated in conscious male rats: (i) whether blockade of H1 or H2 receptors affected the oxytocin and vasopressin responses to prostaglandins and (ii) whether blockade of prostaglandin synthesis affected the oxytocin and vasopressin responses to histamine or to Escherichia coli lipopolysaccharide (LPS), in order to determine any interaction between prostaglandins and histamine in the hypothalamus. Oxytocin secretion was dose-dependently stimulated by intracerebroventricular infusion of 1 or 5 microg of PGE1, PGE2 or PGF2alpha, with PGE2 being the most potent of the compounds used. Prior central infusion of the H1 receptor antagonist mepyramine or the H2 receptor antagonist cimetidine significantly inhibited the oxytocin response to all three prostaglandins by approximately 50%. Vasopressin secretion was increased by PGE1 but not by PGE2 or PGF2alpha. The stimulatory effect of PGE1 was almost annihilated by prior administration of mepyramine or cimetidine. Central infusion of histamine or immunochallenge with LPS administered intraperitoneally increased oxytocin and vasopressin secretion four- and two-fold, respectively. Pretreatment with systemic injection of the prostaglandin synthesis inhibitor indomethacin dose-dependently reduced the oxytocin response and prevented the vasopressin response to histamine or LPS. We conclude that histamine and PGE1, PGE2 or PGF2alpha interact in the regulation of oxytocin secretion, whereas histamine and only PGE1 interact in the regulation of vasopressin secretion. Furthermore, histamine as well as LPS may affect oxytocin and vasopressin neurones via activation of prostaglandins, probably in the hypothalamic supraoptic nucleus.

The neurotransmitter serotonin (5-HT) stimulates the secretion of vasopressin and oxytocin, and 5-HT is involved in the mediation of the vasopressin and oxytocin response to stress. In male Wistar rats, we investigated the 5-HT receptors involved in the 5-HT-induced increase of mRNA expression of vasopressin and oxytocin in the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). The 5-HT precursor, 5-hydroxytryptophan, injected in combination with the 5-HT reuptake inhibitor, fluoxetine, increased oxytocin mRNA expression in the PVN, and the concentration of vasopressin and oxytocin in plasma, whereas mRNA in the SON was not affected. Intracerebroventricular infusion of 5-HT agonists selective for the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptor increased oxytocin mRNA in the SON and PVN. Infusion of agonists selective for the 5-HT2A + 2C receptor increased vasopressin mRNA in the PVN, whereas none of the 5-HT agonists affected vasopressin mRNA in the SON. All the 5-HT agonists infused increased peripheral oxytocin concentration and vasopressin was increased by stimulation of the 5-HT2A, 5-HT2C and 5-HT3 receptor. Intracerebroventricular infusion of 100 nmol 5-HT increased the extracellular hypothalamic concentration of vasopressin as measured by microdialysis in the PVN. To evaluate the involvement of hypothalamic-pituitary system in the 5-hydroxytryptophan and fluoxetine-induced vasopressin secretion, rats were immunoneutralized with a specific anti-corticotropin-releasing hormone antiserum. This treatment reduced plasma vasopressin and oxytocin responses. We conclude that stimulation with 5-hydroxytryptophan or 5-HT agonists increases mRNA expression of oxytocin in the PVN and the SON via stimulation of at least 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors. Vasopressin mRNA in the PVN was increased only via the 5-HT2 receptor, whereas vasopressin mRNA in the SON does not seem to be affected by 5-HT stimulation. Corticotropin-releasing hormone appears to be partly involved in the mediation of 5-HT induced vasopressin and oxytocin secretion.

Serotonin (5-HT), 5-HT agonists, the 5-HT precursor 5-hydroxytryptophan, 5-HT-releasers and -reuptake inhibitors stimulate the release of vasopressin and oxytocin. We investigated the involvement of 5-HT receptors in the serotonergic regulation of vasopressin and oxytocin secretion. Vasopressin and oxytocin secretion was stimulated by 5-HT, the 5-HT1A+1B+5A+7 agonist 5-carboxamidotryptamine (5-CT), the 5-HT2A+2C agonist DOI, the 5-HT2C+2A agonist mCPP, the 5-HT2C agonist MK-212, the 5-HT3 agonist SR 57277 and the 5-HT4 agonist RS 67506. The 5-HT1A agonist 8-OH-DPAT, which had no effect on vasopressin secretion, stimulated oxytocin secretion. The 5-HT-induced release of vasopressin and oxytocin was inhibited by central infusion of the 5-HT antagonists WAY 100635 (5-HT1A ), LY 53857 (5-HT2A+2C ), ICS 205-930 (5-HT3+4 ) and RS 23597 (5-HT4 ). The 5-HT2+6+7 antagonist metergoline in combination with the 5-HT1A+2+7 antagonist methysergide inhibited the stimulatory effect of 5-CT on both hormones, whereas the 5-HT1A+1B antagonist cyanopindolol only inhibited the oxytocin response. The 5-HT2A antagonist 4-(4-flourobenzoyl)-1-(4-phenylbutyl)-piperidine oxalate had no effect on DOI-induced hormone response. The 5-HT2C antagonist Y 25130 partly inhibited the stimulating effect of MK-212. ICS 205-930 and RS 23597 inhibited vasopressin and oxytocin secretion induced by RS 67506. WAY 100635 inhibited 8-OH-DPAT-induced oxytocin secretion. We conclude that 5-HT-induced vasopressin secretion primarily is mediated via 5-HT2C , 5-HT4 and 5-HT7 receptors, whereas 5-HT2A , 5-HT3 and 5-HT5A receptors seem to be of minor importance. 5-HT-induced oxytocin secretion involves 5-HT1A , 5-HT2C and 5-HT4 receptors; in addition an involvement of 5-HT1B , 5-HT5A and 5-HT7 receptors seems likely, whereas 5-HT2A and 5-HT3 receptors seem to be less important.

Objective: Leptin suppresses food intake; however, the precise mechanism is not fully understood. Histamine (HA), which acts as a neurotransmitter in the central nervous system, has also been shown to be involved in feeding and exerts an inhibitory effect through activation of H1 receptors. Therefore, we studied the possible role of HA in short-term leptin-induced suppression of food intake. Methods: We studied the 6-h feeding response of overnight-fasted adult (200 g) male Wistar rats to leptin and the HA synthesis inhibitor α-fluoromethylhistidine (α-FMH). Levels of transcription for neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH), as well as hypothalamic content of HA and the HA metabolite telemethyl-HA were investigated. Results: Central administration of leptin (3, 5 and 10 μg at 09:00 h) in fasted rats caused a decrease in food intake. In contrast, central administration of α-FMH (11, 22 and 112 μg at 09:00 h) increased food intake. Prior administration of α-FMH prevented the leptin-induced decrease in food intake. Leptin decreased hypothalamic histamine content, while increasing the ratio between telemethyl-HA and HA, indicating that leptin reduces HA metabolism. Finally, α-FMH suppressed basal and leptin-induced CRH expression while stimulating NPY expression in fasted rats. Conclusion: Histamine is involved in leptin-induced inhibition of food intake. The role of histamine may be mediating, i.e. leptin may directly activate and/or change the metabolism of the histaminergic system. Alternatively, the histaminergic system may be involved in a permissive manner.

OBJECTIVE:To investigate the involvement of serotonin (5-hydroxytryptamine - 5-HT) receptors in mediation of stress-induced arginine vasopressin (AVP) and oxytocin (OT) secretion in male rats.DESIGN:Experiments on laboratory rats with control groups.METHODS:Different stress paradigms were applied after pretreatment with intracerebroventricular infusion of saline or different 5-HT antagonists.RESULTS:Restraint stress (5 min), hypotensive hemorrhage or dehydration for 24 h increased AVP secretion fivefold and OT secretion threefold. Swim stress for 3 min had no effect on AVP secretion, but increased OT secretion threefold. Ether vapor or hypoglycemia had no effect on AVP or OT secretion. The restraint stress-induced AVP response was inhibited by pretreatment with the 5-HT(2A+2C) antagonists ketanserin (KET) and LY-53857 (LY) and the 5-HT(3+4) antagonist ICS-205930 (ICS), whereas the 5-HT(1A) antagonist WAY-100635 (WAY) had no effect. The OT response to restraint stress was inhibited by WAY, KET and LY but not by ICS. KET and LY inhibited OT response to dehydration, and LY inhibited OT response to hemorrhage. Neither of the antagonists affected AVP responses to dehydration or hemorrhage, nor the swim stress-induced OT response.CONCLUSION:5-HT(2A), 5-HT(2C) and possibly 5-HT(3) and 5-HT(4) receptors, but not 5-HT(1A) receptors, are involved in the restraint stress-induced AVP secretion. 5-HT does not seem to be involved in the dehydration- or hemorrhage-induced AVP response. The restraint stress-induced OT response seems to be mediated via 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors. The dehydration and hemorrhage-induced OT responses are at least mediated by the 5-HT(2A) and 5-HT(2C) receptors. The 5-HT(3) and 5-HT(4) receptors are not involved in stress-induced OT secretion.

The neurotransmitter serotonin (5-HT) stimulates adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary gland via activation of central 5-HT1 and 5-HT2 receptors. The effect of 5-HT is predominantly indirect and may be mediated via release of hypothalamic corticotropin-releasing hormone (CRH). We therefore investigated the possible involvement of CRH in the serotonergic stimulation of ACTH secretion in male rats. Increased neuronal 5-HT content induced by systemic administration of the precursor 5-hydroxytryptophan (5-HTP) in combination with the 5-HT reuptake inhibitor fluoxetine raised CRH mRNA expression in the paraventricular nucleus (PVN) by 64%, increased pro-opiomelanocortin (POMC) mRNA in the anterior pituitary lobe by 17% and stimulated ACTH secretion five-fold. Central administration of 5-HT agonists specific to 5-HT1A, 5-HT1B, 5-HT2A or 5-HT2C receptors increased CRH mRNA in the PVN by 15-50%, POMC mRNA in the anterior pituitary by 15-27% and ACTH secretion three- to five-fold, whereas a specific 5-HT3 agonist had no effect. Systemic administration of a specific anti-CRH antiserum inhibited the ACTH response to 5-HTP and fluoxetine and prevented the 5-HTP and fluoxetine-induced POMC mRNA response in the anterior pituitary lobe. Central or systemic infusion of 5-HT increased ACTH secretion seven- and eight-fold, respectively. Systemic pretreatment with the anti-CRH antiserum reduced the ACTH responses to 5-HT by 80% and 64%, respectively. It is concluded that 5-HT via activation of 5-HT1A, 5-HT2A, 5-HT2C and possibly also 5-HT1B receptors increases the synthesis of CRH in the PVN and POMC in the anterior pituitary lobe, which results in increased ACTH secretion. Furthermore, the results indicate that CRH is an important mediator of the ACTH response to 5-HT.

OBJECTIVES AND METHODS:Circulating cytokines such as interleukin-1 (IL-1), and tumor necrosis factor-alpha as well as lipopolysaccharide (LPS) are potent ACTH secretagogues, acting via stimulation of corticotropin-releasing hormone (CRH) and vasopressinergic neurons in the paraventricular nucleus of the hypothalamus (PVN). Histamine (HA) has been shown to stimulate ACTH secretion in rats, an effect in part mediated by CRH and arginine vasopressin (AVP). We have previously shown that inhibition of neuronal HA synthesis or central blockade of H(1) receptors (H(1)R) decreased the ACTH response to LPS in male rats. To further elucidate the role of neuronal HA in cytokine-induced activation of the HPA axis, we compared the effect of H(1)R knockout on IL-1beta-induced ACTH secretion in adult male mice.RESULTS:In H(1)R knockout mice, ACTH secretion increased from basal levels of 261 to 492 pmol/l in response to IL-1beta whereas the cytokine-induced ACTH secretion increased from 140 to 406 pmol/l in wild-type mice. Plasma corticosterone (CORT) rose from basal levels of 99 to 831 nmol/l in knockout mice upon IL-1beta stimulation, whereas in wild-type mice CORT levels rose from 112 to 841 nmol/l. There was no significant difference in IL-1beta-stimulated plasma ACTH or CORT levels between wild-type and knockout mice. Furthermore, there was no significant difference in basal or IL-1beta-stimulated hypothalamic levels of histamine and tele-methyl-histamine between wild-type and knockout mice. HDC gene expression was significantly lower in knockout mice than in wild-type mice both under basal and IL-1beta-stimulated conditions, while there were no significant differences in CRH gene expression in the PVN in knockout mice under basal and IL-1beta-stimulated conditions. Increased basal expression of AVP in the PVN of knockout mice was observed in this study compared to wild-type mice.CONCLUSION:We conclude that the lack of the gene for histamine H(1)R does not seem to be crucial for the ACTH and CORT response to IL-1beta, either due to possible functional compensation in the H(1)R knockout mouse or due to activation of pathways other than the neuronal histaminergic system.

Objectives and Methods: Circulating cytokines such as interleukin-1 (IL-1), and tumor necrosis factor-alpha as well as lipopolysaccharide (LPS) are potent ACTH secretagogues, acting via stimulation of corticotropin-releasing hormone (CRH) and vasopressinergic neurons in the paraventricular nucleus of the hypothalamus (PVN). Histamine (HA) has been shown to stimulate ACTH secretion in rats, an effect in part mediated by CRH and arginine vasopressin (AVP). We have previously shown that inhibition of neuronal HA synthesis or central blockade of H1 receptors (H1R) decreased the ACTH response to LPS in male rats. To further elucidate the role of neuronal HA in cytokine-induced activation of the HPA axis, we compared the effect of H1R knockout on IL-1s-induced ACTH secretion in adult male mice. Results: In H1R knockout mice, ACTH secretion increased from basal levels of 261 to 492 pmol/l in response to IL-1s whereas the cytokine-induced ACTH secretion increased from 140 to 406 pmol/l in wild-type mice. Plasma corticosterone (CORT) rose from basal levels of 99 to 831 nmol/l in knockout mice upon IL-1s stimulation, whereas in wildtype mice CORT levels rose from 112 to 841 nmol/l. There was no significant difference in IL-1s-stimulated plasma ACTH or CORT levels between wild-type and knockout mice. Furthermore, there was no significant difference in basal or IL-1s-stimulated hypothalamic levels of histamine and tele-methyl-histamine between wild-type and knockout mice. HDC gene expression was significantly lower in knockout mice than in wild-type mice both under basal and IL-1s-stimulated conditions, while there were no significant differences in CRH gene expression in the PVN in knockout mice under basal and IL-1s-stimulated conditions. Increased basal expression of AVP in the PVN of knockout mice was observed in this study compared to wild-type mice. Conclusion: We conclude that the lack of the gene for histamine H1R does not seem to be crucial for the ACTH and CORT response to IL-1s, either due to possible functional compensation in the H1R knockout mouse or due to activation of pathways other than the neuronal histaminergic system.

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

The hypothesis was tested that cardiac output (CO) and stroke volume (SV) are increased by a moderate physiological elevation in sodium intake with a more pronounced effect in the ambulatory upright seated than supine position. Fourteen healthy males were investigated during ambulatory and controlled laboratory conditions at the end of two consecutive 5-day periods with sodium intakes of 70 (low) and 250 (high) mmol/24 h or vice versa, respectively. Comparing high and low sodium intake, plasma volume and plasma protein concentrations were 9 and 8% higher in the seated and the supine position, respectively. When seated during laboratory conditions, CO was 5.3 +/- 0.2 l/min on the high sodium intake vs. 4.8 +/- 0.2 l/min on the low (P < 0.05), and SV was 81 +/- 3 vs. 68 +/- 3 ml (P < 0.05). In the supine position, SV was 107 +/- 3 ml on the high vs. 99 +/- 3 ml (P < 0.05) on the low sodium intake, while CO remained unchanged. The difference in CO and SV induced by the change in sodium intake was significantly higher in the seated than in the supine position (P < 0.05). During upright ambulatory conditions, CO was 5.9 +/- 0.2 l/min during the high and 5.2 +/- 0.2 l/min during the low sodium intake (P < 0.05), and SV was 84 +/- 3 and 69 +/- 3 ml (P < 0.05), respectively. Mean arterial pressure was unchanged by the variations in sodium intake. In conclusion, increments in sodium intake within the normal physiological range increase CO and SV and more so in the seated vs. the supine position. These changes are readily detectable during upright, ambulatory conditions. The results indicate that the higher SV and CO could constitute an arterial baroreflex stimulus for the augmented renal sodium excretion.

The hypothesis was tested that changing the direction of the transverse gravitational stress in horizontal humans modulates cardiovascular and renal variables. On different study days, 14 healthy males were placed for 6 h in either the horizontal supine or prone position following 3 h of being supine. Eight of the subjects were in addition investigated in the horizontal left lateral position. Compared with supine, the prone position slightly increased free water clearance (349 +/- 38 vs. 447 +/- 39 ml/6 h, P = 0.05) and urine output (1,387 +/- 55 vs. 1,533 +/- 52 ml/6 h, P = 0.06) with no statistically significant effect on renal sodium excretion (69 +/- 3 vs. 76 +/- 5 mmol/6 h, P = 0.21). Mean arterial pressure and left atrial diameter were similar comparing effects of supine with prone. The prone position induced an increase in heart rate (54 +/- 2 to 58 +/- 2 beats/min, P < 0.05), total peripheral vascular resistance (13 +/- 1 to 16 +/- 1 mmHg.min(-1).l(-1), P < 0.05), forearm venous plasma concentration of norepinephrine (97 +/- 9 to 123 +/- 16 pg/ml, P < 0.05), and atrial natriuretic peptide (49 +/- 4 to 79 +/- 12 pg/ml, P < 0.05), whereas stroke volume decreased (122 +/- 5 to 102 +/- 3 ml, P < 0.05, n = 6). The left lateral position had no effect on renal variables, whereas left atrial diameter increased (32 +/- 1 to 35 +/- 1 mm, P < 0.05) and mean arterial pressure decreased (90 +/- 2 to mean value of 85 +/- 2 mmHg, P < 0.05). In conclusion, the prone position reduced stroke volume and increased sympathetic nervous activity, possibly because of mechanical compression of the thorax with slight impediment of arterial filling. The mechanisms of the slightly augmented urine output in prone position require further experimentation.

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

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

The hypothesis that graded expansion of central blood volume by water immersion to the xiphoid process and neck would elicit a graded decrease in forearm vascular resistance was tested. Central venous pressure increased (P < 0.05) by 4.2 +/- 0.4 mmHg (mean +/- SEM) during xiphoid immersion and by 10.4 +/- 0.5 mmHg during neck immersion. Plasma noradrenaline was gradually suppressed (P < 0.05) by 62 +/- 8 and 104 +/- 11 pg mL-1 during xiphoid and neck immersion, respectively, indicating a graded suppression of sympathetic nervous activity. Plasma concentrations of arginine vasopressin were suppressed by 1.5 +/- 0.5 pg mL-1 (P < 0.05) during xiphoid immersion and by 2.0 +/- 0.5 pg mL-1 during neck immersion (P < 0.05 vs. xiphoid immersion). Forearm subcutaneous vascular resistance decreased to the same extent by 26 +/- 9 and 28 +/- 4% (P < 0.05), respectively, during both immersion procedures, whereas forearm skeletal muscle vascular resistance declined only during neck immersion by 27 +/- 6% (P < 0.05). In conclusion, graded central blood volume expansion initiated a graded decrease in sympathetic nervous activity and AVP-release. Changes in forearm subcutaneous vascular resistance, however, were not related to the gradual withdrawal of the sympathetic and neuroendocrine vasoconstrictor activity. Forearm skeletal muscle vasodilatation exhibited a more graded response with a detectable decrease only during immersion to the neck. Therefore, the forearm subcutaneous vasodilator response reaches saturation at a lower degree of central volume expansion than that of forearm skeletal muscle.