Renal response to central volume expansion in humans is attenuated at night

The renal response to central volume expansion induced by head-out water immersion was examined in 10 normal, salt-replete subjects studied during the day (0900-1300) and during the night (0000-0400). Sodium excretion in the hour preceding the study was 155 +/- 21 mueq/min and 120 +/- 14 mueq/min, respectively. During the day, immersion was followed by a natriuresis, which reached a mean peak level of 293 +/- 46 mueq/min during the 2nd h of immersion and which was maintained for the remainder of the immersion. During the night, there was no significant increase in sodium excretion from prestudy values during the first 3 h of immersion. Values rose significantly in the 4th h and reached a mean peak level of 211 +/- 20 mueq/min. Potassium excretion rose during the day (from 61 +/- 12 mueq/min to 126 +/- 16 mueq/min) but was unaltered at night. Neither glomerular filtration rate nor plasma levels of aldosterone differed between day and night. To exclude the possibility that the blunted nocturnal natriuresis could be explained by a lesser degree of central fluid translocation induced by immersion at night six normal salt-replete subjects received a 2-liter infusion of normal saline administered over 4 h during the day and during the night. The blunting of the nocturnal natriuresis was again observed. We conclude that, in addition to well-described diurnal variations in electrolyte excretion, there are diurnal variations in the responsivity of volume regulatory mechanisms.     

Renal response to head-out water immersion in Korean women divers

Head-out water immersion (HOI) induces a profound diuresis and natriuresis, which may endanger the body fluid balance of breath-hold divers during prolonged diving work. To investigate if adaptation is acquired by professional breath-hold divers, we have evaluated renal responses to 3-h HOI in 5 Korean women divers (Amas) and 11 nondiving housewives (controls). In both control and diver groups, the average urine flow during 3-h immersion was four times greater and Na⁺ excretion was 70%–80% greater than the pre-immersion value [urine flow: 3.7 (SD 1.0) ml·min^–1 vs 0.9 (SD 0.4), P<0.001, in controls; 4.3 (SD 0.9) vs 1.1 (SD 0.4), P<0.001, in divers; Na⁺ excretion: 270 (SD 176) mol· min^–1 vs 161 (SD 84), P<0.025, in controls; 303 (SD 31) vs 164 (SD 62), P<0.005, in divers]. In all cases, the values for a given period were not significantly different between the two groups. The plasma concentrations of Na⁺ and osmolality, and renal clearance of creatinine did not change significantly. However, the osmolal clearance increased [from 2.0 (SD 0.8) ml·min^–1 to 2.8 (SD 0.7), P<0.05, in the controls; from 2.2 (SD 0.4) to 2.6 (SD 0.4), P<0.05, in the divers] and free water clearance changed from negative to positive values [from -1.1 (SD 0.5) ml·min^–1 to 1.2 (SD 0.3), P<0.005, in the controls; from -1.2 (SD 0.4) to 1.6 (SD 1.1), P<0.01, in the divers] during immersion, again the pattern of change being similar in the two groups. It was, therefore, concluded from our study that the renal response to HOI was unchanged in the Korean women professional breath-hold divers compared to the nondiving women.     

Renal response to volume depletion and expansion in Milan hypertensive rats

In previous studies on Milan hypertensive (MHS) rats, we found an impaired tubuloglomerular feedback (TGF) response before, during and after development of hypertension. In the present study MHS rats and rats of the Milan normotensive strain (MNS) were investigated after 24 hours of volume depletion (VD) and subsequently after 5% isotonic volume expansion (VE) with respect to whole kidney function, interstitial hydrostatic (P_int) and oncotic (II_int) pressures, stop-flow pressure characteristics of TGF and changes in early proximal flow rate in response to increased loop of Henle flow. MHS rats had higher mean arterial blood pressure (P_a) than MNS rats (129 vs. 101 mmHg) both after VD and after subsequent VE. No difference in glomerular filtration rate (GFR) was found. Both strains had a low urine flow rate (1.5 μl min^-1) during VD, which increased fourfold after VE. The interstitium was significantly more dehydrated in MHS, as indicated by a more negative net interstitial pressure (P_int–±_int t than in MNS (-1.3 ± 0.3 vs. ± 0.0 ± 0.5 mmHg) after VE. The TGF mechanism was more activated in MHS during volume depletion, as indicated by a larger drop in stop-flow pressure (P_sf) in response to loop of Henle perfusion (7.1 ± 0.7 vs. 4.7 ± 0.2 mmHg, P < 0.05). However, during VD the loop of Henle flow that elicited half maximal response in P_sf, the turning point (TP), was equally low in MHS and MNS (13.5 ± 0.6 and 14.3 ± 0.4, respectively). After VE, however, TP increased significantly more in MNS to (32.6 ± 2.1 nl min^-1) then in MHS (to 21.8 ± 0.9 nl min^-1, P < 0.05). It is concluded that the blunting of the TGF resetting in response to VE in MHS rats may well be of importance in the development of hypertension in the MHS strain.     

Renal response to volume depletion and expansion in Milan hypertensive rats.

In previous studies on Milan hypertensive (MHS) rats, we found an impaired tubuloglomerular feedback (TGF) response before, during and after development of hypertension. In the present study MHS rats and rats of the Milan normotensive strain (MNS) were investigated after 24 hours of volume depletion (VD) and subsequently after 5% isotonic volume expansion (VE) with respect to whole kidney function, interstitial hydrostatic (P(int)) and oncotic (IIint) pressures, stop-flow pressure characteristics of TGF and changes in early proximal flow rate in response to increased loop of Henle flow. MHS rats had higher mean arterial blood pressure (Pa) than MNS rats (129 vs. 101 mmHg) both after VD and after subsequent VE. No difference in glomerular filtration rate (GFR) was found. Both strains had a low urine flow rate (approximately 1.5 microliters min-1) during VD, which increased fourfold after VE. The interstitium was significantly more dehydrated in MHS, as indicated by a more negative net interstitial pressure (P(int)-IIint than in MNS (-1.3 +/- 0.3 vs. +/- 0.0 +/- 0.5 mmHg) after VE. The TGF mechanism was more activated in MHS during volume depletion, as indicated by a larger drop in stop-flow pressure (Psf) in response to loop of Henle perfusion (7.1 +/- 0.7 vs. 4.7 +/- 0.2 mmHg, P less than 0.05). However, during VD the loop of Henle flow that elicited half maximal response in Psf, the turning point (TP), was equally low in MHS and MNS (13.5 +/- 0.6 and 14.3 +/- 0.4, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of central beta-adrenoceptors in the tachycardia induced by water immersion stress in rats

The purpose of the present study was to investigate whether central beta-adrenoceptors are involved in stress-induced cardiovascular responses in rats. Using a biotelemetry system, blood pressure and heart rate were measured at rest and during stress induced by immersion in 1 cm-deep water. Intracerebroventricular (i.c.v.) injections of a nonselective beta-adrenoceptor antagonist, DL-propranolol (5 or 50 microg), significantly and dose dependently attenuated the tachycardia induced by water immersion stress (drug-induced reduction of tachycardia at 5 min after the start of stress: 61.4 +/- 13.2% for 5 microg, 72.5 +/- 8.2% for 50 microg). The same doses of DL-propranolol had no effect on the resting heart rate. Injection (i.c.v.) of a lower dose (5 microg) of D-propranolol--which has a lower potency as a beta-adrenoceptor antagonist than DL-propranolol, but a similar local anesthetic, membrane-stabilizing activity--did not attenuate the stress-induced tachycardia, although a higher dose (50 microg) did. Intravenous administration of DL-propranolol (5 or 50 microg) significantly attenuated the stress-induced tachycardia (drug-induced reduction of tachycardia at 5 min after the start of stress: 20.0 +/- 7.5% for 5 microg, 42.4 +/- 3.4% for 50 microg). However, the attenuation was much smaller than in the i.c.v. DL-propranolol-injected group. The i.c.v. injection of the 50 microg dose of DL-propranolol significantly augmented both the resting blood pressure and the pressor response to water immersion stress, whereas the lower dose (5 microg) had no effect. The i.c.v. injection of 50 microg D-propranolol also augmented, although not significantly, the resting blood pressure and the pressor response to stress. These results suggest that central beta-adrenoceptors are involved in the tachycardia induced by water immersion stress in rats.     

Renal and cardiovascular responses to water immersion in trained runners and swimmers

The purpose of this study was to determine if fluid-electrolyte, renal, hormonal, and cardiovascular responses during and after multi-hour water immersion were associated with aerobic training. Additionally, we compared these responses in those who trained in a hypogravic versus a 1-g environment. Seventeen men comprised three similarly aged groups: six long-distance runners, five competitive swimmers, and six untrained control subjects. Each subject underwent 5 h of immersion in water [mean (SE)] 36.0 (0.5)°C to the neck. Immediately before and at each hour of immersion, blood and urine samples were collected and analyzed for sodium (Na), potassium, osmolality, and creatinine (Cr). Plasma antidiuretic hormone and aldosterone were also measured. Hematocrits were used to calculate relative changes in plasma volume (%V _pl). Heart rate response to submaximal cycle ergometer exercise (35% peak oxygen uptake) was measured before and after water immersion. Water immersion induced significant increases in urine flow, Na clearance (C _Na), and a 3–5% decrease in V _pl. Urine flow during immersion was greater (P < 0.05) in runners [2.4 (0.4) ml · min^–1] compared to controls [1.3 (0.1) ml · min ^–1]. However, %A V _pl, C _Cr, C _Na and during immersion were not different (P > 0.05) between runners, swimmers, and controls. After 5 h of immersion, there was an increase (P < 0.05) in submaximal exercise heart rate of 9 (3) and 10 (3) beats · min^–1 in both runners and controls, respectively, but no change (P > 0.05) was observed in swimmers. Since swimmers did not experience elevated exercise tachycardia following water immersion compared to runners and sedentary controls, we conclude that exercise training in a hypogravic environment attenuates the acute cardiovascular adaption to microgravity. This effect of hypogravic aerobic training was not associated with the degree of hypovolemia and associated diuresis and natriuresis.     

Ageing reduces sympatho-suppressive response to head-out water immersion in humans

Muscle sympathetic nerve activity (MSNA) is suppressed during thermoneutral head-out water immersion (HOI) in humans. In this study, the effects of ageing on the suppressive response of MSNA to HOI were determined. MSNA was recorded microneurographically from the tibial nerve in 16 healthy men, 10 of whom were aged 19–30 years (young group) and six aged 45–67 years (older group). MSNA was suppressed in all the subjects during HOI. The suppressive response was significantly less prominent in the older group than in the young group. A significant negative correlation between age and the suppressive response of MSNA induced by HOI (r=-0.53, P<0.05) was found. We conclude that suppressive response of sympathetic nerve activity to HOI is reduced with age.     

Lung volume changes in response to altered breathing gas pressure during upright immersion

Summary Since elastic and flow-resistive respiratory work are volume dependent, changes in lung volume during immersion affect respiratory effort. This investigation examined changes in lung volume with air delivery pressure modifications during upright immersion. Static pressure-volume relaxation relationships and lung volumes were obtained from ten immersed subjects breathing air at four delivery pressures: mouth pressure, lung centroid pressure (P _LC), and 0.98 kPa above and belowP _LC. TheP _LC is the static lung pressure which returns the respiratory relaxation volume (V _R) to normal and was previously determined to be + 1.33 kPa relative to pressure at the sternal notch. Lung volume changes observed when breathing air at mouth pressure were reversed when air was supplied atP _LC. The expiratory reserve volume (ERV) and VR were reduced by 58% and 87%, respectively, during uncompensated immersion. These differences indicated an active defence of ERV and implied that additional static respiratory work was required to overcome transrespiratory pressure gradients.     

The effect of graded immersion on heart volume,central venous pressure,pulmonary blood distribution,and heart rate in man

The present experiments have been conducted to study the immediate effects of graded immersion on the central circulation. When taking heart volume as an indicator, it was found that immersion to the diaphragm of a standing subject produces the same changes as assumption of the supine posture. Heart volume increases by approximately 130ml. When the water level is raised to the neck, an extra pressure corresponding to a water column extending from the diaphragm to the surface of the water of approximately 25 cm H₂O forces blood into the thorax. The heart becomes distended by an additional 120ml. Correspondingly the central venous pressure at the height of the right atrium increases from 2.5 to 12.8 mm Hg when the water level rises from the diaphragm to the neck. The greater filling of the pulmonary circulation is accompanied by a decrease in vital capacity and visualized by scintigrams. The preferential increase in blood volume of the apical regions is striking. When raising the water level from the symphysis to the xiphoid heart rate falls by about 15%.     

Role of neural pathways in renin response to intravascular volume expansion

This study was designed to evaluate the physiological importance of cardiopulmonary receptors with vagal afferents in controlling renin release during perturbations in blood volume. Intravascular volume of chloralose-anesthetized dogs was expanded by 7.5 ml/kg body wt, with an isotonic isoncotic solution containing 3% dextran for colloid. Volume expansion resulted in a 50% decline in renin secretion. However, volume expansion after bilateral cervical vagotomy, the proposed afferent limb of the reflex, also suppressed renin release. In another group of animals, the left kidney was surgically denervated and the right kidney extirpated, and again infusion suppressed resin release. In all groups, the infusion significantly suppressed renin release when compared to each dog's own control period, as well as when compared to the corresponding time controls. Our data indicate that the renin response to intravascular volume expansion was not mediated solely by the vagi or renal nerves. A combination of intrarenal factors may, however, have been responsible for the suppression of renin release observed. Our results do not support the hypothesis that the renin-angiotensin system is an efferent limb of the cardiopulmonary reflex during adjustments to alterations in blood volume.     

Age-related heart rate response to exercise in heart transplant recipients. Functional significance

The heart rate (HR) and O(2) uptake (VO(2)) responses to cycle ergometer exercise and the role of O(2) transport in limiting submaximal and maximal aerobic performance were assessed in 33 heart transplant recipients (HTR) [14 children (P-HTR), 11 young adults (YA-HTR) and 8 middle-age adults (A-HTR)] and in 28 age-matched control subjects (CTL). In 7 P-HTR ("responders") the HR response to the onset of exercise (on-response) was as fast as that of CTL, whereas in all other patients ("non-responders") the HR on-response was typical of the denervated heart. Compared with non-responder P-HTR, responder P-HTR were also characterized by a normal peak HR (177+/- 16 vs. 151+/- 25 beats/min), an equally slow time constant for the VO(2) on-response (tau: 54 +/- 11 vs. 62+/- 13 s) and a similar low (approximately 60% of that of CTL) peak VO(2) (28 +/- 7 vs. 26 +/- 10 ml/kg per min). On the other hand non-responder YA-HTR and A-HTR were characterized by a relatively low peak HR (151 +/- 21 and 144 +/- 29 beats/min, respectively), a slow tau for the on-response (63 +/- 12 and 70 +/- 11 s) and a low peak (28 +/- 7 and 19 +/- 6 ml/kg per min). In conclusion, a sizeable number of paediatric patients (responder P-HTR) may reacquire the normal HR response to exercise, both in terms of kinetics and maximal level. Despite the almost complete recovery of cardiovascular function, and, probably, oxygen delivery, both the kinetics of the VO(2) on-response and the maximal aerobic power of the responder P-HTR were similar to those of non-responder P-HTR. The latter finding is probably attributable to peripheral limitations, due to inborn and/or pharmacological muscle deterioration.     

The heart rate response to exercise and circulating catecholamines in heart transplant recipients

The plasma concentration of noradrenaline ([NA]) is higher than that of adrenaline ([A]) both in normal subjects and in heart transplant recipients (HTR). Since in both groups the myocardial density of beta1-adrenergenic receptors is much greater than that of beta2-adrenergenic receptors, the chronotropic response of a denervated heart to changes in plasma [NA] and [A] in the absence of reinnervation should be similar to that of agonist stimulation of beta1-receptors. To test this hypothesis, 17 HTR and 9 healthy subjects (CTL) performed incremental exercise on a cycle ergometer to voluntary exhaustion. Heart rate (HR) was recorded by electrocardiography. [NA] and [A] were measured by high-pressure liquid chromatography at rest and at increasing workloads (w). In both groups, HR and [NA+A] increased with w, and HR with [NA+A]. Normalized HR values, plotted against the logarithm of [NA+A], fitted significantly logistic curves. The affinity constants were different, i.e. 2599+/-350 and 487+/-37 ng.l(-1), for HTR and CTL, respectively. The chronotropic effect of changes in [NA+A] in HTR was similar to that of combined beta1- and beta2-adrenergic activation evoked by applying isoprenaline to isolated heart myocytes (Brodde OE, Pharmacol Ther 60:405-430, 1993). These findings suggest that over time sympathetic reinnervation and the modulation of beta-receptors may take place in HTR, ruling out the hypothesis of persistent heart denervation.     

Isolation and expansion of thymus-derived regulatory T cells for use in pediatric heart transplant patients

Regulatory T-cells (Tregs) are a subset of T cells generated in the thymus with intrinsic immunosuppressive properties. Phase I clinical trials have shown safety and feasibility of Treg infusion to promote immune tolerance and new studies are ongoing to evaluate their efficacy. During heart transplantation, thymic tissue is routinely discarded providing an attractive source of Tregs. In this study, we developed a GMP-compatible protocol for expanding sorted thymus-derived CD3⁺CD4⁺CD25⁺CD127^– (Tregs) as well as CD3⁺CD4⁺CD25⁺CD127^–CD45RA⁺ (RA⁺Tregs) cells. We aimed to understand whether thymic RA⁺Tregs can be isolated and expanded offering an advantage in terms of stability as it has been previously shown for circulating adult CD45RA⁺ Tregs. We show that both Tregs and RA⁺Tregs could be expanded in large numbers and the presence of rapamycin is essential to inhibit the growth of IFN-γ producing cells. High levels of FOXP3, CTLA4, and CD25 expression, demethylation of the FOXP3 promoter, and high suppressive ability were found with no differences between Tregs and RA⁺Tregs. After freezing and thawing, all Treg preparations maintained their suppressive ability, stability, as well as CD25 and FOXP3 expression. The number of thymic Tregs that could be isolated with our protocol, their fold expansion, and functional characteristics allow the clinical application of this cell population to promote tolerance in pediatric heart transplant patients.     

Arginine vasopressin excretion in response to volume expansion in the healthy human,and in patients with glomerulonephritis

The urinary excretion of arginine vasopressin (AVP) was studied during volume expansion (VE) in nine healthy normotensive individuals and 14 patients with active IgA glomerulonephritis (GN). The studies were started after 17–18 h of food and fluid deprivation (hydropenia, HP) and VE was induced by a continuous infusion of Ringer solution up to an amount corresponding to 3% of the body weight. The clearance of inulin and PAH, urine osmolality and urinary excretion of sodium and AVP were determined. The AVP excretion decreased in response to VE in the healthy individuals, both when related to GFR (from 129+ 17 pg min ‘ 100 ml ’ GFR during HP to 65 ± 9 after 3% VE, P < 0.01)andtobody surface area (BSA) (from 134 ± 22 pg min“¹ 1.73 m^-2 BSA to 75 ±11, P < 0.05). In the patients with IgA GN, who had normal blood pressure and normal GFR, the AVP excretion tended to decrease, but the change was not significant (0.05 < P < 0. 1). The patients with hypertension but essentially normal GFR, and those with hypertension and markedly decreased GFR did not change their renal excretion of AVP in response to VE. If related to the GFR, the latter patients had a markedly increased AVP excretion.     

Hormonal and renal response to plasma volume expansion in the primate Macaca mulatta

The purpose of this study was to investigate the hormonal and renal response to plasma volume expansion in the ketamine-anesthetized rhesus monkey. The blood volume was determined in nine animals and found to be 6% of the body weight. Six monkeys received isoncotic isotonic fluid amounting to 25% of the blood volume. Plasma volume expansion led to significant decrease in the plasma concentrations of antidiuretic hormone (46.7%) and aldosterone (78.4%) as well as plasma renin activity (50.0%). The mean arterial pressure, plasma osmolality, and plasma concentrations of Na+ and K+ were unaffected by plasma volume expansion. However, renal plasma flow, glomerular filtration rate, the excretion of Na+ and K+, and urine flow increased. It was concluded that, in the ketamine-anesthetized rhesus monkey, circulating hormones contribute to blood volume homeostasis presumably through a neural mechanism similar to that observed in dogs and humans.