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Aims: Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study. Methods and results: From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m2 and urinary albumin‐to‐creatinine ratio (UACR) ≥30 to <3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose–response relationship. There were possible dose‐dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non‐significant trends towards reduced N‐terminal pro‐B‐type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo. Conclusion: While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo. [ABSTRACT FROM AUTHOR]

Angiotensin II attenuates the natriuresis of water immersion in humans. Am J Physiol Regulatory Integrative Comp Physiol 283: R187-R196, 2002. First,published March 22, 2002; 10.1152/ajpregu.00536. 2001.--The hypothesis was tested that suppression of generation of ANG II is one of the mechanisms of the water immersion (WI)-induced natriuresis in humans. In one protocol, eight healthy young males were subjected to 3 h of 1) WI (WI + placebo), 2) WI combined with ANG II infusion of 0.5 ng*[kg.sup.-1]*[min.sup.-1] (WI + ANG II-low), and 3) a seated time control (Con). In another almost identical protocol, 7-10 healthy young males were investigated to delineate the tubular site(s) of action of ANG II by the lithium clearance method ([C.sub.Li]) and were on an additional fourth study day subjected to infusion of ANG II at a rate of 1.5 ng*[kg.sup-1]*[min.sup.-1] (WI + ANG II-high). During WI + placebo, plasma concentration of ANG II decreased from 16 [+ or -] 2 to 8 [+ or -] 1 pg/ml (P < 0.05) and renal sodium excretion increased from 104 [+ or -] 15 to 294 [+ or -] 27 [micro]mol/ rain (P < 0.05). During WI + ANG II-low, plasma ANG II was not suppressed by WI, and the natriuresis was blunted by 52 [+ or -] 13% (P < 0.05). During WI + ANG II-low and WI + ANG II-high, an increase in [C.sub.Li] was prevented that was otherwise observed during WI, and fractional distal reabsorption of sodium was facilitated. In conclusion, maintaining plasma concentration of ANG II unchanged at the level of control attenuates the natriuresis of WI considerably in humans. Therefore, suppression of generation of ANG II is an important mechanism of the natriuresis of Wi in humans. Furthermore, infusion of ANG II during WI prevents an otherwise induced increase in [C.sub.Li] and facilitates the fractional distal reabsorption of sodium, probably via an effect on aldosterone release. sodium excretion; tubular function

The hypothesis that the carotid baroreceptor stimulation caused by a posture change from upright seated with legs horizontal (Seat) to supine (Sup) participates in the suppression of arginine vasopressin (AVP) release was investigated. Findings showed that vasopressin secretion is suppressed during an antiorthostatic posture change, which increases carotid sinus pressure, arterial pulse pressure (PP) and left arterial diameter (LAD). The suppression is absent when PP and LAD are prevented from increasing.

Abstract Background Sex comparisons between girls and boys in response to exercise in trained adolescents are missing and we investigated similarities and differences as a basis for clinical interpretation and guidance. Methods A total of 24 adolescent females and 27 adolescent males aged 13–19 years underwent a maximal bicycle exercise stress test with measurement of cardiovascular variables, cardiac output, lung volumes, metabolic factors/lactate concentrations and breath-by-breath monitoring of ventilation, and determination of peak VO2. Results Maximum heart rate was similar in females (191 ± 9 bpm) and males (194 ± 7 bpm), cardiac index at maximum exercise was lower in females (7.0 ± 1.0 l/min/m2) than in males (8.3 ± 1.4 l/min/m2, P 2 was lower in females (2.37 ± 0.34 l/min) than in males (3.38 ± 0.49 l/min, P 2 was normalized to leg muscle mass sex differences disappeared (females: 161 ± 21 ml/min/kg vs. males: 170 ± 23 ml/min/kg). The increase in cardiac index during exercise is the key factor responsible for the greater peak VO2 in adolescent boys compared to girls. Conclusions Differences in peak VO2 in adolescent boys and girls disappear when peak VO2 is normalized to estimated leg muscle mass and therefore provide a tool to conduct individual and intersex comparisons of fitness when evaluating adolescent athletes in aerobic sports.

Abstract Background Gene expression microarrays and real-time PCR are common methods used to measure mRNA levels. Each method has a fundamentally different approach of normalization between samples. Relative quantification of gene expression using real-time PCR is often done using the 2^(-ΔΔCt) method, in which the normalization is performed using one or more endogenous control genes. The choice of endogenous control gene is often arbitrary or bound by tradition. We here present an analysis of the differences in expression results obtained with microarray and real-time PCR, dependent on different choices of endogenous control genes. Results In complex tissue, microarray data and real-time PCR data show the best correlation when endogenous control genes are omitted and the normalization is done relative to total RNA mass, as measured before reverse transcription. Conclusion We have found that for real-time PCR in heterogeneous tissue samples, it may be a better choice to normalize real-time PCR Ct values to the carefully measured mass of total RNA than to use endogenous control genes. We base this conclusion on the fact that total RNA mass normalization of real-time PCR data shows better correlation to microarray data. Because microarray data use a different normalization approach based on a larger part of the transcriptome, we conclude that omitting endogenous control genes will give measurements more in accordance with actual concentrations.

During an antiorthostatic posture change, left atrial (LA) diameter and arterial pulse pressure (PP) increase, and plasma arginine vasopressin (AVP) is suppressed. By comparing the effects of a 15-min posture change from seated to supine with those of 15-min seated negative pressure breathing in eight healthy males, we tested the hypothesis that with similar increases in LA diameter, suppression of AVP release is dependent on the degree of increase in PP. LA diameter increased similarly during the posture change and negative pressure breathing (-9 to -24 mmHg) from between 30 and 31 [+ or -] 1 to 34 [+ or -] 1 mm (P < 0.05). The increase in PP from 38 [+ or -] 2 to 44 [+ or -] 2 mmHg (P < 0.05) was sustained during the posture change but only increased during the initial 5 min of negative pressure breathing from 36 [+ or -] 3 to 42 [+ or -] 3 mmHg (P [is less than] 0.05). Aortic transmural pressure decreased during the posture change and increased during negative pressure breathing. Plasma AVP was suppressed to a lower value during the posture change (from 1.5 [+ or -] 0.3 to 1.2 [+ or -] 0.2 pg/ml, P [is less than] 0.05) than during negative pressure breathing (from 1.5 [+ or -] 0.3 to 1.4 [+ or -] 0.3 pg/ml). Plasma norepinephrine was decreased similarly during the posture change and negative pressure breathing compared with seated control. In conclusion, the results are in compliance with the hypothesis that during maneuvers with similar cardiac distension, suppression of AVP release is dependent on the increase in PP and, furthermore, probably unaffected by static aortic baroreceptor stimulation. antidiuretic hormone; baroreceptors; blood pressure; sympathetic nervous system

During prolonged, static carotid baroreceptor stimulation by neck suction (NS) in seated humans, heart rate (HR) decreases acutely and thereafter gradually increases. This increase has been explained by carotid baroreceptor adaptation and/or buffering by aortic reflexes. During a posture change from seated to supine (Sup) with similar carotid stimulation, however, the decrease in HR is sustained. To investigate whether this discrepancy is caused by changes in central blood volume, we compared (n = 10 subjects) the effects of 10 min of seated NS (adjusted to simulate carotid stimulation of a posture change), a posture change from seated to Sup, and the same posture change with left atrial (LA) diameter maintained unchanged by lower body negative pressure (Sup + LBNP). During Sup, the prompt decreases in HR and mean arterial pressure (MAP) were sustained. HR decreased similarly within 30 s of NS (65 [+ or -] 2 to 59 [+ or -] 2 beats/min) and Sup + LBNP (65 [+ or -] 2 to 58 [+ or -] 2 beats/min) and thereafter gradually increased to values of seated. MAP decreased similarly within 5 min during Sup + LBNP and NS (by 7 [+ or -] 1 to 9 [+ or -] 1 mmHg) and thereafter tended to increase toward values of seated subjects. Arterial pulse pressure was increased the most by Sup, less so by Sup + LBNP, and was unchanged by NS. LA diameter was only increased by Sup. In conclusion, static carotid baroreceptor stimulation per se causes the acute ([is less than] 30 s) decrease in HR during a posture change from seated to Sup, whereas the central volume expansion (increased LA diameter and/or arterial pulse pressure) is pivotal to sustain this decrease. Thus the effects of central volume expansion override adaptation of the carotid baroreceptors and/or buffering of aortic reflexes. antidiuretic hormone; baroreceptors; blood pressure; lower body negative pressure; neck suction

To examine if the neuroendocrine link between volume sensing and renal function is preserved in compensated chronic heart failure [HF, ejection fraction 0.29 [+ or -] 0.03 (mean [+ or -] 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 [is less than] 0.05 for all) compared with seated control. Compared with control subjects (n = 9), ANG II, Aldo, and ANP concentrations were increased (P [is less than] 0.05) in HF, whereas absolute and fractional sodium excretion rates were attenuated [47 [+ or -] 16 vs. 88 [+ or -] 15 [micro]mol/min and 0.42 [+ or -] 0.18 vs. 0.68 [+ or -] 0.12% (mean [+ or -] SE), respectively, both P [is less than] 0.05]. When ANG II and Aldo concentrations were further suppressed (P [is less than] 0.05) during WI in HF (by sustained angiotensin-converting enzyme inhibitor therapy, n = 9) absolute and fractional sodium excretion increased (P [is less than] 0.05) to the level of control subjects (108 [+ or -] 34 [micro]mol/min and 0.70 [+ or -] 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. renin-angiotensin system; aldosterone; vasopressin; waterelectrolyte balance

We hypothesized that the more-pronounced hypotensive and bradycardic effects of an antiorthostatic posture change from seated to supine than water immersion are caused by hydrostatic carotid baroreceptor stimulation. Ten seated healthy males underwent five interventions of 15-min each of 1) posture change to supine, 2) seated water immersion to the Xiphoid process (WI), 3) seated neck suction (NS), 4) WI with simultaneous neck suction (-22 mmHg) adjusted to simulate the carotid hydrostatic pressure increase during supine (WI + NS), and 5) seated control. Left atrial diameter increased similarly during supine, WI + NS, and WI and was unchanged during control and NS. Mean arterial pressure (MAP) decreased the most during supine (7 [+ or -] 1 mmHg, P [is less than] 0.05) and less during WI + NS (4 [+ or -] 1 mmHg) and NS (3 [+ or -] 1 mmHg). The decrease in heart rate (HR) by 13 [+ or -] 1 beats/min (P [is less than] 0.05) and the increase in arterial pulse pressure (PP) by 17 [+ or -] 4 mmHg (P [is less than] 0.05) during supine was more pronounced (P [is less than] 0.05) than during WI + NS (10 [+ or -] 2 beats/min and 7 [+ or -] 2 mmHg, respectively) and WI (8 [+ or -] 2 beats/min and 6 [+ or -] 1 mmHg, respectively, P [is less than] 0.05). Plasma vasopressin decreased only during supine and WI, and plasma norepinephtine, in addition, decreased during WI + NS (P [is less than] 0.05). In conclusion, WI + NS is not sufficient to decrease MAP and HR to a similar extent as a 15-min seated to supine posture change. We suggest that not only static carotid baroreceptor stimulation but also the increase in PP combined with low-pressure receptor stimulation is a possible mechanism for the more-pronounced decrease in MAP and HR during the posture change. antidiuretic hormone; blood pressure; lower body negative pressure