BACKGROUND:The circulation of 4-6 m tall giraffes is markedly affected by gravity. To ensure cerebral perfusion, upright giraffes generate a blood pressure in excess of 200 mmHg. Before drinking, the head is lowered by 3-5 m, providing exceptional hemodynamic challenges. Here, we provide quantitative hemodynamic measures during head movement and drinking. METHODS:We measured carotid pressure, jugular pressure, heart rate, and blood flow in awake giraffes, along with circulating blood volume and cerebrospinal fluid pressure in anesthetized giraffes. We also analyzed the contractility and innervation of isolated cerebral and extracranial arteries, and the mechanical properties of jugular veins. RESULTS:When heads were lowered for drinking (i) blood pressure at heart level decreased but increased again during drinking, (ii) jugular pressure increased and oscillated during drinking, (iii) heart rate fell, (iv) carotid blood flow was unchanged, while cephalic hemodynamic resistance increased, and (vi) cranial cerebrospinal fluid pressure increased. Small cerebral arteries exhibited strong myogenic responses, particularly at around 100 mmHg, while extracranial arteries responded at higher pressures (200-250 mmHg). The giraffe's blood volume was small and blood pressure sensitive to minor reductions in blood volume. CONCLUSIONS:Central blood pressure decreased when the head was lowered, but drinking per se caused a surprising rise in blood pressure to pre-drinking levels. This rise in blood pressure is likely due to the transfer of esophageal water boli acting on the jugular veins. The cephalic capillaries are protected by a strong myogenic response and sympathetic innervation.

Hormones are specific molecules measured in biological fluids by elaborate analytical systems requiring meticulous attention. Variation between laboratories can be expected. However, recently published measurements of AVP, OXT, and BNP in human plasma under basal/control conditions include numbers which, between publications, vary by 100-10 000-fold. Generally, the methods descriptions are scant, at best, and provide no information about quality control measures. Clearly, two results describing the same basal hormone concentration by numbers three orders of magnitude apart are incongruent providing reason for concern. Basal concentrations of bioactive AVP, OXT, and BNP in human plasma are in the order of 1-10 pmol/L. Therefore, assay systems applied to plasma must be able to measure concentrations of less than 1 pmol/L with appropriate specificity and accuracy. Basal concentrations of AVP, OXT, and BNP above 100 pmol/L should be reconsidered, as such results do not reflect bioactive hormone levels in humans, rats, or mice. Any concentration above 1000 pmol/L is of concern because such levels of bioactive hormone may be seen only under extreme conditions, if at all.

A follow-up to a recent discussion of urinary acidity focused on Stewarts's theory of 'strong ion difference' (SID). The comments of Vasileiadis et al. warrant a reevaluation of Stewart's approach. Here, it will be discussed (i) that the SID is unlikely to be an independent variable as claimed by Stewart, (ii) that the calculation of [H+ ] based on SID described by Stewart is hardly doable, even in simple electrolyte solutions, (iii) that human metabolism provides an ongoing acid-base disturbance as an independent variable (normally excess H+ accompanied by chloride), (iv) that specific renal regulatory mechanisms indispensable to Stewart's concept, remain unknown, and (v) that studies of biological transmembrane cation transport have progressed to a level making serious opposition to the concept of active transport of H+ meaningless.

Incongruence between new ideas and current concepts fuels scientific progress. Within acid-base physiology, an—apparently new—idea of a ‘strong ion difference’ in plasma (SID) was introduced by Stewart some 40 years ago.1-3 SID is ‘the sum of all strong base cation concentrations minus the sum of all strong acid anion concentrations’,2 in clinical practice often ([Na+] + [K+] − [Cl−]) in mmol/l. Subsequently, the concept was extended to renal function, and recently this was the focus of an editorial in the journal,4 henceforth the editorial. The arguments in the editorial are difficult to follow mainly because (a) they seem to violate the fundamental principle of electroneutrality, (b) they question the mere existence of transmembrane transport of protons and bicarbonate ions and (c) they include peculiar cause-effect relationships for which there are little documentation in the literature. These issues will be discussed below, and—as this is difficult without reference to their background—the ideas of Stewart will be commented. The discussion includes numerical examples taken from a quantitative overview (Figure 1) of essential cause-and-effect relationships representative of a normal person on a typical (H+ generating) Western diet. The editorial describes a hypothetical clinical situation as Acute metabolic acidosis caused by an anionic electrical load in the patient's extracellular fluid […], reducing SIDECF, where SIDECF is the SID of the extracellular fluid. In addition, it is claimed that Renal compensation occurs with the excretion of strong anions… The impression of a deliberate deviation from the electroneutrality principle is augmented when the editorial (a) cites the literature to suggest that a change in the net electrical charge in extracellular space can be restored by a corresponding change in the net electrical charge in urine, taking into account the volume of body fluid where this change takes place and the rate of urinary excretion, and (b) includes an illustration in which the urinary space is provided with dissimilar numbers of cations and anions. This approach is misleading. In any (macroscopic) compartment, the so-called ‘weak’ ions always make up for (differences between) ‘strong’ ions. This is the very essence of the electroneutrality principle which is an unconditional constraint of any analysis of body fluid composition (notably this was correctly emphasized by Stewart1-3). Remarkably, other arguments of the editorial seem to include the electroneutrality principle as a precondition adding to the inconsistencies. The use of a Riemann-Stieltjes integral to address changes over time in the SID concentration of the extracellular compartment only adds to the confusion. The background for the application of this special approach is absent, and the notation does not seem consistent with the formal requirements for such integrals. The editorial claims without arguments that the movement of H+/HCO3− in the aquatic environment of various compartments in the body cannot change their concentration; in fact, it does not really exist. The precise nature of the molecular structure symbolized by H+ is open for discussion. Stewart (2009) described the form {H:(H2O)n}+ as more correct but fortunately settled for the conventional, practical term H+. Clearly, H+, bicarbonate ions and carbonic acid exist as molecular clusters in interactive relationships which occasionally deviate significantly from chemical equilibria depending on time and organ. At the molecular level, transmembrane transport of the carbon atom may take place as diffusion of carbon dioxide. However, the editorial does not provide any argument supporting the notion that the use the simplified, practical symbols for more complex molecular phenomena undermines the reality of energy-dependent, pump-mediated separation of molecular complexes labelled ‘H+’ and ‘bicarbonate ion’. For instance, that the gastric epithelium can generate luminal H+ concentrations a million times higher than that of plasma concomitant with delivery of commensurate amounts of bicarbonate to the blood side. In order to survive, new ideas must simplify complex concepts or explain their complexity. The editorial does neither. The editorial includes cause-effect relationships which are undocumented and seem unrealistic. It is postulated that, according to Stewart, it is the SID concentration which determines the [H+] in body fluids. As discussed below, the reference to Stewart is correct, but the concept is wrong leading to awkward conclusions, also in the present editorial, for example, that Urine acidity change is accomplished by an increase of [Cl−], urinary or of any strong anion concentration, that is not accompanied by a similar increase of urine [Na+], leading to a decrease of [SID]u. The concentration of chloride ions does not cause renal [H+] excretion. This quote is another example of a correct mathematical relation turned into an inappropriate cause-and-effect relationship. In the figure, a representative person is set to generate 15 moles/day of CO2 and 60 millimoles/day of H+ to be exhaled/excreted by appropriate lung and kidney functions, respectively, at arterial plasma H+ concentrations close to 40 nmol/L. Notably, of the 60 000 µmol of H+ generated daily by the metabolism and excreted by the kidney, only some 0.8 µmol are excreted as H+. The excretion of H+ as such is infinitesimal, but essential as its concentration sets the equilibria of the buffer systems. The primary threats to a steady state are changes in the rates at which CO2 and H+ (or OH−) are supplied to the extracellular fluid by the metabolism. From the figure it can be seen that in case the drain of H+ (by metabolism of ingested organic anions (R-COO−)) exceeds the source of H+ (non-metabolizable acids), the net supply of H+ becomes negative, that is, becomes a net supply of OH−. In this case, appropriate regulatory processes cause the kidney to adjust urinary pH and ion excretion rates accordingly. Said metabolic changes are typical of some vegetarian diets. In general, oxidation of protein is a source of [H+] and oxidation of organic anions, including anionic amino acids, removes [H+] 5 meaning that the daily load of H+ (positive, zero or negative) is determined by the metabolism of nutrients absorbed by the gut. When ‘body’ is the system under consideration, the rate of H+ supply is an independent variable determined by the composition of the diet (and appropriate conditions for aerobic metabolism). The title of the editorial is ‘Strong ion difference in urine: A measure of renal proton excretion or of the net plasma charge alteration?’. As to the first question: Normally, renal proton excretion rate is not properly quantified by urinary SID mainly because the significant effect of buffering by phosphates is neglected. In the example in the figure, the excretion of the 60 mmol/d of H+ is split between ammonia and phosphate buffering (58% to ammonia/ammonium ion and 42% to dihydrogen/hydrogen phosphate). The immediate answer to the question is ‘no’. However, these percentages may change dramatically during chronic metabolic acidosis, and under such conditions the use of SID as a measure of ammonium ion/proton excretion might be appropriate—with due respect to the underlying assumptions. The results of several clinical studies do not seem to support a more generalized use of the concept.6, 7 The answer to the second question about ‘net plasma charge’ is also ‘no’. A ‘net plasma charge’ does not exist, therefore, there is no alteration (see above: Electroneutrality). Referring mainly to a few standard textbooks of physical chemistry and with remarkably limited reference to contemporary physiological or clinical literature, Stewart presented what he considered a radical, novel approach to biological acid-base chemistry.1-3 Radical it was. In this, the SID (as defined above) was an essential concept assumed to be an independent variable determining the [H+] in body fluids. Values of independent variables were considered to be imposed on a system from outside.3 In a biological context, it is a fundamental flaw that the SID is not a regulated variable and therefore may change for reasons other than acid-base deviations without consequences for acid-base control. The essence of physiological regulation is feedback systems driven by fluctuations in regulated variables. Stewart's arguments may seem internally consistent, but they lead to staggering inferences such as Hydrogen ion movements between solutions can not affect hydrogen ion concentration; only changes in independent variables can, the conventional treatment of the urine as a vehicle for removing H+ from the body is incorrect and Synthesizing NH3 and excreting it as NH4+ can have no effect on plasma [H+] as well as an explicit rejection of the concept that the gastric epithelium moves H+ into the lumen.3 The promotion of the SID to the position of an important, independent variable of body fluid control is wrong, mainly because it is a variable without a sensor and leads to untenable conclusions. Two additional other comments are warranted. Firstly, at the time, the SID was not a new idea; it is identical to the term buffer base (BB+) suggested decades earlier by Singer and Hastings8 as part of analytical considerations subsequently leading to the current concept of base excess (cf.9). Secondly, Stewart's approach has weird clinical implications, for example, in case plasma protein concentration is not included into the clinical assessment, marked hyperalbuminaemia leads to the diagnosis of metabolic alkalosis even at normal pH, PCO2 and extracellular base excess. For details and examples, see the discussion of Siggaard-Andersen.9 Any specific result (or a sum of results) of plasma and urine analyses may be clinically attractive if it effectively separates the sick from the healthy, narrows the diagnostic possibilities and grades the degree of sickness when present. Therefore, measurement of SID might well be clinically useful under well-defined, specific conditions. However, the association between SID and acid-base metabolism presented by the editorial appears indirect, inconsistent—internally as well as with sound scientific principles—and misleading. The underlying concepts are awkward and incongruent with a rational approach to health and disease. The not-so-new idea of a SID generally applicable to acid-base physiology has not passed the test of time. The authors declare no conflict of interest.

BACKGROUND The mechanisms by which hypertension accelerates coronary artery disease are poorly understood. Patients with hypertension often have confounding humoral changes, and to date, no experimental models have allowed analysis of the isolated effect of pressure on atherosclerosis in a setting that recapitulates the dimensions and biomechanics of human coronary arteries. OBJECTIVES This study sought to analyze the effect of pressure on coronary atherosclerosis and explore the underlying mechanisms. METHODS Using inflatable suprarenal aortic cuffs, we increased mean arterial pressure by >30 mm Hg in the cephalad body part of wild-type and hypercholesterolemic proprotein convertase subtilisin kexin type 9 (PCSK9)(D374Y) Yucatan minipigs for >1 year. Caudal pressures remained normal. RESULTS Under hypercholesterolemic conditions in PCSK9(D374Y) transgenic minipigs, cephalad hypertension accelerated coronary atherosclerosis to almost 5-fold with consistent development of fibroatheromas that were sufficiently large to cause stenosis on computed tomography angiography. This was caused by local pressure forces, because vascular beds shielded from hypertension, but exposed to the same humoral factors, showed no changes in lesion formation. The same experiment was conducted under normocholesterolemic conditions in wild-type minipigs to examine the underlying mechanisms. Hypertension produced clear changes in the arterial proteome with increased abundance of mechanical strength proteins and reduced levels of infiltrating plasma macromolecules. This was paralleled by increased smooth muscle cells and increased intimal accumulation of low-density lipoproteins in the coronary arteries. CONCLUSIONS Increased pressure per se facilitates coronary atherosclerosis. Our data indicate that restructuring of the artery to match increased tensile forces in hypertension alters the passage of macromolecules and leads to increased intimal accumulation of low-density lipoproteins. (C) 2021 by the American College of Cardiology Foundation.

Replicability of experimental results and optimal use of experimental animals are everybody's concern. Current efforts towards increased replicability include guidelines and checklists as tools for experimenters, referees, editors and publishers. Guidelines are also provided for appropriate use of animals. To ensure the quality of experimental results, the number of animals must be adequate, that is, sufficiently large, for the purpose of the given experiment. To comply with current ethical recommendations, the use of animals should be reduced as much as possible. Therefore, determination of the number of animals for a given scientific objective includes contrasting considerations. Current guidelines for animal experimentation, notably from the National Institute of Health, mandate (with very few exceptions) inclusion of animals of both sexes in experimental designs statistically powered to address the difference between the two groups. Notably, absence of evidence for sex differences between the organ or system functions under study does not qualify as an exception. Mandatory, equal representation of both sexes raises several questions including ethical ones. Other guidelines, by public regulators and major publishers, do not seem to have a similar selective focus on sex differences. In summary, current concerns about replicability of scientific results are justified. Concomitantly, the knowledge of sex differences also between non-reproductive, non-endocrine organ functions is increasing. In principle, sex matters in any experimental context. However, an indiscriminate demand for inclusion of both sexes in all experimental protocols seems a waste of animals, money and time, violating traditional principles of animal experimentation, particularly that of reduction.

Autoregulation of cerebral blood flow (CBF) denotes that CBF is constant despite fluctuation of blood pressure within wide limits. Inhibition of the renin-angiotensin system (RAS) is known to decrease the lower and upper limits of CBF autoregulation. We have previously shown that this includes inhibition by the angiotensin receptor blocker (ARB) candesartan. In the present study we investigated the influence of the ARB candesartan on the lower limit of CBF autoregulation in two groups of Sprague-Dawley rats, on high (4.0% Na+) and low (0.004% Na+) sodium diet, respectively. Control animals were given the same diet, but no ARB. CBF was studied with the laser Doppler method. Blood pressure was lowered by controlled bleeding. Results revealed that both high and low sodium diet with low and high renin levels respectively block the influence of candesartan on CBF autoregulation. This was expected in rats on a high salt diet with a low renin level, but unexpected in rats with a low salt intake with a high renin level.

AIMS:In patients with essential hypertension, abnormal renal sodium handling includes exaggerated natriuresis in response to extracellular volume expansion. We tested the hypothesis that exaggerated natriuresis is associated with increases in medullary and/or cortical renal blood flow.METHODS:Patients with mild essential hypertension, but no signs of end organ damage, and control subjects were studied after 4 days of dietary standardization (<60 mmol Na+  day-1 ) preceded in patients by a 14-day drug washout period. On the study day, subjects received a 4-hour intravenous volume expansion with saline (2.1% of body mass). Renal medullary and cortical blood flows were measured by PET scanning using H215 O as tracer; anatomical regions of interest were defined by contrast-enhanced CT scanning.RESULTS:In patients, arterial blood pressure increased during volume expansion (107 ± 2-114 ± 3 mm Hg, P < 0.05) in contrast to the control group (92 ± 2-92 ± 2 mm Hg). Renal sodium excretion increased more in patients than in controls (+133 ± 31 µmol min-1 vs +61 ± 14 µmol min-1 , respectively, P < 0.05) confirming exaggerated natriuresis. During volume expansion, renal medullary blood flow did not change significantly in patients (2.8 ± 0.4-2.5 ± 0.5 mL (g tissue)-1  min-1 ) or in controls (3.2 ± 0.3-3.1 ± 0.2 mL (g tissue)-1 min-1 ). In control subjects, renal cortical blood flow fell during volume expansion (4.1 ± 0.3-3.7 ± 0.2 mL (g tissue)-1  min-1 , P < 0.05) in contrast to patients in which deviations remained insignificant.CONCLUSION:Exaggerated natriuresis, a hallmark of essential hypertension, is not mediated by increases in regional, renal blood flow.

The modern science of physiology began in Europe. Deciding on exactly who the first physiologist was is not easy but excellent candidates include Claude Bernard and Carl Ludwig. The Nobel Prize in Physiology or Medicine was inaugurated in 1901 with the first award mentioning the word “physiology” being made to Ivan Pavlov (Russia) in 1904. Physiology developed rapidly in the last quarter of the nineteenth and first half of the twentieth century in particular in Germany and then the United Kingdom. The success of physiology led to the development of strong, national societies in the UK and Ireland (1876), Germany (1904) and Scandinavia (1925). It has long been realized that there would be great advantages in the various national societies interacting more. Given that the population of Europe is comparable to that of the USA, there is no reason that a European physiology meeting could not be as successful as those held for many years in the USA. There have been many joint meetings between pairs of societies. The Federation of European Physiological Societies (FEPS) was founded in 1991 and stimulated the meeting of groups of societies. However, these meetings have had to compete with the meetings of the richer large national societies, and it was felt that, to be successful, a European-wide meeting would have to include the meetings of these large societies. Over the years, several attempts have been made to do this but foundered due to problems of timetabling. In September 2015, representatives of the three largest societies (German, Scandinavian and The Physiological Society), together with FEPS met in Aarhus, Denmark, to revisit this issue and agreed on a series of three Europhysiology meetings to be held in London (2018), Berlin (2020) and Copenhagen (2022). Importantly, these meetings would replace the main national meetings of all these societies in these years. They are not, however, designed to be restricted to these societies. While it was felt to be impracticable to involve all the 30 or so European national societies in the organization and finance of the initial meetings, it is important to note that the intention is that Europhysiology will provide a framework for future regular meetings of European physiologists not limited to the present organizers. The aim of the Europhysiology meetings was to bring together the broader European physiology community and promote collaboration among scientists. In the last two decades, physiology meetings have been challenged by evolving subdisciplinary and thematic meetings. In this exciting initiative, it is hoped that participation of large numbers of physiologists across Europe will enable organizers to hold specific sessions and thematic symposia to represent all aspects of physiology. In addition, specialized meetings can be held immediately before or after the main meeting as will be the case in London. The meeting promises to deliver physiology of interest to all, with a packed 3-day programme of keynote and plenary lectures, symposia and oral communication slots for each themed area. We have 4 plenary lectures to inspire, given by some of our top physiologists. Frances Ashcroft has pioneered research into the role of the ATP-sensitive potassium channel KATP in insulin secretion in both health and disease with a focus on how mutations in these genes cause human disease. Maiken Nedergaard will bring to light the importance of glial cells in the CNS and their role in neurological conditions such as motoneuron disease, stroke and epilepsy. She will talk about defining new strategies to treat these conditions by targeting astrocytic dysfunction. Peter Ratcliffe will talk about his extensive work on the mechanisms underlying how cells respond to and signal hypoxic changes. With research crossing structural biology, systems physiology, epigenetics through to translational programmes, his talk will be of interest to many. The final plenary is the Annual Review Lecture, which this year will be delivered by Professor Juleen Zierath, who is a world-renowned expert on the cellular mechanisms underlying the development of insulin resistance in type 2 diabetes. Her research incorporates use of cell-based systems, genetically modified animal models, and clinical material from type 2 diabetic patients, and she is particularly interested in the timing of exercise and interventions with respect to circadian rhythms. Our keynote speakers will cover a wide range of subjects, with talks on such research areas as redox regulation in health and disease (Katrin Schrȍder), tuning of the heartbeat through the cytoskeleton (Benjamin Prosser), the translational potential of vascular growth factors (Kari Alitalo), the physiology of temperature and pain sensation (Jan Erik Siemens) and the role of the leucine-rich repeat kinase family in neurodegenerative diseases (Patrick Lewis). We will hear “whispered secrets and public announcements” about the diversity of oxytocin signally from Mike Ludwig and learn about the “ins and outs” of protein trafficking from Robert Fenton. We are also delighted to host the Otto Hutter Teaching Prize lecture, given by Louise Robson. Our symposia were chosen to reflect the interests of the themes, ensuring excellence of science, diversity of gender and geographical representation, but especially to include early career speakers for each symposium. Some symposia cut beautifully across themes and will be of interest to many attending the meeting so we are sure that you will be spoiled for choice in where to enjoy learning about cross-discipline, cutting-edge research. There are over 100 oral communication slots and 3 poster sessions scheduled for physiologists of all career stages to showcase their research. These poster sessions, the informal welcome reception and conference dinner will then enable the important mingling and fostering of new collaborative ventures. With so many physiologists from across Europe and further afield, this is a superb opportunity for scientists at all levels of their career to consider new techniques, interactions, ideas and even careers. Since Europhysiology 2018 in London will also bring together Europe′s next generation of physiologists, the young physiologists of the partner societies are organizing their own symposium on the Thursday morning before the main meeting. The best abstracts from early career physiologists will be selected for oral presentations and compete for the Europhysiology Young Investigator Award 2018. This symposium provides an exceptional opportunity to make first contacts and establish new networks and cooperations across Europe. Likewise, senior colleagues are invited to join the session to identify potential future young group leaders bringing fresh blood into their departments and physiology. In addition, undergraduates and PhD students are encouraged to participate in the entire Europhysiology 2018 meeting at a significantly reduced registration fee. Opportunities for travel fellowships for early career members are available at the organizing partner societies and should be addressed to the respective home society. Following this Early Career meeting, on Thursday afternoon, various Special Interest Groups will hold their meetings. For more information, please visit our website: https://www.europhysiology2018.org.

The classical concepts of human sodium balance include 1) a total pool of Na+ of ≈4,200 mmol (total body sodium, TBS) distributed primarily in the extracellular fluid (ECV) and bone, 2) intake variations of 0.03 to ≈6 mmol·kg body mass-1·day-1, 3) asymptotic transitions between steady states with a halftime (T½) of 21 h, 4) changes in TBS driven by sodium intake measuring ≈1.3 day [ΔTBS/Δ(Na+ intake/day)], 5) adjustment of Na+ excretion to match any diet thus providing metabolic steady state, and 6) regulation of TBS via controlled excretion (90-95% renal) mediated by surrogate variables. The present focus areas include 1) uneven, nonosmotic distribution of increments in TBS primarily in "skin," 2) long-term instability of TBS during constant Na+ intake, and 3) physiological regulation of renal Na+ excretion primarily by neurohumoral mechanisms dependent on ECV rather than arterial pressure. Under physiological conditions 1) the nonosmotic distribution of Na+ seems conceptually important, but quantitatively ill defined; 2) long-term variations in TBS represent significant deviations from steady state, but the importance is undetermined; and 3) the neurohumoral mechanisms of sodium homeostasis competing with pressure natriuresis are essential for systematic analysis of short-term and long-term regulation of TBS. Sodium homeostasis and blood pressure regulation are intimately related. Real progress is slow and will accelerate only through recognition of the present level of ignorance. Nonosmotic distribution of sodium, pressure natriuresis, and volume-mediated regulation of renal sodium excretion are essential intertwined concepts in need of clear definitions, conscious models, and future attention.

Natriuretic peptides are structurally related, functionally diverse hormones. Circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are delivered predominantly by the heart. Two C-type natriuretic peptides (CNPs) are paracrine messengers, notably in bone, brain, and vessels. Natriuretic peptides act by binding to the extracellular domains of three receptors, NPR-A, NPR-B, and NPR-C of which the first two are guanylate cyclases. NPR-C is coupled to inhibitory proteins. Atrial wall stress is the major regulator of ANP secretion; however, atrial pressure changes plasma ANP only modestly and transiently, and the relation between plasma ANP and atrial wall tension (or extracellular volume or sodium intake) is weak. Absence and overexpression of ANP-related genes are associated with modest blood pressure changes. ANP augments vascular permeability and reduces vascular contractility, renin and aldosterone secretion, sympathetic nerve activity, and renal tubular sodium transport. Within the physiological range of plasma ANP, the responses to step-up changes are unimpressive; in man, the systemic physiological effects include diminution of renin secretion, aldosterone secretion, and cardiac preload. For BNP, the available evidence does not show that cardiac release to the blood is related to sodium homeostasis or body fluid control. CNPs are not circulating hormones, but primarily paracrine messengers important to ossification, nervous system development, and endothelial function. Normally, natriuretic peptides are not powerful natriuretic/diuretic hormones; common conclusions are not consistently supported by hard data. ANP may provide fine-tuning of reno-cardiovascular relationships, but seems, together with BNP, primarily involved in the regulation of cardiac performance and remodeling. © 2017 American Physiological Society. Compr Physiol 8:1211-1249, 2018.

Background: Liver cirrhosis is characterized by avid sodium retention where the activation of the renin angiotensin aldosterone system (RAAS) is considered to be the hallmark of the sodium retaining mechanisms. The direct effect of angiotensin II (ANGII) on the AT-1 receptor in the proximal tubules is partly responsible for the sodium retention. The aim was to estimate the natriuretic and neurohumoral effects of an ANGII receptor antagonist (losartan) in the late phase of the disease in a rat model of liver cirrhosis. Methods: Bile duct ligated (BDL) and sham operated rats received 2 weeks of treatment with losartan 4 mg/kg/day or placebo, given by gastric gavage 5 weeks after surgery. Daily sodium and potassium intakes and renal excretions were measured. Results: The renal sodium excretion decreased in the BDL animals and this was not affected by losartan treatment At baseline the plasma renin concentration (PRC) was similar in sham and BDL animals, but increased urinary excretion of ANGII and an increase P-Aldosterone was observed in the placebo treated BDL animals. The PRC was more than 150 times higher in the losartan treated BDL animals (p < 0.001) which indicated hemodynamic impairment. Conclusions: Losartan 4 mg/kg/day did not increase renal sodium excretion in this model of liver cirrhosis, although the urinary ANGII excretion was increased. The BDL animals tolerated Losartan poorly, and the treatment induced a 150 times higher PRC.

To test the hypothesis that use of oral contraceptives (OC) changes diurnal variation in fluid balance mechanisms including blood pressure, secretion of vasopressin and oxytocin, and renal water and electrolyte excretion. Fifteen naturally cycling (NC) women in mid-follicular phase and 11 long-term OC users were included in a 24-h standardized inpatient study for measurements of vasopressin, oxytocin, sodium, and osmolality in plasma as well as urinary excretion of electrolytes, aquaporin-2, and prostaglandin E2. Blood pressure and heart rate were monitored noninvasively. Plasma vasopressin showed circadian rhythm (P = 0.02) and were similar in both groups (P = 0.18) including nighttime increases (P < 0.001). There was no circadian rhythm in plasma oxytocin within (P = 0.84) or between groups (P = 0.22). OC users had significantly lower plasma osmolality (Δosm: 3.05 ± 0.29 mosm/kg, P = 0.04) and lower plasma sodium (ΔNa+: 0.91 ± 0.09 mmol/l, P = 0.05). The two groups showed similar nighttime decreases in diuresis (1.08 ± 0.04 mL/(kg·h), P < 0.001) and increases in urine osmolality (109 ± 9 mosm/kg, P = 0.02), but similar rates of excretion of Aquaporin-2, prostaglandin E2 and sodium. Nighttime decreases in mean arterial pressure of approximately 13% were significant in both groups (P < 0.001), but 24-h average mean arterial pressure was significantly higher in OC users than in controls (+4.7 ± 0.4 mmHg, P = 0.02). Packed cell volumes were similar between groups (P = 0.54). OC does not change the diurnal patterns of renal fluid excretion, but resets the osmoreceptors for vasopressin release and leads to a significant increase in arterial blood pressure.

AIM:The water channel aquaporin 1 (AQP1) promotes endothelial cell migration. It was hypothesized that AQP1 promotes neovascularization and growth of atherosclerotic plaques.METHODS:AQP1 immunoreactivity and protein abundance was examined in human and murine atherosclerotic lesions and aortic aneurysms. Apolipoprotein E (ApoE) knockout (-/-) and AQP1-/-ApoE-/- mice were developed and fed Western diet (WD) for 8 and 16 weeks to accelerate the atherosclerosis process. In ApoE-/- and AQP1-/-ApoE-/- mice abdominal aortic aneurysms (AAA) were induced by angiotensin II (ANGII) infusion by osmotic minipumps for 4 weeks.RESULTS:In human atherosclerotic lesions and AAA, AQP1 immunoreactive protein was associated with intralesional small vessels. In ApoE-/- mouse aorta, APQ1 mRNA levels were increased with time on WD (n = 7-9, P < 0.003). Both in murine lesions at the aortic root and in the abdominal aortic aneurysmal wall, AQP1 immunoreactivity was associated with microvascular structures. The atherosclerotic lesion burden was enhanced significantly in ANGII-infused AQP1-/-ApoE-/- mice compared with ApoE-/- mice, but neither incidence nor progression of AAA was different. The aortic lesion burden increased with time on WD but was not different between ApoE-/- and AQP1-/-ApoE-/- mice at either 8 or 16 weeks (n = 13-15). Baseline blood pressure and ANGII-induced hypertension were not different between genotypes.CONCLUSION:AQP1 is expressed in atherosclerotic lesion neovasculature in human and mouse arteries and AQP1 deficiency augments lesion development in ANGII-promoted atherosclerosis in mice. Normal function of AQP1 affords cardiovascular protection.