A review regarding the article 'Basal natriuresis as a predictor of diuretic resistance and clinical evolution in acute heart failure'.

Acute heart failure (AHF) is characterized by the emergence or intensification of symptoms and signs indicative of congestion or systemic hypoperfusion, stemming from an underlying structural or functional cardiac disorder. Intravenous loop diuretics play a pivotal role in achieving effective decongestion and ensuring clinical stability; the efficacy of these medications is crucial for determining the patient's hospital course and early outpatient progression. Individuals who exhibit a suboptimal response to diuretics or develop diuretic resistance (DR) are at an elevated risk for cardiovascular mortality and readmission due to AHF. However, there is a lack of standardized definition and diagnostic criteria for DR. Early identification of patients with DR is critical, as they may benefit from more aggressive decongestion strategies to mitigate this resistance. Natriuresis, the excretion of sodium in urine, serves as a direct measure of a diuretic's effectiveness. Low levels of natriuresis have been linked to poorer outcomes. Several studies have underscored the prognostic significance of natriuresis across various heart failure scenarios. However, the relationship between natriuresis and in-hospital DR has not been extensively studied. Observational research has indicated that inadequate natriuresis following the administration of loop diuretics correlates with a diminished diuretic response and an increased likelihood of mortality and heart failure rehospitalization. Further investigation is warranted to assess the predictive value of basal natriuresis concerning DR, in-hospital outcomes, and early outpatient cardiovascular events. This would help in identifying patients who are likely to respond poorly to diuretic therapy and may require alternative or more intensive treatment approaches.

Basal natriuresis as a predictor of diuretic resistance and clinical evolution in acute heart failure.

BACKGROUND: Some clinical guidelines recommend serial measurement of natriuresis to detect diuretic resistance (DR) in acute heart failure (AHF) patients, but it adds complexity to the management. OBJECTIVES: To correlate a single measurement of basal natriuresis (BN) on admission with the development of DR and clinical evolution in AHF hospitalized patients. METHODS: Prospective and multicenter study included AHF hospitalized patients, without shock or creatinine >2.5mg%. Patients received 40mg of intravenous furosemide on admission, then BN was measured, and diuretic treatment was guided by protocol. BN was considered low if <70 meq/L. DR was defined as the need of furosemide >240mg/day, tubular blockade (TB), hypertonic saline solution (HSS) or renal replacement therapy (RRT). In-hospital cardiovascular (CV) mortality, CV mortality and AHF readmissions at 60-day post-discharge were evaluated. RESULTS: 157 patients were included. BN was low in 22%. DR was development in 19% (12.7% furosemide >240mg/day, 8% TB, 4% RRT). Low NB was associated with DR (44% vs 12%; p 0.0001), persistence of congestion (26.5% vs 11.4%; p 0.05), furosemide >240 mg/day (29% vs 8%; p 0.003), higher cumulative furosemide dose at 72 hours (220 vs 160mg; p 0.0001), TB (20.6 vs 4.9%; p 0.008), RRT (11.8 vs 1.6%; p 0.02), worsening of AHF (27% vs 9%; p 0.01), inotropes use (21% vs 7%; p 0.48), respiratory assistance (12% vs 2%; p 0.02) and a higher in-hospital CV mortality (12% vs 4%; p 0.1). No association was demonstrated with post-discharge endpoints. CONCLUSIONS: In AHF patients, low BN was associated with DR, persistent congestion, need for aggressive decongestion strategies, and worse in-hospital evolution.

Renal Sodium Avidity in Heart Failure.

BACKGROUND: Increased renal sodium avidity is a hallmark feature of the heart failure syndrome. SUMMARY: Increased renal sodium avidity refers to the inability of the kidneys to elicit potent natriuresis in response to sodium loading. This eventually causes congestion, which is a major contributor to hospital admissions and mortality in heart failure. KEY MESSAGES: Important novel concepts such as the renal tamponade hypothesis, accelerated nephron loss, and the role of hypochloremia, the sympathetic nervous system, inflammation, the lymphatic system, and interstitial sodium buffers are involved in the pathophysiology of renal sodium avidity. A good understanding of these concepts is crucially important with respect to treatment recommendations regarding dietary sodium restriction, fluid restriction, rapid up-titration of guideline-directed medical therapies, combination diuretic therapy, natriuresis-guided diuretic therapy, use of hypertonic saline, and ultrafiltration.

The impact of GLP-1 receptor agonist liraglutide on blood pressure profile, hydration, natriuresis in diabetic patients with severely impaired kidney function.

Chronic treatment with GLP-1R agonists may moderately lower blood pressure due to increased natriuresis and RAAS inhibition. Short-term effect of these drugs on blood pressure may be opposite and its mechanism remains unclear. We investigated the effect of a single dose of liraglutide on diurnal blood pressure profile, natriuresis, hydration and serum concentration of renin, aldosterone and atrial natriuretic peptide (ANP) in diabetic kidney disease (DKD). 17 patients with eGFR < 30 ml/min/1.73 m2 and 17 with > 60 ml/min/1.73 m2 received in a random order a single subcutaneous dose 1.2 mg liraglutide and placebo with subsequent 24 h blood pressure and natriuresis monitoring. Before and after each medication thoracic fluid index and plasma renin, aldosterone and ANP were also assessed. The blood pressure load in the daytime and nighttime were significantly increased after liraglutide compared to placebo in patients with eGFR < 30 ml/min/1.73 m2. In patients with eGFR > 60 ml/min/1.73 m2 the changes of arterial pressure were comparable, while the morning surge was significantly reduced after liraglutide compared to placebo. After liraglutide 24 h urine sodium excretion increased in both groups vs. placebo (p < 0.001), the effect was greatest in subjects with eGFR > 60 ml/min/1.73 m2. Plasma ANP increased after liraglutide in both groups, most in patients with eGFR < 30 ml/min/1.73 m2 group. Plasma aldosterone (p = 0.013) and thoracic fluid index (p = 0.01) decreased after liraglutide compared to placebo (p = 0.013 and p + 0.01, respectively. Plasma renin concentration remained unchanged. In severe chronic kidney disease liraglutide induces a transient increase of blood pressure due to reduced natriuresis. The natriuretic effect of liraglutide in DKD may be related to increased ANP and decreased aldosterone secretion.

Naringen's Effects on Diuresis and Prevention of Urolithiasis in Hypertensive Rats.

This research demonstrates the diuretic effect of naringenin, a flavanone aglycone found in citrus, on spontaneously hypertensive female and male rats (SHR). The data reinforces existing literature findings that male SHR exhibits higher systolic blood pressure than age-matched females. Urine volume assessed over 8 hours was lower when obtained from SHR males than females. When these animals were orally treated with different doses of naringenin (0.1-1 mg/kg), this increased urinary volume in both genders at the highest dose tested. In contrast, the lowest dose promoted a significant natriuretic effect. The other electrolytes analyzed in urine were not significantly altered, except potassium excretion, which was shown to be increased in the urine of SHR males. Furthermore, naringenin showed promise in reducing calcium oxalate (CaOx) crystal formation in an in vitro model, presenting potential advantages in lithiasis prevention.

Sodium loading in ambulatory patients with heart failure with reduced ejection fraction: Mechanistic insights into sodium handling.

AIMS: Sodium restriction was not associated with improved outcomes in heart failure patients in recent trials. The skin might act as a sodium buffer, potentially explaining tolerance to fluctuations in sodium intake without volume overload, but this is insufficiently understood. Therefore, we studied the handling of an increased sodium load in patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Twenty-one ambulatory, stable HFrEF patients and 10 healthy controls underwent a 2-week run-in phase, followed by a 4-week period of daily 1.2 g (51 mmol) sodium intake increment. Clinical, echocardiographic, 24-h urine collection, and bioelectrical impedance data were collected every 2 weeks. Blood volume, skin sodium content, and skin glycosaminoglycan content were assessed before and after sodium loading. Sodium loading did not significantly affect weight, blood pressure, congestion score, N-terminal pro-brain natriuretic peptide, echocardiographic indices of congestion, or total body water in HFrEF (all p > 0.09). There was no change in total blood volume (4748 ml vs. 4885 ml; p = 0.327). Natriuresis increased from 150 mmol/24 h to 173 mmol/24 h (p = 0.024), while plasma renin decreased from 286 to 88 µU/L (p = 0.002). There were no significant changes in skin sodium content, total glycosaminoglycan content, or sulfated glycosaminoglycan content (all p > 0.265). Healthy controls had no change in volume status, but a higher increase in natriuresis without any change in renin. CONCLUSIONS: Selected HFrEF patients can tolerate sodium loading, with increased renal sodium excretion and decreased neurohormonal activation.

Cardiorenal Interactions in Acute Heart Failure: Renal Proximal Tubules in the Spotlight.

BACKGROUND: The maladaptive neurohormonal activation, an integral mechanism in the pathophysiology of heart failure (HF) and cardiorenal syndrome, has a profound impact on renal sodium handling. Congestion is the primary reason for hospitalization of patients with HF and the main target of therapy. As sodium is the main determinant of extracellular volume, the goal is to enhance urinary sodium excretion in order to address excess fluid. The interventions to increase natriuresis have conventionally focused on distal nephron as the primary segment that counterbalances the effects of loop diuretics. SUMMARY: Recent developments in the field of cardiorenal medicine have resulted in a shift of attention to renal proximal tubules (e.g., emerging evidence on proximal tubular dysfunction beyond handling of sodium). Herein, we discuss the three main mechanisms of sodium transport in the proximal tubules with emphasis on their intrinsic links to one another as well as to more distal transporters of sodium. Then, we provide an overview of the findings of the most recent clinical studies that have tried to enhance the conventional decongestive strategies through simultaneous blockade of these mechanisms. KEY MESSAGE: Interventions aiming at renal proximal tubules have the potential to significantly improve our ability to decongest patients with acute HF.

Evidence That Binding of Cyclic GMP to the Extracellular Domain of NKA (Sodium-Potassium ATPase) Mediates Natriuresis.

BACKGROUND: Extracellular renal interstitial guanosine cyclic 3',5'-monophosphate (cGMP) inhibits renal proximal tubule (RPT) sodium (Na+) reabsorption via Src (Src family kinase) activation. Through which target extracellular cGMP acts to induce natriuresis is unknown. We hypothesized that cGMP binds to the extracellular α1-subunit of NKA (sodium-potassium ATPase) on RPT basolateral membranes to inhibit Na+ transport similar to ouabain-a cardiotonic steroid. METHODS: Urine Na+ excretion was measured in uninephrectomized 12-week-old female Sprague-Dawley rats that received renal interstitial infusions of vehicle (5% dextrose in water), cGMP (18, 36, and 72 µg/kg per minute; 30 minutes each), or cGMP+rostafuroxin (12 ng/kg per minute) or were subjected to pressure-natriuresis±rostafuroxin infusion. Rostafuroxin is a digitoxigenin derivative that displaces ouabain from NKA. RESULTS: Renal interstitial cGMP and raised renal perfusion pressure induced natriuresis and increased phosphorylated SrcTyr416 and Erk 1/2 (extracellular signal-regulated protein kinase 1/2)Thr202/Tyr204; these responses were abolished with rostafuroxin coinfusion. To assess cGMP binding to NKA, we performed competitive binding studies with isolated rat RPTs using bodipy-ouabain (2 µM)+cGMP (10 µM) or rostafuroxin (10 µM) and 8-biotin-11-cGMP (2 µM)+ouabain (10 µM) or rostafuroxin (10 µM). cGMP or rostafuroxin reduced bodipy-ouabain fluorescence intensity, and ouabain or rostafuroxin reduced 8-biotin-11-cGMP staining. We cross-linked isolated rat RPTs with 4-N3-PET-8-biotin-11-cGMP (2 µM); 8-N3-6-biotin-10-cAMP served as negative control. Precipitation with streptavidin beads followed by immunoblot analysis showed that RPTs after cross-linking with 4-N3-PET-8-biotin-11-cGMP exhibited a significantly stronger signal for NKA than non-cross-linked samples and cross-linked or non-cross-linked 8-N3-6-biotin-10-cAMP RPTs. Ouabain (10 µM) reduced NKA in cross-linked 4-N3-PET-8-biotin-11-cGMP RPTs confirming fluorescence staining. 4-N3-PET-8-biotin-11-cGMP cross-linked samples were separated by SDS gel electrophoresis and slices corresponding to NKA molecular weight excised and processed for mass spectrometry. NKA was the second most abundant protein with 50 unique NKA peptides covering 47% of amino acids in NKA. Molecular modeling demonstrated a potential cGMP docking site in the ouabain-binding pocket of NKA. CONCLUSIONS: cGMP can bind to NKA and thereby mediate natriuresis.

Renal sympathetic activity: A key modulator of pressure natriuresis in hypertension.

Hypertension is a complex disorder ensuing necessarily from alterations in the pressure-natriuresis relationship, the main determinant of long-term control of blood pressure. This mechanism sets natriuresis to the level of blood pressure, so that increasing pressure translates into higher osmotically driven diuresis to reduce volemia and control blood pressure. External factors affecting the renal handling of sodium regulate the pressure-natriuresis relationship so that more or less natriuresis is attained for each level of blood pressure. Hypertension can thus only develop following primary alterations in the pressure to natriuresis balance, or by abnormal activity of the regulation network. On the other hand, increased sympathetic tone is a very frequent finding in most forms of hypertension, long regarded as a key element in the pathophysiological scenario. In this article, we critically analyze the interplay of the renal component of the sympathetic nervous system and the pressure-natriuresis mechanism in the development of hypertension. A special focus is placed on discussing recent findings supporting a role of baroreceptors as a component, along with the afference of reno-renal reflex, of the input to the nucleus tractus solitarius, the central structure governing the long-term regulation of renal sympathetic efferent tone.

Angiotensin Type-2 Receptors: Transducers of Natriuresis in the Renal Proximal Tubule.

Angiotensin II (Ang II) type-2 receptors (AT2R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na+) retention induced by Ang II stimulation of Ang II type-1 receptor (AT1R). Natriuresis induced by AT1R blockade is due at least in part to AT2R activation and whole body deletion of AT2Rs reduces the natriuretic response to increased blood pressure (BP). The major endogenous AT2R agonist mediating the natriuretic response is Ang III, the Ang II heptapeptide metabolite generated by aminopeptidase A, and the principal nephron site mediating inhibition of Na+ reabsorption by the AT2R is the renal proximal tubule (RPT). AT2Rs induce natriuresis via a bradykinin, nitric oxide and cyclic GMP (cGMP) signaling cascade. Recent studies demonstrated a key role for protein phosphatase 2A (PP2A) in the AT2R-mediated natriuretic response upstream of cGMP. By inducing natriuresis, AT2Rs lower BP in the Ang II-infusion model of hypertension. PP2A activation and the natriuretic response to AT2R stimulation are defective in spontaneously hypertensive rats, a model of primary hypertension in humans. AT2R agonists are candidates for proximal tubule natriuretic agents in Na+ and fluid retention disorders.

Potential Role of Natriuretic Response to Furosemide Stress Test During Acute Heart Failure.

BACKGROUND: Poor natriuresis has been associated with a poorer response to diuretic treatment and worse prognosis in acute heart failure. Recommendations on how and when to measure urinary sodium (UNa) are lacking. We aim to evaluate UNa quantification after a furosemide stress test (FST) capacity to predict appropriate decongestion during acute heart failure hospitalization. METHODS: Patients underwent an FST on day-1 of admission, and UNa was measured 2 hours after, dividing patients into low or high UNa based on the sample median value. A semiquantitative composite congestive score (CCS; 0-9) and NT pro-BNP (N-terminal pro-B-type natriuretic peptide) quantification were assessed before the FST and at day 5 after the FST. RESULTS: Median UNa after FST in the 65 patients included was 113 (97-122) mmol/L. At day 5, a lower proportion of patients with a low UNa reached a 30% decrease in NT-proBNP levels (21 [66%] for low UNa versus 31 [94%] for high UNa; P=0.005) and an appropriate grade of decongestion (CCS<3) (20 [62%] for low UNa versus 32 [97%] for high UNa; P<0.001). A UNa>83 mmol/L 2 hours after FST had a 96% sensitivity to predict an NT-proBNP reduction ≥30% and 95% to predict a CCS<3 at day 5. Low UNa patients presented a lower cumulative diuresis and weight loss and presented more often with prolonged hospitalization, worsening heart failure, and readmission because of acute heart failure or death at 6 months. CONCLUSIONS: Low natriuresis after an FST identified patients at a higher risk of an inadequate diuretic response and an inappropriate decongestion. FST-guided diuretic treatment might help to improve decongestion, shorten hospitalizations, and to reduce adverse outcomes.

Proximal Tubule-Specific Deletion of Angiotensin II Type 1a Receptors in the Kidney Attenuates Circulating and Intratubular Angiotensin II-Induced Hypertension in PT-Agtr1a-/- Mice.

[Figure: see text].

Thiazide-Sensitive NCC (Sodium-Chloride Cotransporter) in Human Metabolic Syndrome: Sodium Sensitivity and Potassium-Induced Natriuresis.

The thiazide-sensitive sodium-chloride cotransporter (NCC;SLC12A3) is central to sodium and blood pressure regulation. Metabolic syndrome induces NCC upregulation generating sodium-sensitive hypertension in experimental animal models. We tested the role of NCC in sodium sensitivity in hypertensive humans with metabolic syndrome. Conversely, oral potassium induces NCC downregulation producing potassium-induced natriuresis. We determined the time course and magnitude of potassium-induced natriuresis compared with the natriuresis following hydrochlorothiazide (HCTZ) as a reference standard. We studied 19 obese hypertensive humans with metabolic syndrome during 13-day inpatient confinement. We determined sodium sensitivity by change in 24-hour mean systolic pressure by automated monitor from days 5 (low sodium) to 10 (high sodium). We determined NCC activity by standard 50 mg HCTZ sensitivity test (day 11). We determined potassium-induced natriuresis following 35 mmol KCl (day 13). We determined (1) whether NCC activity was greater in sodium-sensitive versus sodium-resistant participants and correlated with sodium sensitivity and (2) time course and magnitude of potassium-induced natriuresis following 35 mmol KCl directly compared with 50 mg HCTZ. NCC activity was not greater in sodium-sensitive versus sodium-resistant humans and did not correlate with sodium sensitivity. Thirty-five-millimoles KCl produced a rapid natriuresis approximately half that of 50 mg HCTZ with a greater kaliuresis. Our investigation tested a key hypothesis regarding NCC activity in human hypertension and characterized potassium-induced natriuresis following 35 mmol KCl compared with 50 mg HCTZ. In obese hypertensive adults with metabolic syndrome ingesting a high-sodium diet, 35 mmol KCl had a net natriuretic effect approximately half that of 50 mg HCTZ.

The Renal Extraction and the Natriuretic Action of GLP-1 in Humans Depend on Interaction With the GLP-1 Receptor.

PURPOSE: The natriuretic effect of glucagon-like peptide-1 (GLP-1) in humans is independent of changes in renal plasma flow (RPF) and glomerular filtration rate (GFR) but may involve suppression of angiotensin II (ANG II) and a significant (~45%) renal extraction of GLP-1. The current study was designed to investigate the consequences for the renal extraction and the natriuretic effect of blocking GLP-1 receptors with the specific GLP-1 receptor antagonist, Exendin 9-39 (Ex 9-39). METHODS: Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study where GLP-1 or vehicle was infused (1). In the present new experiments, participants were examined during a 3-hour infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-hour infusion of Ex 9-39 (900 pmol/kg/min). Timed urine collections were conducted throughout the experiments. Renal extraction of GLP-1 as well as RPF and GFR were measured via Fick's principle after catheterization of a renal vein. Arterial plasma renin, ANG II, and aldosterone concentrations were measured. RESULTS: Co-infusion of Ex 9-39 significantly reduced renal extraction of GLP-1 to ~25% compared with GLP-1 infusion alone (~45%). Urinary sodium excretions remained at baseline levels during co-infusion of Ex 9-39 as well as vehicle. By contrast, GLP-1 infusion alone resulted in a 2-fold increase in natriuresis. Ex 9-39 abolished the GLP-1-induced decrease in arterial ANG II concentrations. RPF and GFR remained unchanged during all experiments. CONCLUSIONS: Renal extraction of GLP-1 and its effect on natriuresis are both dependent on GLP-1 receptor activation in healthy humans.

Role for ovarian hormones in purinoceptor-dependent natriuresis.

BACKGROUND: Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y2 and P2Y4 purinoceptor can be considered potential contributors to hypertension due to their emerging roles in regulating renal tubular Na+ transport. Activation of these receptors inhibits epithelial Na+ channel activity (ENaC) via a phospholipase C (PLC)-dependent pathway resulting in natriuresis. We recently reported that activation of P2Y2 and P2Y4 receptors in the renal medulla by UTP promotes natriuresis in male and ovariectomized (OVX) rats, but not in ovary-intact females. This led us to hypothesize that ovary-intact females have greater basal renal medullary activity of P2 (P2Y2 and P2Y4) receptors regulating Na+ excretion compared to male and OVX rats. METHODS: To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 µg/kg/min) on urinary Na+ excretion in anesthetized male, ovary-intact female, and OVX Sprague Dawley rats, (ii) mRNA expression and protein abundance of P2Y2 and P2Y4 receptors, and (iii) mRNA expression of their downstream effectors (PLC-1δ and ENaCα) in renal inner medullary tissues obtained from these three groups. We also subjected cultured mouse inner medullary collecting duct cells (segment 3, mIMCD3) to different concentrations of 17ß-estradiol (E2, 0, 10, 100, and 1000 nM) to test whether E2 increases mRNA expression of P2Y2 and P2Y4 receptors. RESULTS: Acute P2 inhibition attenuated urinary Na+ excretion in ovary-intact females, but not in male or OVX rats. We found that P2Y2 and P2Y4 mRNA expression was higher in the inner medulla from females compared to males or OVX. Inner medullary lysates showed that ovary-intact females have higher P2Y2 receptor protein abundance, compared to males; however, OVX did not eliminate this sex difference. We also found that E2 dose-dependently upregulated P2Y2 and P2Y4 mRNA expression in mIMCD3. CONCLUSION: These data suggest that ovary-intact females have enhanced P2Y2 and P2Y4-dependent regulation of Na+ handling in the renal medulla, compared to male and OVX rats. We speculate that the P2 pathway contributes to facilitated renal Na+ handling in premenopausal females.

Aldosterone-dependent and -independent regulation of Na+ and K+ excretion and ENaC in mouse kidneys.

We investigated the regulation of Na+ and K+ excretion and the epithelial Na+ channel (ENaC) in mice lacking the gene for aldosterone synthase (AS) using clearance methods to assess excretion and electrophysiology and Western blot analysis to test for ENaC activity and processing. After 1 day of dietary Na+ restriction, AS-/- mice lost more Na+ in the urine than AS+/+ mice did. After 1 wk on this diet, both genotypes strongly reduced urinary Na+ excretion, but creatinine clearance decreased only in AS-/- mice. Only AS+/+ animals exhibited increased ENaC function, assessed as amiloride-sensitive whole cell currents in collecting ducts or cleavage of αENaC and γENaC in Western blots. To assess the role of aldosterone in the excretion of a K+ load, animals were fasted overnight and refed with high-K+ or low-K+ diets for 5 h. Both AS+/+ and AS-/- mice excreted a large amount of K+ during this period. In both phenotypes the excretion was benzamil sensitive, indicating increased K+ secretion coupled to ENaC-dependent Na+ reabsorption. However, the increase in plasma K+ under these conditions was much larger in AS-/- animals than in AS+/+ animals. In both groups, cleavage of αENaC and γENaC increased. However, Na+ current measured ex vivo in connecting tubules was enhanced only in AS+/+ mice. We conclude that in the absence of aldosterone, mice can conserve Na+ without ENaC activation but at the expense of diminished glomerular filtration rate. Excretion of a K+ load can be accomplished through aldosterone-independent upregulation of ENaC, but aldosterone is required to excrete the excess K+ without hyperkalemia.

Epoxy Fatty Acids: From Salt Regulation to Kidney and Cardiovascular Therapeutics: 2019 Lewis K. Dahl Memorial Lecture.

Epoxyeicosatrienoic acids (EETs) are epoxy fatty acids that have biological actions that are essential for maintaining water and electrolyte homeostasis. An inability to increase EETs in response to a high-salt diet results in salt-sensitive hypertension. Vasodilation, inhibition of epithelial sodium channel, and inhibition of inflammation are the major EET actions that are beneficial to the heart, resistance arteries, and kidneys. Genetic and pharmacological means to elevate EETs demonstrated antihypertensive, anti-inflammatory, and organ protective actions. Therapeutic approaches to increase EETs were then developed for cardiovascular diseases. sEH (soluble epoxide hydrolase) inhibitors were developed and progressed to clinical trials for hypertension, diabetes mellitus, and other diseases. EET analogs were another therapeutic approach taken and these drugs are entering the early phases of clinical development. Even with the promise for these therapeutic approaches, there are still several challenges, unexplored areas, and opportunities for epoxy fatty acids.

A Role of Inflammation and Immunity in Essential Hypertension-Modeled and Analyzed Using Petri Nets.

Recent studies have shown that the innate and adaptive immune system, together with low-grade inflammation, may play an important role in essential hypertension. In this work, to verify the importance of selected factors for the development of essential hypertension, we created a Petri net-based model and analyzed it. The analysis was based mainly on t-invariants, knockouts of selected fragments of the net and its simulations. The blockade of the renin-angiotensin (RAA) system revealed that the most significant effect on the emergence of essential hypertension has RAA activation. This blockade affects: (1) the formation of angiotensin II, (2) inflammatory process (by influencing C-reactive protein (CRP)), (3) the initiation of blood coagulation, (4) bradykinin generation via the kallikrein-kinin system, (5) activation of lymphocytes in hypertension, (6) the participation of TNF alpha in the activation of the acute phase response, and (7) activation of NADPH oxidase-a key enzyme of oxidative stress. On the other hand, we found that the blockade of the activation of the RAA system may not eliminate hypertension that can occur due to disturbances associated with the osmotically independent binding of Na in the interstitium. Moreover, we revealed that inflammation alone is not enough to trigger primary hypertension, but it can coexist with it. We believe that our research may contribute to a better understanding of the pathology of hypertension. It can help identify potential subprocesses, which blocking will allow better control of essential hypertension.

Sodium Handling and Interaction in Numerous Organs.

Salt (NaCl) is a prerequisite for life. Excessive intake of salt, however, is said to increase disease risk, including hypertension, arteriosclerosis, heart failure, renal disease, stroke, and cancer. Therefore, considerable research has been expended on the mechanism of sodium handling based on the current concepts of sodium balance. The studies have necessarily relied on relatively short-term experiments and focused on extremes of salt intake in humans. Ultra-long-term salt balance has received far less attention. We performed long-term salt balance studies at intakes of 6, 9, and 12 g/day and found that although the kidney remains the long-term excretory gate, tissue and plasma sodium concentrations are not necessarily the same and that urinary salt excretion does not necessarily reflect total-body salt content. We found that to excrete salt, the body makes a great effort to conserve water, resulting in a natriuretic-ureotelic principle of salt excretion. Of note, renal sodium handling is characterized by osmolyte excretion with anti-parallel water reabsorption, a state-of-affairs that is achieved through the interaction of multiple organs. In this review, we discuss novel sodium and water balance concepts in reference to our ultra-long-term study. An important key to understanding body sodium metabolism is to focus on water conservation, a biological principle to protect from dehydration, since excess dietary salt excretion into the urine predisposes to renal water loss because of natriuresis. We believe that our research direction is relevant not only to salt balance but also to cardiovascular regulatory mechanisms.