The potential mechanism by which sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent cardiovascular disease (CVD) is being widely investigated. Improved insulin resistance, along with decreased body fat mass associated with SGLT2 inhibitor treatment is consistent with previously well-established factors contributing to the prevention of CVD. These factors are responsible for reduction of oxidative stress as well as improvement of systemic inflammation. Because heart failure was one of the most dramatically improved cardiovascular events in various clinical trials and because SGLT2 inhibitors promote osmotic diuresis and natriuresis, hemodynamic changes are considered as a critical mechanism responsible for the cardioprotective effect of SGLT2 inhibitors. Restored tubuloglomerular feedback by SGLT2 inhibitors might play a role in renoprotection, which in turn, leads to fewer CVDs. Finally, blood ketone body increments in response to SGLT2 inhibition might act as a “super-fuel” for salvaging the failing diabetic heart.
Adipose Tissue ; Cardiovascular Diseases ; Diabetes Mellitus ; Diuresis ; Heart ; Heart Failure ; Hemodynamics ; Inflammation ; Insulin Resistance ; Ketones ; Natriuresis ; Oxidative Stress ; Sodium-Glucose Transport Proteins

The pathophysiology of hypertension, which affects over 1 billion individuals worldwide, involves the integration of the actions of multiple organ systems, including the kidney. The kidney, which governs sodium excretion via several mechanisms including pressure natriuresis and the actions of renal sodium transporters, is central to long term blood pressure regulation and the salt sensitivity of blood pressure. The impact of renal sodium handling and the salt sensitivity of blood pressure in health and hypertension is a critical public health issue owing to the excess of dietary salt consumed globally and the significant percentage of the global population exhibiting salt sensitivity. This review highlights recent advances that have provided new insight into the renal handling of sodium and the salt sensitivity of blood pressure, with a focus on genetic, inflammatory, dietary, sympathetic nervous system and oxidative stress mechanisms that influence renal sodium excretion. Increased understanding of the multiple integrated mechanisms that regulate the renal handling of sodium and the salt sensitivity of blood pressure has the potential to identify novel therapeutic targets and refine dietary guidelines designed to treat and prevent hypertension.
Blood Pressure ; Genetics ; Hypertension ; Inflammation ; Kidney ; Natriuresis ; Nutrition Policy ; Oxidative Stress ; Public Health ; Sodium* ; Sympathetic Nervous System

Neuromyelitis optica spectrum disorder (NMOSD) may present with area postrema syndrome, which is characterized by intractable vomiting and hiccups. Hyponatremia is common in NMOSD and is mostly associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In contrast to SIADH, cerebral salt wasting syndrome (CSWS) causes hyponatremia, which is associated with severe natriuresis and extracellular volume depletion in patients with cerebral disease. To our knowledge, hyponatremia associated with CSWS has not been reported in a patient with NMOSD. Here, we describe a NMOSD presenting with hyponatremia, which may be caused by CSWS following area postrema syndrome.
Area Postrema ; Hiccup ; Humans ; Hyponatremia ; Inappropriate ADH Syndrome ; Natriuresis ; Neuromyelitis Optica* ; Vomiting ; Wasting Syndrome*

Since 2008, the Food and Drug Administration has required cardiovascular (CV) safety trials for all anti-diabetic medications available in the USA. Thus, new agents like dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 receptor agonists have been tested in CV safety trials. The results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) were released last year. Of the sodium-glucose cotransporter 2 (SGLT2) inhibitors tested, empagliflozin demonstrated a CV benefit in this trial. Another study of the renal protective effects of empagliflozin was released this year. The mechanisms supporting the cardio- and reno-protective effects of empagliflozin remain controversial. Hemodynamic changes related to SGLT2 inhibitors via natriuresis and osmotic diuresis are one potential mechanism. The Canadian Diabetes Association and European Society of Cardiology recently suggested SGLT2 inhibitors as an optimal anti-diabetic medication for patients with type 2 diabetes with overt CV disease. Further studies elucidating the potential mechanisms of cardio- and reno-protective effects of SGLT2 are needed.
Cardiology ; Diabetes Mellitus, Type 2* ; Dipeptidyl-Peptidase IV Inhibitors ; Diuresis ; Glucagon-Like Peptide-1 Receptor ; Hemodynamics ; Humans ; Natriuresis ; Prescriptions* ; United States Food and Drug Administration

Hypertension is a complex trait determined by both genetic and environmental factors and is a major public health problem due to its high prevalence and concomitant increase in the risk for cardiovascular disease. With the recent large increase of dietary salt intake in most developed countries, the prevalence of hypertension increases tremendously which is about 30% of the world population. There is substantial evidence that suggests some people can effectively excrete high dietary salt intake without an increase in arterial BP, and another people cannot excrete effectively without an increase in arterial BP. Salt sensitivity of BP refers to the BP responses for changes in dietary salt intake to produce meaningful BP increases or decreases. The underlying mechanisms that promote salt sensitivity are complex and range from genetic to environmental influences. The phenotype of salt sensitivity is therefore heterogeneous with multiple mechanisms that potentially link high salt intake to increases in blood pressure. Moreover, excess salt intake has functional and pathological effects on the vasculature that are independent of blood pressure. Epidemiologic data demonstrate the role of high dietary salt intake in mediating cardiovascular and renal morbidity and mortality. Almost five decades ago, Guyton and Coleman proposed that whenever arterial pressure is elevated, pressure natriuresis enhances the excretion of sodium and water until blood volume is reduced sufficiently to return arterial pressure to control values. According to this hypothesis, hypertension can develop only when something impairs the excretory ability of sodium in the kidney. However, recent studies suggest that nonosmotic salt accumulation in the skin interstitium and the endothelial dysfunction which might be caused by the deterioration of vascular endothelial glycocalyx layer (EGL) and the epithelial sodium channel on the endothelial luminal surface (EnNaC) also play an important role in nonosmotic storage of salt. These new concepts emphasize that sodium homeostasis and salt sensitivity seem to be related not only to the kidney malfunction but also to the endothelial dysfunction. Further investigations will be needed to assess the extent to which changes in the sodium buffering capacity of the skin interstitium and develop the treatment strategy for modulating the endothelial dysfunction.
Arterial Pressure ; Blood Pressure ; Blood Volume ; Cardiovascular Diseases ; Developed Countries ; Epithelial Sodium Channels ; Glycocalyx ; Homeostasis ; Hypertension* ; Kidney* ; Mortality ; Natriuresis ; Negotiating ; Phenobarbital ; Phenotype ; Prevalence ; Public Health ; Skin ; Sodium ; Water

Cerebral salt-wasting syndrome (CSWS) is a rare disease characterized by a extracellular volume depletion and hyponatremia induced by marked natriuresis. It is mainly reported in patients who experience a central nervous system insult, such as cerebral hemorrhage or encephalitis. The syndrome of inappropriate antidiuretic hormone secretion is a main cause of severe hyponatremia after hematopoietic stem cell transplantation, whereas CSWS is rarely reported. We report 3 patients with childhood acute leukemia who developed CSWS with central nervous system complication after hematopoietic stem cell transplantation. The diagnosis of CSW was made on the basis of severe hyponatremia accompanied by increased urine output with clinical signs of dehydration. All patients showed elevated natriuretic peptide and normal antidiuretic hormone. Aggressive water and sodium replacement treatment was instituted in all 3 patients and 2 of them were effectively recovered, the other one was required to add fludrocortisone administration.
Central Nervous System ; Cerebral Hemorrhage ; Dehydration ; Diagnosis ; Encephalitis ; Fludrocortisone ; Hematopoietic Stem Cell Transplantation* ; Hematopoietic Stem Cells* ; Humans ; Hyponatremia ; Leukemia ; Natriuresis ; Polyuria ; Rare Diseases ; Sodium ; Water

Cerebral salt wasting is characterized by inappropriate natriuresis and volume contraction with associated cerebral pathology. It is distinct from the syndrome of inappropriate antidiuretic hormone secretion, which is characterized by inappropriate retention of free water. We report a patient with a porencephalic cyst who developed cerebral salt wasting. His initial treatment was supplementation of water and salt, which did not improve natriuresis or volume contraction. Fludrocortisone administration effectively managed the cerebral salt wasting.
Adolescent ; Fludrocortisone/*therapeutic use ; Humans ; Hyponatremia/*drug therapy ; Male ; Natriuresis/physiology ; Sodium Chloride/therapeutic use

Cerebral Salt Wasting Syndrome (CSWS) is defined as the development of extracellular volume depletion due to a dysfunction of the renal sodium transport system. Differentiation of CSWS from the Symdrome of Inappropriate Secretion of Antidiuretic Hormone in patients with intracranial disease is difficult because both syndromes include hyponatremia and concentrated urine with natriuresis. However, distinguishing between these two syndromes is very important because the treatment options differ. We report a 41 year-old Asian woman who presented initially with hyponatremia, and was finally diagnosed with CSWS after an operation for an acoustic neuroma. Based on this case, we discuss a possible mechanism and disclose insights about differential diagnosis thereof.
Acoustics ; Asian Continental Ancestry Group ; Cerebrum ; Diagnosis, Differential ; Female ; Humans ; Hyponatremia ; Natriuresis ; Neuroma ; Neuroma, Acoustic ; Sodium ; Wasting Syndrome

OBJECTIVETo investigate the effect of AT₁ receptor on the changes of tyrosine hydroxylase-immunoreactivity (TH-IR) in rostral ventrolateral medulla (RVLM) induced by brain cholinergic stimuli in rats.

METHODSMale SD rats were randomly divided into 4 groups: NS + CBC group, Los + CBC group, Los + NS group and NS + NS group. AT₁ was blocked by pretreatment of 20 μg losartan in Los + CBC and Los + NS groups; intracerebroventricular injection of 0.5 μg carbachol was used for cholinergic stimuli in NS + CBC and Los + CBC groups; normal saline (NS) was used for control. The output amount of natrium in kidney, glomerular filtration rate (GFR) and renal plasma flow (PRF) were observed. The changes of TH-IR in the RVLM were observed by immunohistochemistry.

RESULTIn NS + CBC group carbachol induced potent natriuresis, after pretreatment of losartan the natriuretic effect was partially inhibited in Los + CBC group. Both the number and optical density of TH-IR positive neurons in NS + CBC group were markedly increased than those in NS + NS group (P < 0.05); while those in Los + CBC group were significantly lower than those in NS+CBC group (P < 0.05). Intracerebroventricular injection of carbachol and losartan had no effect on GFR and RPF(P > 0.05).

CONCLUSIONThe results suggest that cholinergic stimuli can induce potent natriuresis and increase the activity of adrenergic neurons in the RVLM; the above effects can be down regulated by blockade of brain AT₁ receptor.

Animals ; Carbachol ; administration & dosage ; pharmacology ; Drug Antagonism ; Glomerular Filtration Rate ; drug effects ; Losartan ; pharmacology ; Male ; Medulla Oblongata ; drug effects ; metabolism ; Natriuresis ; drug effects ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 1 ; physiology ; Tyrosine 3-Monooxygenase ; metabolism

PURPOSE: We observed excessive renal excretion of salt and water, without underlying renal diseases or definite causes, accompanied with severe hypotension in critically ill patients. This study investigates the clinical courses and characteristics of these patients. METHODS: We retrospectively analyzed 13 patients with polyuria of unknown origin, which persited equal to or longer than 3 days, among hypotensive patients, who were admitted to intensive care unit. RESULTS: The causes of hypotension included sepsis in 11 patients and adrenal insufficiceny in one patient. The cause of hyptension was unknown in one patient. Vassopressors were used in all patients, and hypotension persisted for 13.2+/-8.6 days. Polyuria persisted for 10.6+/-8.2 days, and the duration of polyuria was strongly correlated with that of hypotension (R=0.919, p<0.001). Low dose steroid was used in 8 patients for the treatment of hypotension, and hypotension improved in 3 patients within 2 days after steroid administration. Four patients died during the hosptialization, and the duration of hypotension in non-survivors was greater than that in survivors (21.2+/-9.7 days and 9.6+/-5.2 days respectively, p=0.020). CONCLUSION: In critically ill patients with severe hypotension, we observed 13 cases of inappropriate natriuresis and polyuria. These results suggest that the persistence of poyluria and hypotension might affect the prognosis of these patients, and adrenal insufficicieny might be associated with this appearance in some patients. Further studies are needed to establish causes and treatments for this appearance.
Adrenal Insufficiency ; Critical Illness ; Humans ; Hypotension ; Intensive Care Units ; Natriuresis ; Polyuria ; Prognosis ; Retrospective Studies ; Sepsis ; Survivors