Increased Sodium Reabsorption Research Articles

Diuretic therapy in acute decompensated heart failure

Episodes of congestion characterize the disease course of patients with heart failure, resulting in a high morbidity with the need for urgent hospitalization. The main treatment goal is to alleviate signs and symptoms of congestion to reach euvolemia. Loop diuretics remain the cornerstone in the treatment, however diuretic response is unpredictable and therapy should be individualized. The neurohormonal activation result in an increased sodium reabsorption along the whole nephron. Each segment provides a different target site to increase diuretic and natriuretic response. This manuscript provides further insight in the pathophysiology behind the cardiorenal interactions, which lead to the increased sodium avidity in heart failure. In addition, the different therapeutic options to enhance diuretic response in patients with acute heart failure is discussed, as well as the assessment of the diuretic response based on the urinary sodium concentration.

Adrenoceptors and Hypertension.

Hypertension is a very prevalent condition associated with high mortality and morbidity, secondary to changes resulting in blood vessels and resultant end-organ damage. Haemodynamic changes, including an initial rise in cardiac output followed by an increase in total peripheral resistance, denote the early changes associated with borderline or stage 1 hypertension, especially in young men. Increased sodium reabsorption leading to kidney damage is another mechanism proposed as one of the initial triggers for essential hypertension. The underlying pathophysiological mechanisms include catecholamine-induced α1- and ß1-adrenoceptor stimulation, and renin-angiotensin-aldosterone system activation leading to endothelial dysfunction which is believed to lead to persistent blood pressure elevation.α1 blockers, α2 agonists, and ß blockers were among the first oral anti-hypertensives. They are no longer first-line therapy after outcome trials did not demonstrate any benefits over and above other agents, despite similar blood pressure reductions. Angiotensin-converting enzyme inhibitors(or angiotensin receptor blockers), calcium channel blockers, and thiazide-like diuretics are now considered the first line of therapy, although adrenoceptor agents still have a role as second- or third-line therapy. The chapter also highlights hypertension in specific medical conditions such as pregnancy, phaeochromocytoma, hyperthyroidism, portal hypertension, pulmonary arterial hypertension, and ocular hypertension, to provide an overview for clinicians and researchers interested in the role of adrenoceptors in the pathophysiology and management of hypertension.

What is the relationship between serum uric acid level and insulin resistance?: A case-control study

Diabetes, arises from either an absolute or relative insufficiency of insulin or insulin resistance of peripheral tissues. For assessing long-term blood glucose concentration and insulin resistance, the utilization of glycosylated hemoglobin (HbA1c) and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) is widespread. Insulin resistance can lead to hyperuricemia by reducing the kidney ability to excrete urate, thus increasing sodium reabsorption. The aim of this study was to investigate the possible relationship between serum uric acid levels and insulin resistance. This was a retrospective case-control study. A total of 2530 applications in 2-year time were included in the study. Patient, known hypertension status, fasting plasma glucose, insulin, uric acid, HDL, low-density lipoprotein (LDL), triglyceride/Tg, HbA1c laboratory values and Tg/HDL ratio were examined. A statistically significant difference existed in the median uric acid values between the insulin-resistant and insulin-sensitive groups (P < .001). Additionally, a weak positive statistical correlation was identified between uric acid and HOMA-IR values (R = 0.299; P < .001) and uric acid and Tg/HDL values (R = 0.357; P < .001). This study concludes that there is a positive correlation between serum uric acid levels and insulin resistance.

Proteolytic Activation of the Epithelial Sodium Channel (ENaC): Its Mechanisms and Implications.

Epithelial sodium channel (ENaC) are integral to maintaining salt and water homeostasis in various biological tissues, including the kidney, lung, and colon. They enable the selective reabsorption of sodium ions, which is a process critical for controlling blood pressure, electrolyte balance, and overall fluid volume. ENaC activity is finely controlled through proteolytic activation, a process wherein specific enzymes, or proteases, cleave ENaC subunits, resulting in channel activation and increased sodium reabsorption. This regulatory mechanism plays a pivotal role in adapting sodium transport to different physiological conditions. In this review article, we provide an in-depth exploration of the role of proteolytic activation in regulating ENaC activity. We elucidate the involvement of various proteases, including furin-like convertases, cysteine, and serine proteases, and detail the precise cleavage sites and regulatory mechanisms underlying ENaC activation by these proteases. We also discuss the physiological implications of proteolytic ENaC activation, focusing on its involvement in blood pressure regulation, pulmonary function, and intestinal sodium absorption. Understanding the mechanisms and consequences of ENaC proteolytic activation provides valuable insights into the pathophysiology of various diseases, including hypertension, pulmonary disorders, and various gastrointestinal conditions. Moreover, we discuss the potential therapeutic avenues that emerge from understanding these mechanisms, offering new possibilities for managing diseases associated with ENaC dysfunction. In summary, this review provides a comprehensive discussion of the intricate interplay between proteases and ENaC, emphasizing the significance of proteolytic activation in maintaining sodium and fluid balance in both health and disease.

Mechanisms and treatment of obesity-related hypertension-Part 1: Mechanisms.

The prevalence of obesity has tripled over the past five decades. Obesity, especially visceral obesity, is closely related to hypertension, increasing the risk of primary (essential) hypertension by 65%-75%. Hypertension is a major risk factor for cardiovascular disease, the leading cause of death worldwide, and its prevalence is rapidly increasing following the pandemic rise in obesity. Although the causal relationship between obesity and high blood pressure (BP) is well established, the detailed mechanisms for such association are still under research. For more than 30 years sympathetic nervous system (SNS) and kidney sodium reabsorption activation, secondary to insulin resistance and compensatory hyperinsulinemia, have been considered as primary mediators of elevated BP in obesity. However, experimental and clinical data show that severe insulin resistance and hyperinsulinemia can occur in the absence of elevated BP, challenging the causal relationship between insulin resistance and hyperinsulinemia as the key factor linking obesity to hypertension. The purpose of Part 1 of this review is to summarize the available data on recently emerging mechanisms believed to contribute to obesity-related hypertension through increased sodium reabsorption and volume expansion, such as: physical compression of the kidney by perirenal/intrarenal fat and overactivation of the systemic/renal SNS and the renin-angiotensin-aldosterone system. The role of hyperleptinemia, impaired chemoreceptor and baroreceptor reflexes, and increased perivascular fat is also discussed. Specifically targeting these mechanisms may pave the way for a new therapeutic intervention in the treatment of obesity-related hypertension in the context of 'precision medicine' principles, which will be discussed in Part 2.

Early Interleukin-6 Mediated Activation of SGK1 is Primarily via Variant 6

Hypertension is associated with inflammation, including elevated interleukin-6 (IL-6) levels. IL-6 is an inflammatory cytokine, which we have previously shown to activate the mineralocorticoid receptor (MR) and the downstream sodium (Na) transporters- Na-chloride cotransporter (NCC) and the epithelial Na channel (ENaC). However, how IL-6 activates the MR is still unknown. IL-6 is also linked to Serum and Glucocorticoid-regulated Kinase 1 (SGK1), which is a downstream effector of the MR. SGK1 regulates both NCC and ENaC, increasing activity and tubular reabsorption of Na. This increased Na reabsorption favors water retention, thus increasing blood pressure. Previously, IL-6 has also been linked with SGK1 activation. We hypothesize that IL-6 increases SGK1 mRNA and protein expression in renal epithelial cells. To test this, we used in vitro renal epithelial cell models of both the late distal convoluted tubule (DCT2) and inner medullary collecting duct (IMCD), mDCT15 and IMCD3, respectively. Cells were treated with an IL-6 time-course (100ng/ml for 1, 3 and 6 hours). There are 6 known transcriptional variants for SGK1. We designed variant-specific PCR primers and, a pilot study based on regular PCR concluded that expression levels of only variants 5 and 6 (V5, V6) are significant. Using Real Time quantitative RT-PCR, we were then able to quantify transcript levels of both SGK1 V5 and V6 variants. With IL-6 treatment, we observed a 160%-211% increase at early time points (30mins-1hr) in SKG1 V6 and a lesser response (26%-88% increase) with V5 as compared to vehicle treated mDCT15 cells. Since SGK1 has been observed in the membrane fraction and in the cytoplasm, protein extracts from cells were fractionated (mPER kit) to assess membrane and cytosolic SGK1 protein levels using immunoblots. Densitometric analysis of immunoblots demonstrated a 5.5- and 3.1-fold increase in SGK1 protein expression at 1hr in mDCT15 and IMCD3 cells, respectively. These data suggest that IL-6 induces increases in SGK1 transcription and translation. Interestingly, we also found that majority of SGK1 was in the membrane fraction and the level was consistent. Together, these data suggest that SGK1 V6 may be responsible for the increased sodium reabsorption in response to IL-6 stimulation in renal epithelial cells. NIH funding This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hydration as a modulator of renal vascular control during physical work in the heat

Occupational heat stress increases the risk of developing kidney injury (KI), which is due to the development of hyperthermia and/or hypohydration. It is speculated that this KI is caused by a relative mismatch in oxygen supply (i.e., reductions in renal perfusion) and demand (due to increased sodium reabsorption) in the renal tubules. That said, the modulatory role of hydration on renal vascular control during physical work in the heat is largely unknown. Recent observations indicate that ad lib drinking largely prevents hypohydration during simulated occupational heat stress. Thus, we tested the hypothesis that, compared to ad libitum drinking, fluid restriction induces a pro-vasoconstrictor state in the renal vasculature during physical work in the heat.On two occasions, six healthy adults (1 woman) completed 2 h of exercise in a wet bulb globe temperature of 30±0°C, conditions that are commonly experienced by U.S. outdoor workers. Exercise consisted of completing eight circuits involving treadmill walking (10 min) and rowing (5 min) at a workload eliciting an oxygen uptake of 1.2 L/min, the work intensity observed during agriculture work. In the drinking trial (Drink), subjects were provided 237 mL of sport drink every 15 min and drank ad libitum, which is compliant with workplace hydration recommendations. In the fluid restriction trial (NoDrink), no fluid was provided. Rectal temperature and body mass loss were recorded in each trial. Blood pressure and right renal segmental blood velocity (BV, Doppler ultrasound) was measured before, and following 60 and 120 min of exercise. Before and following exercise, a cold pressor test (CPT) was used to assess the renal vasoconstrictor response to sympathetic activation by immersing the subject’s foot in an agitated ice slurry for 2 min. Blood pressure and segmental BV were measured during each minute of the CPT. Segmental artery vascular resistance (VR) was calculated as mean arterial pressure divided by segmental BV. Data presented as mean ± SD.Average rectal temperature was not different between Drink (37.8±0.4°C) and NoDrink (37.9±0.4°C, p=0.517). Body mass loss was greater in NoDrink (3.1±0.7%) vs. Drink (1.8±0.8%, p=0.014). Segmental BV did not change differently between trials (interaction: p=0.651). Segmental VR did not differ between trials before (Drink: 2.7±0.6, NoDrink: 2.5±0.6 mmHg/cm/s) or after 60 (Drink: 2.8±0.7, NoDrink: 2.6±0.6 mmHg/cm/s) and 90 (Drink: 2.5±0.3, NoDrink: 2.3±0.8 mmHg/cm/s) min of exercise (interaction: p=0.988). Peak increases in segmental VR during the CPT did not differ between trials before (Drink: 0.5 ± 0.7, NoDrink: 0.9 ± 0.6 mmHg/cm/s) or after (Drink: 0.4 ± 0.7, NoDrink: 0.4 ± 0.6 mmHg/cm/s) exercise (interaction: p=0.405).These findings preliminarily indicate that fluid replacement does not modify renal vascular control during physical work in the heat. NCT: NCT05458843. Supported by: R01OH011528 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cerebral salt wasting syndrome: A case report

Introduction: The development of extracellular volume reduction due to decreased renal sodium transport in individuals with the intracranial illness and normal adrenal and thyroid function is known as a cerebral salt wasting syndrome (CSWS). Complications of cerebral salt-wasting syndrome include symptomatic hyponatremia and dehydration. We reported and discussed the diagnostic approach and the management of a 66-year-old woman who experienced severe hyponatremia with a history of head trauma and was treated at Udayana University Hospital. Case Description: A 66-year-old female patient complained of decreased consciousness. According to family information, the patient complained of having decreased consciousness one hour before admission and was accompanied by vomiting one time. Two weeks before admission, the patient had fallen, and the back of the patient's head had hit the table. The patient also had time to experience stiffness in the right and left hands and stomping. Urine collected 24 hours as much as 3880 ml on the first day of treatment. Conclusion: In cerebral salt wasting syndrome (CSWS) the management mainly focuses on the correction of intravascular volume depletion using 0.9% sodium chloride and hyponatremia, as well as on the replacement of ongoing urinary sodium loss, usually with iv hypertonic saline solutions, Fludrocortisone/mineralocorticoid that directly acts on the renal tubules to increase sodium reabsorption showed a favorable response in CSWS.

Commentary on glucose reduction in type 2 diabetes (GRADE).

Commentary on glucose reduction in type 2 diabetes (GRADE).

Diagnosis and Treatment of Monogenic Hypertension in Children.

Although the majority of individuals with hypertension (HTN) have primary and polygenic HTN, monogenic HTN is a secondary type that is widely thought to play a key role in pediatric HTN, which has the characteristics of early onset, refractory HTN with a positive family history, and electrolyte disorders. Monogenic HTN results from single genetic mutations that contribute to the dysregulation of blood pressure (BP) in the kidneys and adrenal glands. It is pathophysiologically associated with increased sodium reabsorption in the distal tubule, intravascular volume expansion, and HTN, as well as low renin and varying aldosterone levels. Simultaneously increased or decreased potassium levels also provide clues for the diagnosis of monogenic HTN. Discovering the genetic factors that cause an increase in BP has been shown to be related to the choice of and responses to antihypertensive medications. Therefore, early and precise diagnosis with genetic sequencing and effective treatment with accurate antihypertensive agents are critical in the management of monogenic HTN. In addition, understanding the genetic architecture of BP, causative molecular pathways perturbing BP regulation, and pharmacogenomics can help with the selection of precision and personalized medicine, as well as improve morbidity and mortality in adulthood.

Renal lysophospholipase A1 contributes to Enterococcus faecalis-induced hypertension by enhancing sodium reabsorption.

Our recent study has found that gut bacteria Enterococcus faecalis contributes to hypertension and upregulates lysophospholipase A1 (LYPLA1) in the renal medulla of rats. This work aimed to investigate the role of LYPLA1 in the development of E.faecalis-induced hypertension. Compared to control, E.faecalis treatment increased blood pressure (BP), serum angiotensin II, sodium reabsorption, and expression of αENaC and LYPLA1 in the renal medulla of mice, and these effects were attenuated by knockdown of LYPLA1. Moreover, the intrarenal lypla1 overexpression increased sodium reabsorption and BP. Further studies showed that LYPLA1 promoted the accumulation of renal glycerophosphocholine (GPC), which directly elevated the expression of αENaC and sodium reabsorption. In addition, enriched abundance of LYPLA1 in the renal medulla and urine was also observed in other hypertensive animals. Overall, our results demonstrate that LYPLA1 contributes to E.faecalis-induced hypertension by accumulating GPC and activating ENaC in the renal medulla.

Ang II acutely stimulates Na,K-pump in cells from proximal tubules by increasing its phosphorylation at S938 via a PI3K/AKT pathway.

Angiotensin II (Ang II)-dependent stimulation of the AT1 receptor in proximal tubules increases sodium reabsorption and blood pressure. Reabsorption is driven by the Na,K-pump that is acutely stimulated by Ang II, which requires phosphorylation of serine-938 (S938). This site is present in humans and only known to phosphorylated by PKA. Yet, activation of AT1 decreases cAMP required to activate PKA and inhibiting PKA does not block Ang II-dependent phosphorylation of S938. We tested the hypothesis that Ang II-dependent activation is mediated via increased phosphorylation at S938 through a PI3K/AKT-dependent pathway. Experiments were conducted using opossum kidney cells, a proximal tubule cell line, stably co-expressing the AT1 receptor and either the wild-type (α-1.wild-type) or an alanine substituted (α-1.S938A) form of rat kidney Na,K-pump. A 5-min exposure to 10pM Ang II significantly activated Na,K-pump activity (56%) measured as short-circuit current across polarized α-1.wild-type cells. Wortmannin, at a concentration that selectively inhibits PI3K, blocked that Ang II-dependent activation. Ang II did not stimulate Na,K-pump activity in α-1.S938A cells. Ang II at 10 and 100 pM increased phosphorylation at S938 in α-1.wild-type cells measured in whole cell lysates. The increase was inhibited by wortmannin plus H-89, an inhibitor of PKA, not by either alone. Ang II activated AKT inhibited by wortmannin, not H-89. These data support our hypothesis and show that Ang II-dependent phosphorylation at S938 stimulates Na,K-pump activity and transcellular sodium transport.

New Strategies for Volume Control in Patients with Diabetes Mellitus, a Narrative Review.

Sodium is reabsorbed all along the renal tubules. The positive impacts of sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitor (ARNI) and mineralocorticoid receptor antagonists (MRA) on hard renal and/or cardiac endpoints calls for the role of diuretics in nephroprotection and cardioprotection in patients with diabetes mellitus to be reviewed. Here, we review: (a) the mechanisms of action of the available natriuretics; (b) the physiological adaptations to chronic loop diuretic usage that lead to increased sodium reabsorption in the proximal and distal convoluted tubules; (c) the physiology of sodium retention in patients with diabetes mellitus; and (d) the mechanisms of aldosterone breakthrough. We show the rationale for combined diuretics to target not only the loop of Henle, but also the proximal and distal convoluted tubules. Indeed, higher residual proteinuria in patients treated with renin-angiotensin-aldosterone system (RAAS) blockers portends poorer renal and cardiovascular outcomes. Diuretics are known to optimize the reduction of proteinuria, in addition to RAAS blockers, but may favor aldosterone breakthrough in the absence of MRA. The aim of our study is to support a combined diuretics strategy to improve the management of patients with diabetes mellitus and chronic kidney disease or heart failure.

Activation of the Hypoxia-Inducible Factor Pathway Inhibits Epithelial Sodium Channel-Mediated Sodium Transport in Collecting Duct Principal Cells.

Active sodium reabsorption is the major factor influencing renal oxygen consumption and production of reactive oxygen species (ROS). Increased sodium reabsorption uses more oxygen, which may worsen medullary hypoxia and produce more ROS via enhanced mitochondrial ATP synthesis. Both mechanisms may activate the hypoxia-inducible factor (HIF) pathway. Because the collecting duct is exposed to low oxygen pressure and variations of active sodium transport, we assessed whether the HIF pathway controls epithelial sodium channel (ENaC)-dependent sodium transport. We investigated HIF's effect on ENaC expression in mpkCCD cl4 cells (a model of collecting duct principal cells) using real-time PCR and western blot and ENaC activity by measuring amiloride-sensitive current. We also assessed the effect of hypoxia and sodium intake on abundance of kidney sodium transporters in wild-type and inducible kidney tubule-specific Hif1α knockout mice. In cultured cells, activation of the HIF pathway by dimethyloxalylglycine or hypoxia inhibited sodium transport and decreased expression of β ENaC and γ ENaC, as well as of Na,K-ATPase. HIF1 α silencing increased β ENaC and γ ENaC expression and stimulated sodium transport. A constitutively active mutant of HIF1 α produced the opposite effect. Aldosterone and inhibition of the mitochondrial respiratory chain slowly activated the HIF pathway, suggesting that ROS may also activate HIF. Decreased γ ENaC abundance induced by hypoxia in normal mice was abolished in Hif1α knockout mice. Similarly, Hif1α knockout led to increased γ ENaC abundance under high sodium intake. This study reveals that γ ENaC expression and activity are physiologically controlled by the HIF pathway, which may represent a negative feedback mechanism to preserve oxygenation and/or prevent excessive ROS generation under increased sodium transport.

ATRAP, a receptor-interacting modulator of kidney physiology, as a novel player in blood pressure and beyond.

Pathological activation of kidney angiotensin II (Ang II) type 1 receptor (AT1R) signaling stimulates tubular sodium transporters, including epithelial sodium channels, to increase sodium reabsorption and blood pressure. During a search for a means to functionally and selectively modulate AT1R signaling, a molecule directly interacting with the carboxyl-terminal cytoplasmic domain of AT1R was identified and named AT1R-associated protein (ATRAP/Agtrap). We showed that ATRAP promotes constitutive AT1R internalization to inhibit pathological AT1R activation in response to certain stimuli. In the kidney, ATRAP is abundantly distributed in epithelial cells along the proximal and distal tubules. Results from genetically engineered mice with modified ATRAP expression show that ATRAP plays a key role in the regulation of renal sodium handling and the modulation of blood pressure in response to pathological stimuli and further suggest that the function of kidney tubule ATRAP may be different between distal tubules and proximal tubules, implying that ATRAP is a target of interest in hypertension.

Dysfunction of Cullin 3 RING E3 ubiquitin ligase causes vasoconstriction and increased sodium reabsorption in diabetes

Impaired endothelium-mediated vasodilation and/or increased sensitivity to vasoconstrictors lead to vascular smooth muscle cell (VSMC) dysfunction in individuals with diabetes. Diabetic nephropathy is associated with a considerably higher risk of cardiovascular disease and death than their nondiabetic counterparts. We studied the activity of Cullin 3 RING ubiquitin ligase (CRL3) and its substrates in mice using an intraperitoneal injection of streptozotocin (STZ) and db/db mice. The levels of CRL3 adaptors, including Kelch-like 2/3 (KLHL2/3) and Rho-related BTB domain-containing protein 1, were significantly decreased in the aortic tissues and heart of the STZ group, whereas the levels of Cullin 3 (CUL3) and its neddylated derivatives were substantially increased. Decreased KLHL3 expression and significantly increased expression of NEDD8 conjugates were observed in the kidneys of db/db mice. The neddylation inhibitor MLN4924 decreased the degradation of KLHL2/KLHL3 under high-glucose conditions with/without insulin, and transfection with KLHL2 promoted the degradation of its substrates with-no-lysine (WNK) kinases. Increased abundance of WNK3, RhoA/ROCK activity and phosphodiesterase 5 enhanced the sensibility to vasoconstrictors and impaired vasodilation. Moreover, WNK3 localized in VSMCs undergoing cell division, and high-glucose medium increased WNK3 signaling in VSMCs undergoing mitosis, which might explain the increased thickness of aortic tissues in subjects with diabetes. Increases in WNK4 abundance resulted in increased sodium reabsorption in the distal renal tubules. Thus, KLHL2/RhoBTB1/KLHL3 inactivation in the aortic tissues and kidney is a result of excessive activation of neddylation in hyperglycemia and hyperinsulinemia, which affects vascular tone and sodium reabsorption.

ENaC and N‐methyl‐D‐aspartate (NMDA) receptors interact in the connecting tubule inducing renal vasodilation and blood pressure changes

Introduction N-methyl-D-aspartate (NMDA) receptors are expressed throughout the nephron, including distal nephron principal cells (PC), and induce renal vasodilation through an unknown mechanism. Connecting tubule-glomerular feedback (CNTGF) is a vasodilator feedback mechanism mediated by PC's ENaC producing afferent arteriole (AfA) vasodilatation and promote sodium excretion. We hypothesized that NMDA receptors activation stimulate ENaC and consequently CNTGF, and that the inhibition of NMDA receptors decrease CNTGF inducing hypertension. Methods To determine the effect of NMDA receptor on CNTGF-mediated AfA dilation, we measured CNTGF-mediated AfA dilation in the presence or absence of NMDA receptor antagonists with and without NMDA antagonist (MK801), using a double-perfusion method of the AfA and CNT ex vivo in rabbits and stop-flow pressure (SFP) technique in vivo in rats. To investigate NMDAr-ENsC interaction we measured ENaC open probability (NPo) on split open tubules (CCD) from mice at baseline and with the NMDA agonist. To evaluate the effect of the NMDA receptor in blood pressure regulation, we use the NMDA inhibitor MK801 infused by osmotic minipumps for 7 days in liddle syndrome mouse (β ENaC mutated allele on129/Sv background) on normal salt diet. Under normal salt diet, blood pressure (BP) is not different from wild type despite evidence for increased sodium reabsorption in distal colon and low plasma aldosterone, suggesting chronic hypervolemia. BP was measure using tail cuff methods. Results In pre-constricted AfA, in vitro NMDA agonist application to the connecting tubule lumen increased AfA dilation (p<0.001). This amino-acid-induced dilation was blocked with the CNTGF inhibitor benzamil and blunted with the NMDA receptor blocker MK-801. In vivo, NMDA agonist increase CNTGF (P<0.01). In split open tubules, NMDA activation increased ENaC NPo (p=0.04), suggesting an interaction between those channels. Basal BP was similar in both mice group (p=0.4). The infusion of NMDA inhibitor (Mk-801) during 7 days induces hypertension (SBP 146±8 mmHg) while the vehicle infused mice remained normotensives (110.7±7.7 mmHg; p<0.01). Conclusions NMDA receptor activation induced renal vasodilation by increasing the ENaC dependent CNTGF responses . NMDA inhibition decrease ENaC activation and consequently inhibit CNTGF induced-vasodilation and promote hypertension. These results provide evidence on the role of NMDA receptors on renal hemodynamic and blood pressure regulation.

N-METHYL-D-ASPARTATE (NMDA) RECEPTORS IN THE CONNECTING TUBULE INDUCE RENAL VASODILATION AND REGULATES BLOOD PRESSURE

Objective: N-methyl-D-aspartate (NMDA) receptors are expressed throughout the nephron, including distal nephron principal cells (PC), and induce renal vasodilation through an unknown mechanism. Connecting tubule-glomerular feedback (CNTGF) is a vasodilator feedback mechanism producing afferent arteriole (AfA) vasodilatation and promote sodium excretion. We hypothesized that NMDA receptors activation stimulate CNTGF and that the inhibition of NMDA receptors decrease CNTGF inducing hypertension. Design and method: To determine the effect of NMDA receptor on CNTGF-mediated AfA dilation, we measured CNTGF-mediated AfA dilation in the presence or absence of NMDA receptor antagonists with and without NMDA antagonist (MK801), using a double-perfusion method of the AfA and CNT ex vivo in rabbits and stop-flow pressure (SFP) technique in vivo in rats. To evaluate the effect of the NMDA receptor in blood pressure regulation, we use the NMDA inhibitor MK801 infused by osmotic minipumps for 7 days in liddle syndrome mouse (βENaC mutated allele on129/Sv background) on normal salt diet. Under normal salt diet, blood pressure (BP) is not different from wild type despite evidence for increased sodium reabsorption in distal colon and low plasma aldosterone, suggesting chronic hypervolemia. BP was measure using tail cuff methods. Results: In pre-constricted AfA, in vitro NMDA agonist application to the connecting tubule lumen increased AfA dilation (p &lt; 0.001). This amino-acid-induced dilation was blocked with the CNTGF inhibitor benzamil and blunted with the NMDA receptor blocker MK-801. In vivo, NMDA agonist increase CNTGF (P &lt; 0.01). Basal BP was similar in both mice group (p = 0.4). The infusion of NMDA inhibitor (Mk-801) during 7 days induces hypertension (SBP 146 ± 8 mmHg) while the vehicle infused mice remained normotensives (110.7 ± 7.7 mmHg; p &lt; 0.01). Conclusions: NMDA receptor activation induced renal vasodilation by increasing CNTGF responses. NMDA inhibition decrease CNTGF induced-vasodilation and promote hypertension. These results provide evidence on the role of NMDA receptors on renal hemodynamic and blood pressure regulation.

Hypertension Editors' Picks: Hyperaldosteronism.

Hypertension Editors' Picks: Hyperaldosteronism.

Role of spironolactone in patients with resistant hypertension

Treatment-resistant hypertension (RH) is defined as uncontrolled blood pressure (BP) despite use of at least three different antihypertensive agents (including angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, calcium channel blocker, and a diuretic) at their optimal doses. It is important to properly diagnose and treat RH because patients are at high risk of end-organ damage. Activated renin-angiotensin-aldosterone system, increased renal sympathetic nervous system activity (increase sodium and water reabsorption and thus increase in extracellular fluid volume), and increased arterial stiffness become the main reason for hypertension. Therefore, a controlled BP can be achieved by the use of mineralocorticoid receptor blockers as add-on treatment to the first-line triple-drug combination therapy. In this review, we provide evidences from various studies comparing spironolactone treatment with other comparators (diuretics or other mineralocorticoid receptor blockers) or placebo signifying spironolactone is beneficial for controlling BP in patients with RH. Furthermore, there is a greater need to increase the use of mineralocorticoid receptor blocker, spironolactone, as fourth-line medication add-on to three drug therapy in patients with RH.