Renal Sodium Retention Research Articles

Association study of variants in two ion-channel genes (TSC and CLCNKB) and hypertension in two ethnic groups in Northwest China

Background Abnormalities in renal sodium and water retention and membrane ion transport play important roles in development of hypertension. Recently, Arg904Gln variant of thiazide-sensitive NaCl-cotransporter gene (TSC) and Thr418Ser variant of renal epithelial Cl-channel ClC-Kb gene (CLCNKB) were found implicated in the prevalence of essential hypertension (EH). The objective of this study was to examine the role of these two variants on EH in two Chinese minorities—Kazaks and Uyghurs. Methods A case–control study was conducted in Kazak herdsmen and Uyghur farmers live in Xinjiang Uyghur Autonomous Region of Northwest China. Results For the Arg904Gln polymorphism in the TSC gene, we observed a stronger trend of 904Gln allele in controls than hypertensives in Uyghurs ( p = 0.058), but the greater prevalence of genotype of 904Gln carrier reached significance ( p = 0.015). No association or trend with hypertension was observed at Arg904Gln in Kazaks. For the Thr418Ser variant of the CLCNKB gene in Kazaks, we observed a significantly higher prevalence of 418Ser allele frequencies in hypertensives than controls ( p = 0.037), but the higher prevalence of genotype of 418Ser carrier did not reach significance ( p = 0.08).No association with hypertension was observed at Thr418Ser in Uyghurs. Conclusion The risk reduction effect of 904Gln to hypertension in Uyghurs and the association of 418Ser to hypertension in Kazaks are weak. Given that we have explored two polymorphisms in each of two populations, for a total of four independent tests, a Bonferroni correction for multiple tests (0.05/4) renders non-significant of our results in our two Chinese populations ( α = 0.0125). The roles of Thr418Ser polymorphism of the CLCNKB gene and Arg904Gln polymorphism in the TSC gene on essential hypertension need to be explored in other ethnic groups.

Endogenous bufadienolide mediates pressor response to ethanol withdrawal in rats

An endogenous natriuretic and vasoconstrictor Na/K-ATPase inhibitor, marinobufagenin (MBG), is implicated in NaCl-induced hypertension and in ethanol addiction. In rats, MBG suppresses voluntary alcohol intake, while immunization against MBG induces alcohol-seeking behavior. Since alcohol withdrawal is associated with elevation of blood pressure (BP) and renal sodium retention, we hypothesized that MBG mediates pressor response to ethanol withdrawal. In male Sprague–Dawley rats, forced ethanol intake (20% v/v, 2.8 ± 0.2 g/day for 7 days) did not affect BP and MBG excretion. Ethanol withdrawal was associated with a 21 mm Hg increase in BP, a 10% decrease in hematocrit, and a three-fold increase in renal MBG excretion. In vivo administration of anti-MBG antibody to rats prevented withdrawal-induced BP elevation. Therefore, MBG mediates pressor response to ethanol withdrawal, and may link mechanisms of ethanol dependence and hypertension.

Ciclosporin-induced hypertension is associated with increased sodium transporter of the loop of Henle (NKCC2)

Hypertension induced by cyclosporine is associated with renal sodium and water retention. Using immunoblotting of kidney homogenates, we investigated the regulation of sodium and water transport proteins in a rat model of cyclosporine-induced hypertension. Rats were treated with cyclosporine (25 mg/kg/day intraperitoneally) during 7 days. Control rats received vehicle. Cyclosporine-treated rats had an increase in blood pressure with a decrease in renal sodium excretion compared with control rats. There were no differences either in sodium intake or in plasma creatinine levels between the two groups of rats. These data suggest that the decrease in sodium excretion in the cyclosporine-treated rats was due to an increase in renal sodium absorption. The densitometric analysis of the renal immunoblot showed an increase in the Na-K-2Cl cotransporter of the loop of Henle (NKCC2) in cyclosporine-treated rats (178% +/- 36) compared with control rats (100% +/- 18; P < 0.05*). This protein rise was associated with an increase in the NKCC2 mRNA pointing to a transcriptional regulation of this sodium transporter. There were no statistically significant changes in the sodium proton exchange (NHE-3) of the proximal tubule although in this renal segment, aquaporin-1 was increased in cyclosporine-treated rats compared with control rats (control 100% +/- 6 vs cyclosporine 119% +/- 6; P < 0.05*). Our results pointed to the thick ascending limb of the loop of Henle as an important site of sodium retention in cyclosporine-induced hypertension. This data may have potential clinical implications for the treatment of hypertension induced by cyclosporine.

Decreased Effective Blood Volume in Edematous Disorders

Edematous patients with renal sodium and water retention, particularly cardiac failure and cirrhosis, have been suggested to have a decreased "effective blood volume." This enigmatic and undefined term was coined because edematous patients were found to have increased, rather than the earlier proposed decreased, blood volumes. This article discusses the advances that have occurred in understanding the pathophysiology of edema as occurs in conditions such as cardiac failure, cirrhosis, and pregnancy. The regulatory mechanisms that lead to increased sodium and water retention by the normal kidney are related to arterial underfilling, as a result of a decrease in cardiac output, arterial vasodilation, or both.

A new cholestatic mouse model provides insights into renal reabsorption of sodium

A new cholestatic mouse model provides insights into renal reabsorption of sodium

Sodium retention and ascites formation in a cholestatic mice model

Renal sodium retention in experimental liver cirrhosis originates from the distal nephron sensitive to aldosterone. The aims of this study were to (1) determine the exact site of sodium retention along the aldosterone-sensitive distal nephron, and (2) to evaluate the role of aldosterone and mineralocorticoid receptor activation in this process. Liver cirrhosis was induced by bile duct ligation in either adrenal-intact or corticosteroid-clamped mice. Corticosteroid-clamp was achieved through adrenalectomy and corticosteroid supplementation with aldosterone and dexamethasone via osmotic minipumps. 24-hours renal sodium balance was evaluated in metabolic cages. Activity and expression of sodium- and potassium-dependent adenosine triphosphatase were determined in microdissected segments of nephron. Within 4-5 weeks, cirrhosis induced sodium retention in adrenal-intact mice and formation of ascites in 50% of mice. At that time, sodium- and potassium-dependent adenosine triphosphatase activity increased specifically in cortical collecting ducts. Hyperaldosteronemia was indicated by increases in urinary aldosterone excretion and in sgk1 (serum- and glucocorticoid-regulated kinase 1) mRNA expression in collecting ducts. Corticosteroid-clamp prevented induction of sgk1 but not cirrhosis-induced sodium retention, formation of ascites and stimulation of sodium- and potassium-dependent adenosine triphosphatase activity and expression (mRNA and protein) in collecting duct. These findings demonstrate that sodium retention in cirrhosis is independent of hyperaldosteronemia and of the activation of mineralocorticoid receptor. Bile duct ligation in mice induces cirrhosis which, within 4-5 weeks, leads to the induction of sodium- and potassium-dependent adenosine triphosphatase in cortical collecting ducts, to renal sodium retention and to the formation of ascites. Sodium retention, ascites formation and induction of sodium- and potassium-dependent adenosine triphosphatase are independent of the activation of mineralocorticoid receptors by either aldosterone or glucocorticoids.

Hepatorenal syndrome: an update.

Hepatorenal syndrome (HRS) is the development of renal failure in patients with chronic previous liver disease, without clinical or laboratory evidence of previous kidney disease. It affects up to 18% of cirrhotic patients with ascites during the first year of follow-up, reaching 39% in five years and presenting a survival of about two weeks after its establishment. HRS diagnosis is based on clinical and laboratory data. The occurrence of this syndrome is related to the mechanism for ascites development, involving vasoconstriction, low renal perfusion, water and sodium retention, increased plasma volume, and consequent overflow at the splanchnic level. Renal vasoactive mediators like endothelin 1, thromboxane A2, and leukotrienes are also involved in the genesis of this syndrome, which culminates in functional renal insufficiency. The treatment of choice can be pharmacological or surgical, although liver transplantation is the only permanent and effective treatment, with a four-year survival rate of up to 60%. Liver function recovery is usually followed by renal failure reversion. Early diagnosis and timely therapeutics can increase life expectancy for these patients while they are waiting for liver transplantation as a definitive treatment.

Cross-Talk Between Angiotensin II Receptor Types 1 and 2

Angiotensin (Ang) II exerts its important physiological functions through 2 distinct receptor subtypes, the type 1 (AT1) and type 2 (AT2) receptors.1 The AT1 receptor is expressed in diverse adult tissues, and its distribution is indicative of the fundamental role of Ang II on the regulation of cardiovascular and renal homeostasis. The predominant actions of Ang II, such as vasoconstriction, cellular proliferation and growth, renal sodium retention, and release of aldosterone, are linked to the activation of various signal-transduction pathways modulated by the AT1 receptor. Although the AT2 receptor is highly expressed in the fetus, its expression in adult tissues is low but increases in response to injury.2–5 It has been demonstrated that AT1 and AT2 receptors have counterregulatory interactions in the cardiovascular system.2 The AT2 receptor has been shown to exert an inhibitory effect on the growth-promoting action of the AT1 receptor.6 The cross-talk between AT1 and AT2 receptors has also been suggested to participate in the regulation of blood pressure. Ang II binding to the AT1 receptor activates G protein-coupled phospholipase C and inositol-1,4,5-triphosphate, which increases intracellular Ca2+ levels resulting in vasoconstriction. On the other hand, Ang II binding to the AT2 receptor activates a counterregulatory pathway …

Volumenüberladung bei Herzinsuffizienz, nephrotischem Syndrom und Leberzirrhose

Volume retention in heart failure, nephrotic syndrome, and liver cirrhosis reflects pathological changes in homeostatic mechanisms that regulate the extracellular volume (sympathetic activity, renin-angiotensin-aldosterone system [RAAS], natriuretic peptides) and plasma osmolality (antidiuretic hormone [ADH]). In heart failure and liver cirrhosis, these changes are induced by a reduction of the effective circulating volume, which is the part of the extracellular fluid that is within the arterial system and effectively perfusing the tissues. This reduction in the effective circulating volume is caused by reduced cardiac output (heart failure), or by splanchnic vasodilatation with arterial underfilling (liver cirrhosis). In both cases, baroreceptors in both the carotid sinuses and in the glomerular afferent arterioles upregulate RAAS- and sympathetic activity, resulting in systemic vasoconstriction and renal sodium (and volume) retention. More severe reductions in the effective circulating volume may additionally stimulate ADH release, thus increasing the reabsorption of free water with subsequent hyponatriemia. In nephrotic syndrome, volume retention results either directly from the primary renal disease, which induces renal sodium and volume retention ("overfilling"), or indirectly from the reduced plasma oncotic pressure due to hypoalbuminemia, which induces a fluid shift from the intravascular to the interstitial space ("underfilling") with subsequent acitivation of baroreceptors and secondary sodium and volume retention.

Role of Angiotensin Type 2 Receptors in Vasodilation of Resistance and Capacitance Vessels

Angiotensin II (Ang II), the major effector component of the renin-angiotensin system, has an important regulatory role in cardiovascular and renal function. Ang II exerts its actions by binding with equal affinity to angiotensin type 1 (AT1) and type 2 (AT2) receptors.1 The predominant receptor subtype found in the vasculature of adults is the AT1 receptor. Ang II activation of AT1 receptors induces vasoconstriction, cellular proliferation, tissue growth, renal sodium retention, sympathetic nervous system stimulation, and aldosterone secretion, the integrated response of which leads to increased blood pressure.1 The AT2 receptor is expressed in large quantities in the fetus and decreases markedly after birth but is still present in low amounts in adult tissues.1,2 AT2 receptors are upregulated under conditions associated with cardiovascular tissue damage, such as myocardial infarction, heart failure, and hypertension.3 The relatively low expression level of AT2 receptors compared with that of AT1 receptors is a major reason why the actions and cell signaling mechanisms of AT1 receptors are well characterized compared with those of AT2 receptors. Ang II binding to AT2 receptors activates a counterregulatory pathway whereby …

Increased renal phosphodiesterase-5 activity mediates the blunted natriuretic response to ANP in the pregnant rat

Normal rat pregnancy is characterized by plasma volume expansion due to renal sodium retention and is associated with a blunted response to natriuretic stimuli, such as atrial natriuretic peptide (ANP). ANP signals via cGMP, and phosphodiesterases (PDE) inactivate cGMP and terminate the natriuretic response. We previously reported that increased medullary PDE-5 activity occurs in rat pregnancy, which may be the mechanism of the blunted natriuretic effect of ANP. Here, we used anesthetized 16-day pregnant and virgin rats to investigate whether intrarenal infusion of a selective PDE-5 inhibitor, sildenafil, would reverse the blunted response to ANP in pregnancy. We measured blood pressure, renal clearances using inulin and p-aminohippuric acid, and electrolyte excretion at baseline and during an ANP infusion. ANP caused a fall in mean arterial pressure in all groups, and sildenafil induced a further reduction. We observed an increase in sodium excretion with ANP in all rats, but this was blunted in the vehicle-infused pregnant rats. This could not be explained by differences in renal hemodynamics and was of tubular origin, as reflected by the reduced rise in fractional excretion of sodium with ANP in the pregnant rat given vehicle (45 +/- 11 vs. 204 +/- 49%; P < 0.05). However, intrarenal sildenafil increased the natriuretic response and the rise in fractional excretion of sodium to the virgin value (226 +/- 23 vs. 245 +/- 73%; not significant), whereas the blunting persisted in the contralateral kidney. This demonstrates that increased intrarenal PDE-5 mediates the blunted natriuretic response to ANP during pregnancy and may contribute to the physiological volume expansion.

Mechanisms of Sympathetic Activation in Obesity-Related Hypertension

Obesity prevalence is soaring in industrialized countries and progressively increasing in the developing world. Altered patterns of nutrition and reduction in work-related energy expenditure have led to obesity becoming a truly global health issue. The central thermodynamic formulation for the origins of obesity, a mismatched energy balance equation, with an excess of dietary calorie intake over body energy expenditure, is a first step in the understanding of this phenomenon but leaves the diverse causal issues unexplored. Dietary calorie intake is modified by multiple social, economic, and cultural issues. Similarly, the reduction in energy expenditure in recent decades has complex origins, deriving from demographic and social change, which includes third-world transition from a labor-intensive agricultural economy to an industrial base, the introduction of household labor-saving devices, the popularity of transportation modes not reliant on physical effort, and from changed recreational habits, particularly in childhood (computer games instead of physical games). The prevalence of childhood obesity is escalating, having whimsically but not entirely unrealistically been attributed to “potato chips and computer chips.” Obesity and hypertension are intimately associated, and both very commonly coexist in individual patients with insulin resistance, hyperinsulinemia, and hyperlipidemia, this clustering of adverse health factors1 being designated the metabolic syndrome. The pathophysiological mechanisms by which obesity leads to hypertension remain uncertain. Understanding these processes might, perhaps, provide a more rational basis for drug treatment of obesity-related hypertension. Attempts at reduction in body weight, although pivotal in the treatment of obesity-related hypertension, more often than not fail, so that antihypertensive drug therapy is often needed. This review analyses the proposition that obesity is characterized by activation of the sympathetic nervous system and that obesity-related hypertension is, in fact, neurogenic, being initiated and sustained by neural mechanisms. At one time, this idea would have been held to fly in the …

Renal sodium retention in cirrhotic rats depends on glucocorticoid-mediated activation of mineralocorticoid receptor due to decreased renal 11β-HSD-2 activity

Downregulation of the renal glucocorticoid-metabolizing enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD-2) during liver cirrhosis may allow activation of the mineralocorticoid receptor (MR) by glucocorticoids and contribute to sodium retention. We tested this hypothesis in male Wistar rats with decompensated liver cirrhosis and ascites 7 wk after bile duct ligation (BDL). Renal 11beta-HSD-2 mRNA, protein, and activity were significantly decreased in decompensated rats. The urinary Na(+)/K(+) ratio was reduced by 40%. Renal epithelial sodium channel (ENaC) mRNA and immunostaining were only slightly affected. Complete metabolic studies, including fecal excretion, showed that the BDL rats had avid renal sodium retention. Treatment of the BDL rats with dexamethasone suppressed endogenous glucocorticoid production, normalized total sodium balance and renal sodium excretion, and reduced ascites formation to the same degree as direct inhibition of MR with K-canrenoate. Total potassium balance was negative in the BDL rats, whereas renal potassium excretion was unchanged. In the distal colon, expression of ENaC was increased in BDL rats. Fecal potassium excretion was increased in cirrhotic rats, and this was corrected by treatment with K-canrenoate but not dexamethasone. We conclude that development of sodium retention and decompensation in cirrhotic rats is associated with downregulation of renal 11beta-HSD-2 activity and inappropriate activation of renal sodium reabsorption by endogenous glucocorticoids. In addition, the overall potassium loss in the BDL model is due to increased fecal potassium excretion, which is associated with upregulation of ENaC in distal colon.

PPARγ agonists: safety issues in heart failure

PPARgamma agonists (or thiazolidinediones, TZD) are popular oral drugs for glycaemic control in patients with diabetes mellitus. However, side-effects of fluid retention, oedema and congestive heart failure have been reported in the literature as well as observed in clinical registries and trials. Concerns regarding the safety of TZD use in patients with underlying heart failure have been implicated by its propensity to cause fluid retention. There is relatively good documentation in the literature that TZDs do not produce adverse haemodynamic consequences. TZD-induced fluid retention is often sub-acute in nature, developed over weeks to months following initiation, and primarily located in the periphery. Drug withdrawal may lead to complete resolution of fluid retention. Current approval of TZD use in patients with mild (NYHA class I - II) and stable heart failure is supported by existing literature and clinical experience. There have been few reports of severe adverse consequences following drug withdrawal, and emerging data are suggesting potential benefits of TZDs in the diabetic population with or without underlying heart failure. Future research should therefore be directed at better understanding PPARgamma-related mechanisms of renal sodium retention and endothelial vascular permeability of the periphery, as well as development of newer compounds without this side-effect.

Sleep and Hypertension

The article by Gangwisch et al1 in this issue of Hypertension identifies another significant health hazard associated with inadequate sleep. The authors document ≈2-fold greater risk for hypertension among adults in their fourth to sixth decades who sleep ≤5 hours each night. Whereas the independent risk of short sleep duration for developing hypertension is attenuated to ≈1.6-fold after adjusting for obesity and diabetes, short sleep duration is a risk factor for obesity and diabetes.2,3 The investigators provide plausible mechanisms linking short sleep duration to hypertension.1 Potential mechanisms include an increased blood pressure (BP) load resulting from prolongation of higher BP while awake and truncation of the BP dip characteristic of sleep. A decrease in sleep duration leads to both greater BP load1 and prolonged exposure to an activated sympathetic nervous system,4 which could accentuate structural remodeling and augment renal sodium retention. Structural changes in key target organs participating in BP regulation including the kidney, heart, and vasculature could serve to perpetuate and accelerate age-related increases in BP, especially in those at risk. In this regard, it is interesting to note a study of rapid eye movement sleep deprivation in spontaneously hypertensive, normotensive Wistar-Kyoto, and borderline hypertensive …

Obesity and the renin– angiotensin–aldosterone system

The renin–angiotensin–aldosterone system (RAAS) is a key regulator of cardiovascular function. RAAS activity is upregulated in obesity despite concurrent renal sodium retention, which is a hallmark and principle determinant of obesity-associated hypertension. The contribution of adipose tissue to increased angiotensinogen and aldosterone plasma levels in obesity is probably due to the secretion of angiotensinogen and, as yet, unidentified aldosterone secretagogues by adipocytes. Increased circulating renin activity, on the other hand, is probably due to increased sympathetic activity in the obese. Modest weight reduction significantly reduces RAAS activity by uncertain mechanisms. Pharmacological blockade of the RAAS yielded promising results, both with regard to cardiovascular function and metabolic complications of obesity. These studies suggest that the activated RAAS is a prime pharmacological target for reducing the cardiometabolic risk in obese patients.

Dysregulation of ENaC in Animal Models of Nephrotic Syndrome and Liver Cirrhosis

Nephrotic syndrome and liver cirrhosis are common clinical manifestations, and are associated with avid sodium retention leading to the development of edema and ascites. However, the mechanism for the sodium retention is still incompletely understood and the molecular basis remains undefined. We examined the changes of sodium (co)transporters and epithelial sodium channels (ENaCs) in the kidneys of experimental nephrotic syndrome and liver cirrhosis. The results demonstrated that puromycin- or HgCl2-induced nephrotic syndrome was associated with 1) sodium retention, decreased urinary sodium excretion, development of ascites, and increased plasma aldosterone level; 2) increased apical targeting of ENaC subunits in connecting tubule and collecting duct segments; and 3) decreased protein abundance of type 2 11β-hydroxysteroid dehydrogenase (11βHSD2). Experimental liver cirrhosis was induced in rats by CCl4 treatment or common bile duct ligation. An increased apical targeting of alpha-, beta-, and gamma-ENaC subunits in connecting tubule, and cortical and medullary collecting duct segments in sodium retaining phase of liver cirhosis but not in escape phase of sodium retention. Immunolabeling intensity of 11βHSD2 in the connecting tubule and cortical collecting duct was significantly reduced in sodium retaining phase of liver cirrhosis, and this was confirmed by immunoblotting. These observations therefore strongly support the view that the renal sodium retention associated with nephrotic syndrome and liver cirrhosis is caused by increased sodium reabsorption in the aldosterone sensitive distal nephron including the connecting tubule and collecting duct, and increased apical targeting of ENaC subunits plays a role in the development of sodium retention in nephrotic syndrome and liver cirrhosis.

Impaired 11β‐hydroxysteroid dehydrogenase contributes to renal sodium avidity in cirrhosis

Exaggerated renal sodium retention with concomitant potassium loss is a hallmark of cirrhosis and contributes to the accumulation of fluid as ascites, pleural effusion, or edema. This apparent mineralocorticoid effect is only partially explained by increased aldosterone concentrations. I present evidence supporting the hypothesis that cortisol confers mineralocorticoid action in cirrhosis. The underlying molecular pathology for this mineralocorticoid receptor (MR) activation by cortisol is a reduced activity of the 11 beta-hydroxysteroid dehydrogenase type 2, an enzyme protecting the MR from promiscuous activation by cortisol in healthy mammalians.

Enhanced sympathetic control of renal function in rats congenic for the hypertension‐related region on chromosome 1

Recent studies suggest that a quantitative trait locus (QTL) for blood pressure (BP) on rat chromosome 1 is associated with exaggerated sympathetic nervous activity. The aim of the present study was to examine whether this QTL can affect BP by altering sympathetic control of renal function. Male stroke-prone spontaneously hypertensive rats of Izumo origin (SHRSP/Izm), Wistar-Kyoto rats (WKY/Izm) and rats from a WKY/Izm congenic strain that contains an SHRSP/Izm chromosomal segment between D1Wox29 and D1Arb21 (WKYpch1.0) were used. Clearance and micropuncture experiments were performed in anaesthetized rats after acute unilateral renal denervation (DN). Mean BP in sham-operated WKYpch1.0 was significantly higher than that in WKY/Izm. The DN procedure elicited a greater reduction in renal noradrenaline levels in SHRSP/Izm and WKYpch1.0 than in WKY/Izm. In both SHRSP/Izm and WKYpch1.0, DN decreased renal vascular resistance and filtration fraction, whereas it increased renal blood flow and urinary and fractional excretion of sodium. Unilateral renal denervation did not affect these parameters in WKY/Izm. Unilateral renal denervation decreased the tubuloglomerular feedback (TGF) responsiveness only in SHRSP/Izm, whereas it increased the non-perfused early proximal flow rate in SHRSP/Izm and WKYpch1.0. The results of the present study indicate that the renal sympathetic nervous system exerts enhanced tonic control of the renal vasculature and tubular function in SHRSP/Izm and WKYpch1.0, but not in WKY/Izm. Neural impact on the TGF response in WKYpch1.0 is indiscernible. Thus, a gene or genes in the QTL may influence BP, at least in part, through renal vasoconstriction and sodium retention mediated by the enhanced activity of the renal sympathetic nerves.

Cardioprotection by Aldosterone Receptor Antagonism in Heart Failure: 1. The Role of Aldosterone in Heart Failure

In recent years understanding of the role of aldosterone has expanded beyond the known classic effects of promoting renal sodium retention and potassium and magnesium loss. It is now well documented that aldosterone causes myocardial and perivascular fibrosis, blocks the myocardial uptake of norepinephrine, and increases plasminogen activator inhibitor levels. In conjunction with angiotensin II, aldosterone causes vascular damage, endothelial dysfunction, and decreased vascular compliance. Therefore, the renin-angiotensin-aldosterone system (RAAS) plays a major role in the development of both hypertension and heart failure and is therefore, a key target for therapeutic interventions. Commonly prescribed medications for control of hypertension and congestive heart failure are inhibitors of the RAAS, including angiotensin converting enzyme inhibitors (ACE-I) and Angiotensin II (A-II) receptor antagonists. There is a well-documented increase in aldosterone levels that occurs over several months during chronic treatment with an ACE-I or A-II receptor antagonist. Such suppression of circulating aldosterone however, is transient, as exemplified by the term "escape" used to describe the phenomenon. This rebound of aldosterone even occurs when patients receive both an ACE-I and A-II receptor antagonist. In addition, ACE-I and A-II receptor antagonists are less effective in controlling BP in the estimated 60% of hypertensive patients who are salt (volume) sensitive and more prone to hypertension-associated morbidity such as black patients and type 2 diabetics. Thus chronic and complete blockade of aldosterone action requires an aldosterone receptor antagonist. The "Randomized Aldactone Evaluation Study" (RALES) trial results in patients with severe heart failure NYHA class III or IV and a left ventricular ejection fraction of no more than 35 percent showed that administration of a sub-hemodynamic dose of spironolactone (25 mg a day) as an add on therapy to ACE-I plus standard treatment resulted in a significant mortality reduction due both to decreased death from progressive heart failure and sudden cardiac death. These findings support the pivotal role of aldosterone in the pathophysiology of progressive heart failure. Although it is an effective antialdosterone agent, widespread use of spironolactone in humans is limited by its tendency to produce undesirable sexual side effects. At standard doses, impotence and gynaecomastia can be induced in men, whereas pre-menopausal women may experience menstrual disturbances. Data on a selective aldosterone receptor antagonist, eplerenone, appear promising for the effective blockade of aldosterone and its harmful effects without the sexual disturbances of spironolactone. Recently Eplerenone was successfully introduced for the treatment of hypertension and heart failure. Growing number of experimental studies are finding a broader role for Aldosterone in driving the pathophysiology of both heart failure and hypertension. When added to conventional therapy aldosterone receptor blockers show benefits which are in addition to those conferred by ACE-I and/or AII receptor blockers.