Spironolactone; the ultimate blocker of RAAS cascade in hypertensive patients with special reference to its cardiovascular benefits: Revisiting the forgotten ways

Acknowledgement: All the authors would like to express their heartfelt thanks to Dr Jagadeesh Tangudu, Mtech, MS, PhD and Sowmya Jammula, M Tech for their immense and selfless contribution towards manuscript preparation, language editing and final approval of text. Abstract: Hypertension is a major risk factor for various macro and microvascular complications in a patient with diabetes. Control of hypertension is of paramount importance in the care of a diabetes subject. The goals for blood pressure in diabetes subjects are below 130/ 80 mmHg and below 125/75 mmHg if accompanying renal impairment is there. Spironolactone is a medication that has been used to treat high blood pressure since the 1960s. While there is some belief spironolactone reduces blood pressure, there are concerns due to the potential for this drug to cause adverse effects. Previous Meta analysis has shown that spironolactone reduces systolic/diastolic blood pressure by approximately 20/7 mmHg compared to placebo. Spironolactone has also been shown to decrease morbidity and mortality in patients with heart failure. We have tried to emphasize upon the usage of this old but important drug in management of resistant hypertension with reference to its mode of action, benefits and recent studies pertinent to cardiovascular benefits of spironolactone. Data Source: We searched PUBMED and MEDLINE database for relevant articles including key words. References of each article were further reviewed for final synthesis of the manuscript.


Introduction:
The renin-angiotensin-aldosterone system (RAAS) plays an integral role in regulation of blood pressure and has been a long target of pharmacologic approaches to control blood pressure (BP) and other conditions like diabetic nephropathy, heart failure, myocardial infarction and other nondiabetic nephropathies.Clinical interventions involving the RAAS have focused mainly on inhibiting the action of angiotensin II (Ang II) with angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs), while limited attention has been focused on the direct inhibition of aldosterone 1.In recent years, advances in the role of aldosterone producing nephropathy and cardiovascular injury have brought to for the importance of aldosterone in the management of these conditions.Aldosterone synthesis and regulation: brief overview.Aldosterone in the circulation is produced in the zona glomerulosa of the adrenal cortex.A series of enzymatic steps lead to the conversion of dietary or endogenous cholesterol to aldosterone 2 .Its production is regulated at 2 critical steps: conversion of cholesterol to pregnenolone by cholesterol side chain cleavage enzyme, and conversion of corticosterone to aldosterone by aldosterone synthase.Many factors modify aldosterone secretion; angiotensin II and potassium are the most important factors.Other factors such as ACTH, neural mediators and natriuretic factors are also involved.The major effect of aldosterone is to increase the transport of sodium across the cell in exchange for potassium and hydrogen ions 2 .

Aldosterone: Target organs and effects
In the past, the focus was on aldosterone and its target organs resided in the classical target, the kidneys.
Increasing evidence now points towards the fact that aldosterone can be synthesized in extraadrenal tissue, in the heart and the vasculature 2 .Aldosterone synthase, the enzyme responsible for the last step in aldosterone biosynthesis is expressed in heart, blood vessels and brain 3 .These non epithelial tissues also express mineral corticoid receptors which have properties similar to that of renal receptors but produce a wide variety of effects.Apart from a role in maintaining the renal electrolyte balance, aldosterone promotes cardiac fibrosis 4 , abnormal endothelial function 5 and regulates sympathetic tone in the central nervous system 6 ; factors which contribute to increased systemic vascular resistance 7 and consequent hypertension and cardiovascular disease (Figure 1).

Aldosterone: Genomic and non genomic effects
Steroid hormones produce their actions by binding to intracellular receptors, this hormone-receptor complex further binds to DNA and activates or regresses transcription of target genes.However, all steroid hormones can also act through non-genomic mechanisms and alter the physiological processes 8 .The non-genomic effects have a rapid onset and are insensitive to inhibitors of transcription and translation.Similarly aldosterone also produces nongenomic effects on various target organs like vascular smooth muscle cells, endothelial cells, skeletal muscle cells, lymphocytes, cardiac myocytes, colonic epithelial cells and kidney cells.Kidneys are the classical target organ for the non-genomic as well as genomic effects, where aldosterone stimulates sodium reabsorption and potassium secretion 9 .Aldosterone as mediator of renal dysfunction.
Aldosterone binds with cytosolic the mineralocorticoid receptor and translocated into the nucleus where it binds to the regulatory region of the target gene promoters and enhances its expression.Sodium reabsorption in renal tubular cells depends mostly on aldosterone induced transcriptional regulation of Na+/ K+-ATPase.Aldosterone enhances the gene expression of profibrotic molecules like collagen and transforming growth factor ß (TGF-ß), matrix proliferating molecules like epithelial growth factor receptor (EGFR), and prothrombotic molecules like plasminogen Ativator Inhibitor type 1 (PAI-1).It also stimulates inflammation through the generation of reactive oxygen species (ROS), gene expression of proinflammatory molecules like intracelluler adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1).Nongenomic effects include upregulating the expression of pro-inflammatory transcription factors like extracellular signal regulated kinase 1and related molecules like.All these factors induce inflammation and extracellular matrix accumulation resulting in renal tissue fibrosis and ultimately renal scarring 10 .
In fact, aldosterone is an important pathogenic factor in progressive renal disease.It has been demonstrated that patients with diabetic nephropathy with renal insufficiency have increased aldosterone levels when compared to healthy individuals.Furthermore, it has also been seen that the highest aldosterone levels are observed among those patients who have the greatest renal function impairment.Hene et al observed that at comparable serum potassium and plasma rennin activity and with creatinine clearance lower than 50% of normal, the plasma aldosterone is elevated in a majority of subjects 11 .KK Sunil, J Sruti, KK Siva, P Sandip, KM Lalit, D M Kirtikumar

Aldosterone as mediator of hypertension
Although, primary aldosteronism is known to be an important cause of secondary hypertension, initial studied of serum aldosterone levels in hypertensive patients' demonstrated inconsistent results.Vasan et al in the Framingham offspring Study observed increased serum aldosterone even within normal range was associated with an increased risk of developing hypertension 12 .The study analyzed the effect of increasing serum aldosterone in a cohort of 1688 nonhypertensive individuals.More than 40% of these subjects had blood pressures lower than 120/ 80 mmHg at the onset of observation period.Mean serum aldosterone levels were similar in men and women at onset (10.7 ng/dl vs 11.3 ng/dl, respectively).After a follow up period of approximately 4 years, a proportion of patients or were found to be hypertensive (Figure II).Since mineralcorticoid receptors are widely distributed throughout the vasculature, myocardium and central nervous system, serum levels of aldosterone may underestimate its true effects on blood pressure.
In addition to genomic effects, aldosterone also induces rapid non-genomic effects predominantly in the non epithelial tissue 13 .These effects are mediated by a wide variety of intracellular second messengers as well as by RAAS.There is cross talk between angiotensin II and type 1 angiotensin II receptor regulated pathways and aldosterone and the mineralocorticoid receptor in vascular smooth muscle cells and cardiomyocytes.Despite multiple and complicated actions, it may be stated that synergistic actions between aldosterone and angiotension II in endothelial cells and vascular smooth muscle cells cause direct target organ damage, and also directly promote vascular inflammation, fibrosis, remodelling and finally hypertension.

Aldosterone and cardiovascular disease
The mineralocorticoid receptors and the enzyme 11hydroxysteroid dehydrogenase have been demonstrated in the heart, and in addition to its classical effects of fluid and sodium retention and potassium excretion, it also exerts direct effects on the myocardium.It promotes increased collagen accumulation and the development of fibrosis in hypertrophied cardiac ventricles, reduces myocardial perfusion and increases the incidence of cardiovascular events 14 .Significant relationship between plasma aldosterone and echocardiographic parameters of the left ventricle such as left ventricular size and mass, and cardiac index have been demonstrated 15,16 .Aldosterone causes autonomic imbalance, electrolyte abnormalities, contributing to myocardial dysfunction, arrhythmias, cardiovascular events and sudden cardiac death 17 .
Further support comes from the Cooperative North Scandinavian Enalapril Survival Study (CONSEN-SUS) which established that elevated plasma aldosterone was associated with the pathogenesis and progression of heart failure 18 .All these observations indicate that direct and indirect actions of aldosterone play an important role in the myocardial structural changes that lead to pathological hypertrophy.

Inhibitors of aldosterone through mineralocorticoid receptor blockade
Blockade of the mineralocorticoid receptor has been demonstrated as a useful target for antihypertensive therapy and may be used as monotherapy or add-on therapy in the treatment of hypertension and other conditions such as heart failure.Patients with a clinical condition for an aldosterone receptor antagonist should be initiated on these drugs, only if, they have a baseline serum K+ < 5.0 meq/l and a serum creatinine <2.5 mg/ dl for men or 2,0 mg/ dl for women 19 .
Serum K+ and creatinine levels should be monitored 4 weeks after the start of treatment or after 1 week in those patients with an increased risk of severe hyperkalemia (6.0 meq/l) such as patients with diabetes or reduced renal function with a glomerular filtration rate <60 ml/ minute Amongst patients with left ventricular systolic dysfunction, almost 1/3rd have clinically important levels of aldosterone despite serological evidence of complete ACE inhibition 15 .This phenomenon as aldosterone breakthrough may explain the beneficial effects of aldosterone receptor antagonists when added to ACEIs in patients with symptomatic congestive heart failure 20 .

Spironolactone
Spironolactone is a nonselective aldosterone receptor antagonist that is extensively metabolized to its active metabolites in the liver.The plasma half life of the drug is 1.4 hours, but this duration may increase by up to five fold in patients with congestive heart failure because of the hepatic congestion.Spironolactone is structurally similar to progesterone, thereby allowing sex-steroid receptor cross activity.This phenomenon accounts for the antiprogesterone and antiandrogen effects observed in some patients treated with spironolactone.Spironolactone is indicated for use in severe (NYHA class III-IV) CHF with LV systolic dysfunction, essential hypertension and primary hyperaldosteronism.
Spironolactone produces its actions chiefly by inducing natriuresis but it probably also produces other effects as it has been shown to reduce blood pressures even in anuric patients on maintenance hemodialysis 21 .Spironolactone has been demonstrated to lower blood pressure as effectively as thiazide diuretics in patients with low rennin levels and aldosterone to rennin ratio 22 .Spironolactone is also effective in patients with resistant hypertension when used as fourth line agent at very low doses 23,24 .
Another study has demonstrated the efficacy of low dose spironolactone in chronic kidney disease with resistant hypertension 25 .Adding spironolactone 25 mg/day to an angiotensin receptor blocker in patients with chronic glomerulonephritis resulted in further BP reduction and a 13% decrease in proteinuria 26 .
Spironolactone was also found to be useful in New York Heart Association (NYHA) class III to IV patients with LV systolic dysfunction, in the RALES trial where it reduced the mortality by 30% over 24 months when added to an ACEI and loop diuretic therapy 27 .

Eplerenone
Eplerenone is a second generation selective aldosterone receptor antagonist derived from spironolactone but with a major difference that it has limited affinity for the progesterone and androgen receptors and therefore lacks sex related adverse side effects.Eplerenone is metabolized by cytochrome P450 and KK Sunil, J Sruti, KK Siva, P Sandip, KM Lalit, D M Kirtikumar has a plasma half life of 4 to 6 hours; the steady state drug levels are usually achieved 48 hours after the first dose.Eplerenone is indicated for use in severe (NYHA class III-IV) CHF after myocardial infarction and hypertension.Aldosterone mediated increase in vascular tone is related to a non-genomic mechanism.It is interesting to note that eplerenone is effective in blocking the vasoconstrictor action of aldosterone and non-genomic effects on sodium proton exchanger activity or intracellular calcium responses 28 .Eplerenone has been found to be as effective as spironolactone for lowering the blood pressure and more effective than other commonly used drugs in the management of hypertension.An important observation with eplerenone has been the beneficial role in hypertensive patients with vascular remodeling; eplerenone prevents remodel-ling by inhibiting both, in-vitro cell stiffening and reduction in nitric oxide synthesis in endothelial cells 29 .
In lines with results of RALES 27 , the addition of eplerenone to optimal medical therapy in the EPH-ESUS (Eplerenone Post-Myocardial Infarction Heart Failure Efficacy and Survival) trial demonstrated that the drug contributed to the improvement in survival and hospitalization rates among patients with acute myocardial infarction complicated by left ventricular dysfunction 30    Eplerenone treatment led to an increased incidence of serious hyperkalemia, though there were no deaths in the eplerenone group attributable to hyperkalemia.The risk \was significantly increased among patients who had a decreased creatinine clearance at baseline (< 50 ml/ minute).Strict monitoring of serum potassium excluding patients with a baseline serum potassium concentration of more than 5 Meq/l, a baseline serum creatinine concentration of more than 2.5 mg/ dl, or both could help in optimizing the utilization of this drug.

Summary
Scientific advances have helped in improving our understanding about the relationship between hyperaldosteronism and cardiovascular dysfunction and expanded the spectrum of patients who may benefit from pharmacotherapy towards aldosterone blockade.These advances have also prompted the use of aldosterone receptor antagonists for the treatment of cardiovascular diseases, particularly hypertension where these agents are underused.Evidence from RALES and EPHESUS was a significant first step and will form the platform over which future trials in order to gain more evidence and improve our understanding and patient care.

Figure
Figure II: Blood pressure status at 4 year follow up in 1688 normotensive patients in the Framingham Offspring study.

Figure
Figure III: Blood pressure outcomes at 4 years

Figure IV :
Figure IV: Mechanisms involved in aldosterone mediated hypertension Spironolactone; the ultimate blocker of RAAS cascade in hypertensive patients with special reference to its cardiovascular benefits: Revisiting the forgotten ways

Figure V :
Figure V: Eplerenone therapy on primary outcomes in the EPHESUS trial Eplerenone treatment also produced significant beneficial effects on the secondary endpoints (Figure VI).

Figure
Figure VI: Eplerenone therapy on secondary end points in the EPHESUS trial . The number of deaths from any cause was significantly lower in the eplerenone group in comparison to the placebo group.Similarly, deaths from cardiovascular cause or hospitalization for a cardiovascular event were also reduced with eplerenone therapy (FigureV).