**1. Introduction**

66 Antihypertensive Drugs

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Abbreviations and acronyms in this chapter.

ENaC: amiloride-sensitive epithelial sodium channel; ROMK: renal outer medullary K channel; BK K+: flow-sensitive maxi K channel; AQP-2: apical aquaporin; AQP-3 and 4: basolateral aquaporin; 11β-HSD2: 11β-hydroxysteroid dehydrogenase; NAD: nicotinamide adenine dinucleotide; ROS: reactive oxygen species; CYP11B2: aldosterone synthase; GPR30: G protein coupled receptor; PI3K: phosphatidylinositol 3-kinase; ERK: extracellular signalregulated kinase; NYHA: New York Heart Association; HFPSF: heart failure and preserved systolic function (HFPSF); ACE: angiotensin-converting enzyme; CCB: calcium-channel blockers.

Many clinical studies have reported that cardiovascular morbidity and mortality have a continuous relationship with both systolic and diastolic blood pressures. Although some of these studies have reported that this relationship is steeper for stroke, in some European countries the attributable risk, that is the excess of events due to increased blood pressure, appears to be greater for coronary artery disease (Prospective Studies Collaboration, 2002). Current evidence indicates that both systolic and diastolic blood pressure levels have a continuous and independent relationship with a variety of additional organ complications, including congestive heart failure, renal failure, and peripheral artery disease. The wide prevalence of hypertension in the general population (Wolf-Maier et al. 2003) explains why hypertension has been identified as the first cause of death worldwide by the World Health Organization. This is also why today hypertension is considered as the most important correctable risk factor for cardiovascular diseases.

Recent guidelines have put strong emphasis on the relevance of hypertension-related subclinical organ damage and have prescribed that signs of organ involvement should be sought with great care. In fact, a large body of evidence indicates that hypertensive subclinical organ damage, including left ventricular hypertrophy, microalbuminuria, and thickening of inner vascular layers, is critical in determining the cardiovascular risk of individuals with high blood pressure (The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension and of the European Society of Cardiology, 2007). In patients with high blood pressure, left ventricular hypertrophy has been shown repeatedly to be associated with an increased incidence of cardiovascular events, and similar evidence has been obtained for carotid intima-media thickening and microalbuminuria. Also and most important, prospective studies have demonstrated that reduction in left ventricular mass, intima-media thickness, and urinary protein excretion

Potassium-Sparing Diuretics in Hypertension 69

Aldosterone is a steroid hormone that is secreted by the zona glomerulosa of the adrenal cortex and is involved in regulation of blood pressure exerting its main effects on the distal tubular site of the nephron where it increases water and sodium chloride reabsorption thereby leading to expansion of the extracellular fluid volume. Recent views indicate that, in addition to its renal effects and regulatory role on body water and electrolyte balance, aldosterone acts on a variety of cell types affecting cellular mechanisms that mediate important tissue responses, including hypertrophy and fibrosis. Recent evidence obtained from experimental animal studies indicates that chronic exposure to inappropriately high aldosterone levels or activation of the mineralocorticoid receptors can induce tissue damage in specific organ sites with mechanisms that are independent of blood pressure elevation. These animal studies have demonstrated that tissue damage can be prevented by removal of

Spironolactone and eplerenone (Figure 1) are mineralocorticoid receptor antagonists commonly employed to reduce blood pressure, left ventricular hypertrophy, and urinary albumin excretion in patients with essential hypertension or primary aldosteronism. The latter effects occur beyond what is expected from the mere reduction of blood pressure, suggesting that activation of the mineralocorticoid receptor plays a central role in the development of cardiac and renal abnormalities in hypertensive patients. In agreement with

Spironolactone

Canrenone

Eplerenone

Fig. 1. Structure of the mineralocorticoid receptor antagonists currently available for clinical

these findings, currently available evidence strongly supports the notion that aldosterone receptor antagonists are of considerable therapeutic value in patients with systolic heart failure with a cardioprotective effect that is already appreciable in the early functional

use

adrenal glands or administration of aldosterone antagonists.

induced by antihypertensive treatment are associated with reduced incidence of cardiovascular events. This indicates that assessment of subclinical organ damage is critical not only for quantification of the cardiovascular risk, but also to monitor the beneficial effects of treatment. Large clinical trials that have evaluated the effects of blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have demonstrated a specific ability of these agents in preventing progression and inducing regression of hypertension-related subclinical organ damage. It must be noticed, however, that a significant percentage of hypertensive patients with left ventricular hypertrophy fail to achieve full regression of left ventricular mass when treated with renin-angiotensin system blockers, a fact that might be ascribed to plasma aldosterone escape from the inhibitory effect of these drugs. This hypothesis received the support of studies in which it was demonstrated that with use of renin-angiotensin system blockers left ventricular mass does not decrease in hypertensive patients with aldosterone escape as opposed to a decline in left ventricular mass that is observed in patients without aldosterone escape.

Several randomized controlled trials have tested the benefits of blood pressure lowering treatment providing undisputable evidence. Also, several meta-analyses that have collected an impressive number of patients have confirmed the evidence of benefits of treatment in event-based trials comparing active treatment with placebo, different active treatments, and more or less intense blood pressure lowering strategies. Findings of all these studies indicate that: a) use of antihypertensive drugs causes significant reductions of cardiovascular morbidity and mortality; b) reduction of cardiovascular risk is comparable in hypertensive patients of different ethnicity; c) the benefit of antihypertensive treatment is evident even in the elderly patients with isolated systolic hypertension; d) relative reduction of risk is greater for stroke (approximately 35%) than for coronary artery disease (approximately 20%). Overall, studies comparing different types of antihypertensive drugs show that differences in the incidence of cardiovascular morbidity and mortality are not relevant in the presence of comparable blood pressure reduction, thus supporting the conclusion that benefits of treatment are largely dependent on blood pressure reduction *per se*.

Diuretics decrease the total body pool of sodium-chloride and are included among the five major classes of antihypertensive agents that are suitable for the initiation and maintenance of antihypertensive treatment alone or in combination. This is due to the evidence of effective blood pressure lowering and effective prevention of cardiovascular events that has been obtained with thiazide diuretics. Current guidelines indicate congestive heart failure, isolated systolic hypertension, hypertension in blacks, and end-stage renal disease (this for loop diuretics) as conditions favoring use of diuretics versus other antihypertensive drugs. However, side effect of these drugs including decrease in plasma potassium, and increase in plasma glucose, cholesterol, triglyceride, and uric acid are important limiting factors.

Other classes of diuretics that are used in hypertension as monotherapy, but more frequently as combinations, are the so-called potassium-sparing diuretics. These include a group of drugs that act with different mechanisms at the distal tubular site of the nephron where the mineralocorticoid receptors are expressed and mediate the tubular effects of aldosterone and other mineralocorticoid hormones. The aldosterone-sensitive tubular site of the distal tubule handles only a small amount of sodium chloride and this is why the natriuretic effect of agents acting at this site is relatively modest. However, this tubular site contributes greatly to regulation of body potassium content and acid-base equilibrium by modulation of exchange of sodium with either potassium or hydrogen ions.

induced by antihypertensive treatment are associated with reduced incidence of cardiovascular events. This indicates that assessment of subclinical organ damage is critical not only for quantification of the cardiovascular risk, but also to monitor the beneficial effects of treatment. Large clinical trials that have evaluated the effects of blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have demonstrated a specific ability of these agents in preventing progression and inducing regression of hypertension-related subclinical organ damage. It must be noticed, however, that a significant percentage of hypertensive patients with left ventricular hypertrophy fail to achieve full regression of left ventricular mass when treated with renin-angiotensin system blockers, a fact that might be ascribed to plasma aldosterone escape from the inhibitory effect of these drugs. This hypothesis received the support of studies in which it was demonstrated that with use of renin-angiotensin system blockers left ventricular mass does not decrease in hypertensive patients with aldosterone escape as opposed to a decline in left ventricular mass that is observed in patients without aldosterone

Several randomized controlled trials have tested the benefits of blood pressure lowering treatment providing undisputable evidence. Also, several meta-analyses that have collected an impressive number of patients have confirmed the evidence of benefits of treatment in event-based trials comparing active treatment with placebo, different active treatments, and more or less intense blood pressure lowering strategies. Findings of all these studies indicate that: a) use of antihypertensive drugs causes significant reductions of cardiovascular morbidity and mortality; b) reduction of cardiovascular risk is comparable in hypertensive patients of different ethnicity; c) the benefit of antihypertensive treatment is evident even in the elderly patients with isolated systolic hypertension; d) relative reduction of risk is greater for stroke (approximately 35%) than for coronary artery disease (approximately 20%). Overall, studies comparing different types of antihypertensive drugs show that differences in the incidence of cardiovascular morbidity and mortality are not relevant in the presence of comparable blood pressure reduction, thus supporting the conclusion that

benefits of treatment are largely dependent on blood pressure reduction *per se*.

Diuretics decrease the total body pool of sodium-chloride and are included among the five major classes of antihypertensive agents that are suitable for the initiation and maintenance of antihypertensive treatment alone or in combination. This is due to the evidence of effective blood pressure lowering and effective prevention of cardiovascular events that has been obtained with thiazide diuretics. Current guidelines indicate congestive heart failure, isolated systolic hypertension, hypertension in blacks, and end-stage renal disease (this for loop diuretics) as conditions favoring use of diuretics versus other antihypertensive drugs. However, side effect of these drugs including decrease in plasma potassium, and increase in

plasma glucose, cholesterol, triglyceride, and uric acid are important limiting factors.

modulation of exchange of sodium with either potassium or hydrogen ions.

Other classes of diuretics that are used in hypertension as monotherapy, but more frequently as combinations, are the so-called potassium-sparing diuretics. These include a group of drugs that act with different mechanisms at the distal tubular site of the nephron where the mineralocorticoid receptors are expressed and mediate the tubular effects of aldosterone and other mineralocorticoid hormones. The aldosterone-sensitive tubular site of the distal tubule handles only a small amount of sodium chloride and this is why the natriuretic effect of agents acting at this site is relatively modest. However, this tubular site contributes greatly to regulation of body potassium content and acid-base equilibrium by

escape.

Aldosterone is a steroid hormone that is secreted by the zona glomerulosa of the adrenal cortex and is involved in regulation of blood pressure exerting its main effects on the distal tubular site of the nephron where it increases water and sodium chloride reabsorption thereby leading to expansion of the extracellular fluid volume. Recent views indicate that, in addition to its renal effects and regulatory role on body water and electrolyte balance, aldosterone acts on a variety of cell types affecting cellular mechanisms that mediate important tissue responses, including hypertrophy and fibrosis. Recent evidence obtained from experimental animal studies indicates that chronic exposure to inappropriately high aldosterone levels or activation of the mineralocorticoid receptors can induce tissue damage in specific organ sites with mechanisms that are independent of blood pressure elevation. These animal studies have demonstrated that tissue damage can be prevented by removal of adrenal glands or administration of aldosterone antagonists.

Spironolactone and eplerenone (Figure 1) are mineralocorticoid receptor antagonists commonly employed to reduce blood pressure, left ventricular hypertrophy, and urinary albumin excretion in patients with essential hypertension or primary aldosteronism. The latter effects occur beyond what is expected from the mere reduction of blood pressure, suggesting that activation of the mineralocorticoid receptor plays a central role in the development of cardiac and renal abnormalities in hypertensive patients. In agreement with

these findings, currently available evidence strongly supports the notion that aldosterone receptor antagonists are of considerable therapeutic value in patients with systolic heart failure with a cardioprotective effect that is already appreciable in the early functional

Potassium-Sparing Diuretics in Hypertension 71

inflammatory changes of perivascular tissue, and that both inflammation and fibrosis can be prevented by administration of mineralocorticoid receptor antagonists or adrenalectomy. Similar evidence was obtained in the kidney of uninephrectomized and stroke-prone spontaneously hypertensive rats in which aldosterone produced intrarenal vascular damage, glomerular injury, and tubulointerstitial fibrosis. Elevated aldosterone also caused aortic fibrosis and hypertrophy in different rat models of hypertension, and administration of eplerenone to hypertensive rats corrected vascular remodeling and fibrosis, suggesting a

Fig. 2. Sodium, potassium, and water transport in principal cells of connecting tubule and cortical collecting duct. ENaC: amiloride-sensitive epithelial sodium channel; ROMK: renal outer medullary K channel; BK K+: flow-sensitive maxi K channel; AQP-2: apical aquaporin;

All these studies consistently indicate that aldosterone causes tissue damage only in the context of inappropriate salt status. It was suggested that untoward effects of high-salt intake are largely dependent on activation of mineralocorticoid receptors and that this activation might reflect increased oxidative stress. Mineralocorticoid receptors are found in epithelial and nonepithelial tissues with high affinity for aldosterone and glucocorticoid hormones, such as cortisol and corticosterone. Under physiological conditions, the majority of mineralocorticoid receptors in nonepithelial tissues are occupied by greater concentrations of cortisol, whereas in epithelial tissues, binding of cortisol to receptors is prevented by 11β-hydroxysteroid dehydrogenase (11β-HSD2), the enzyme that converts cortisol to the receptor-inactive cortisone. In addition to the conversion of cortisol to cortisone, activity of 11β-HSD2 generates NADH from NAD and produces changes in the intracellular redox potential that might, in turn, inactivate the glucocorticoid–receptor complex. 11β-HSD2 is not present in nonepithelial tissues including the heart, but in such tissues, changes of the intracellular redox potential can result from generation of reactive oxygen species (ROS) and thereby affect the activity of the mineralocorticoid receptor.

mineralocorticoid receptor-mediated mechanism.

AQP-3 and 4: basolateral aquaporin.

stages. Also, recent evidence suggests that the benefits of aldosterone antagonists in the context of cardiac failure are not restricted to patients with impaired systolic function but can be extrapolated also to patients with diastolic dysfunction. Finally, some studies support the view that mineralocorticoid receptor blockade may exert an antialbuminuric effect in patients with proteinuria, an effect that occurs independent of blood pressure reduction.

The use of classic mineralocorticoid receptor antagonists, however, has been limited by the high incidence of breast engorgement and gynecomastia and the risk of severe hyperkalemia. To overcome these tolerance problems, new aldosterone blockers have been developed (Garthwaite & McMahon 2004) using two different strategies that include search for non-steroidal antagonists and inhibition of aldosterone synthesis. Inhibition of aldosterone synthesis could have an additional benefit due to blockade of the mineralocorticoid receptor-independent pathways that might account for some of the untoward effects of aldosterone. The new aldosterone blockers are currently having extensive preclinical evaluation, and one of them has passed phase-II trials showing promising results in patients with essential hypertension and primary aldosteronism.
