**1. Introduction**

Cardiovascular diseases are the leading cause of morbility and mortality worldwide. The main risk factor that contributes to the development of these cardiovascular diseases is hypertension. Hypertension increases the risk of injury in the vascular beds of various target organs such as retina, brain, heart and kidneys. Morbility and mortality associated with hypertension is associated mainly with cardiovascular complications. The main goal in the treatment of hypertension is not only controlling blood pressure (BP), but also reducing cardiovascular risk. (Chobanian et al., 2003)

The therapeutical management of hypertension has advanced considerably in recent decades, both in terms of its efficacy in available treatments as in its safety and tolerability profiles.(Table.1) Multiple effective antihypertensive drugs exist to carry out a logical choice. It is necessary to take into account the pathogenic alterations of renin secretion, sympathetic tone, renal sodium excretion, changes in cardiac output, peripheral vascular resistance and blood volume, without forgetting the individual considerations in each patient. However, none of the antihypertensive drugs currently available are able to control all cases of hypertension by themselves. For this reason, monotherapy alone is not usually able to lower BP to optimal levels in most patients. The use of combination therapy with antihypertensive drugs has become the norm. (Calhoun et al., 2008). However, the number of people with uncontrolled hypertension has increased, despite the innumerable evidence of the benefit of BP control and the advances in therapy. (Kearney et al., 2005)

At present the new knowledge obtained about the renin angiotensin aldosterone system (RAAS), the role of the endothelium and nitric oxide (NO), and the ion channels in the homeostasis of BP among others, have opened new lines of study. Therapeutical developments have recently emerged that could improve control of BP, either because they are new and alternative therapeutic strategies, such as carotid sinus stimulation devices, renal denervation and vaccination or due to the improved knowledge of existing alternatives.

This review will focus on little used antihypertensive drugs or on the emerging and application of new therapeutic strategies such as vaccination, renal denervation and the activation of baroreceptors.

#### **2. Renin inhibitors**

The importance of the RAAS in the pathogenesis of cardiovascular and renal diseases and hypertension among them has encouraged research to achieve blocking it partially or

New Therapeutics in Hypertension 3

monotherapy or ACE inhibitors and ARBs. (Weir et al., 2007) Aliskiren is effective and safe in its combination with thiazide diuretics, ACE inhibitors, ARBs and blockers channels of calcium (Sica et al., 2006, Drummond et al., 2007, Andersen et al., 2008, Parving et al., 2008) With respect to the incidence of adverse events, serious and non serious, there are no statistically significant differences between placebo and therapeutic doses of aliskiren, only at doses of 600 mg of the drug showed an increase in the number of patients who had

A comprehensive program of clinical trials: the ASPIRE HIGHER was assigned to evaluate the influence of aliskiren on cardiovascular and renal protection beyond their antihypertensive action. This big test covers four broad areas: the cardiorenal morbility and mortality, the cardioprotective, the renoprotective and hypertension with approximately 35,000 patients in 14 studies. (ASPIRE HIGHER Clinical Trial Program) the final results of

In the study AVOID (Aliskiren in Evaluation of Proteinuria in Diabetes) aliskiren (150-300 mg/day) was administered to diabetic hypertensive patients with proteinuria. The study found that in 6 months of treatment, the addition of aliskiren to conventional therapy in patients with losartan 100 mg per day, conditioned a further reduction of 20% in the rate of urinary albumin excretion, with a reduction greater than or equal to 50% in the urinary excretion rate of albumin in 24.7% of patients receiving aliskiren compared with 12.5% of patients receiving losartan alone. An important aspect that is worth noting is that the rate of adverse effects did not increase in percentage or statistically with the addition of aliskiren to

The ALOFT study (Aliskiren Observation Of Heart Failure Treatment) evaluated the effect of adding aliskiren to the standard therapy for HF in a group of patients (including an ACE inhibitor or an ARBs, but not both, as well as betablockers and diuretics if needed). The addition of 150 mg of aliskiren conditioned significant reductions in natriuretic peptide (NP), proBNP, and echocardiographic parameters related to diastolic function of patients tested, compared with the group of patients who received conventional treatment.

In the study ALLAY (Aliskiren in Left Ventricular Assessment of Hypertrophy) a group of patients with hypertension, obesity and left ventricular hypertrophy were randomized to receive: aliskiren (300 mg), losartan (100 mg), or the combination of aliskiren and losartan with the doses mentioned. The primary endpoint was the evaluation of decreased left ventricular mass after 34 weeks of treatment in the groups already defined. Aliskiren provided a 15% decrease in left ventricular mass greater than the losartan, and the association of aliskiren and losartan provided a drop of 36% higher than losartan alone. This study confirmed the good tolerability of aliskiren and its combination with losartan.

Although the rest of the clinical trials that make up the ASPIRE HIGHER are not avaible, the use of aliskiren opens a new expectation, not only in the treatment and control of hypertension, but also due to its effects on target organ damage and the reduction of

diarrhea.

three are already known.

(McMurray et al., 2008)

(Solomon et al., 2008)

cardiovascular risk.

losartan therapy. (Parving et al., 2008)

completely. The RAAS is composed of peptides and enzymes that lead to the synthesis of angiotensin (Ang) II, which effects are mediated by the action of AT1 and AT2 receptors and are involved in controlling cardiovascular function and hemodynamic equilibrium. (Morales Olivas & Estañ Yago, 2010)

After more than a century of research on the RAAS, Ondetti and colleagues, discovered in 1977 captopril (first inhibitor of angiotensin converting enzyme or ACE inhibitors). (Ondetti, Rubin & Cushman., 1977) In 1988, Timmermans and colleagues, (Timmermans et al., 1991) developed losartan (first AT1 antagonist receptor or ARBs). Both ACE inhibitors and ARBs have demonstrated their effectiveness in the control of hypertension delay, the natural progression of heart failure (HF), diabetes mellitus, and reverse target organ damage such as cardiac hypertrophy and thereby reduce cardiovascular and renal morbility and mortality. (Chobanian et al., 2003) It is not until 2007 that the Food and Drug Administration (FDA) approved the clinical use of aliskiren (first direct renin inhibitor taken orally). (Nussberger et al., 2002) This new group of drugs may represent a superior therapeutical strategy than that of other drugs that inhibit the RAAS, as they not only inhibit the actions mediated by Ang II synthesis but also the direct actions of prorenin and renin through the stimulation of prorenin receptors.


Table 1. Hystoric evolution in antihypertensive therapeutics.

Aliskiren is a potent non peptide renin inhibitor. When there is binding of aliskiren to the active site of renin (S1/S3), it blocks the activity of Asp32 and Asp215 of aspartate residue, thus preventing the conversion of angiotensinogen to Ang I. Aliskiren is a hydrophilic molecule with a high solubility in water, which facilitates their oral bioavailability. Aliskiren is absorbed via the gut, it has a bioavailability of 2.5 to 3%, but its high affinity for renin compensates the low bioavailability of the drug. Following oral administration, the peak concentration is reached within 3 to 4 hours. Its half life is 36 hours reaching its stable level in 7 days. Recent studies suggest that CYP3A4 is the enzyme responsible for aliskiren metabolism. 90% of aliskiren is purified through the feces. (Wood et al., 2003) In controlled clinical trials, aliskiren was shown to be as effective an antihypertensive drug as

completely. The RAAS is composed of peptides and enzymes that lead to the synthesis of angiotensin (Ang) II, which effects are mediated by the action of AT1 and AT2 receptors and are involved in controlling cardiovascular function and hemodynamic equilibrium. (Morales

After more than a century of research on the RAAS, Ondetti and colleagues, discovered in 1977 captopril (first inhibitor of angiotensin converting enzyme or ACE inhibitors). (Ondetti, Rubin & Cushman., 1977) In 1988, Timmermans and colleagues, (Timmermans et al., 1991) developed losartan (first AT1 antagonist receptor or ARBs). Both ACE inhibitors and ARBs have demonstrated their effectiveness in the control of hypertension delay, the natural progression of heart failure (HF), diabetes mellitus, and reverse target organ damage such as cardiac hypertrophy and thereby reduce cardiovascular and renal morbility and mortality. (Chobanian et al., 2003) It is not until 2007 that the Food and Drug Administration (FDA) approved the clinical use of aliskiren (first direct renin inhibitor taken orally). (Nussberger et al., 2002) This new group of drugs may represent a superior therapeutical strategy than that of other drugs that inhibit the RAAS, as they not only inhibit the actions mediated by Ang II synthesis but also the direct actions of prorenin and renin through the stimulation of

**1950** Reserpine, hydralazine, guanethidine, thiazide diuretics, ganglionic blockers

**1970** α 1 adrenergic receptor antagonists, ECA inhibitors, serotonin antagonists &

**1990** ARBs, antagonist of endothelin receptors, aminopeptidase A inhibitors, crosslink breakers of the end products of advanced glycation, Rho kinase inhibitors

inhibitors, modulators of the endocannabinoid, vasopeptidase inhibitors, renin

Dual inhibitors of endothelin converting enzyme and neutral endopeptidase NO releasing drugs with dual action: NO releasing sartans + NO releasing statins

Aliskiren is a potent non peptide renin inhibitor. When there is binding of aliskiren to the active site of renin (S1/S3), it blocks the activity of Asp32 and Asp215 of aspartate residue, thus preventing the conversion of angiotensinogen to Ang I. Aliskiren is a hydrophilic molecule with a high solubility in water, which facilitates their oral bioavailability. Aliskiren is absorbed via the gut, it has a bioavailability of 2.5 to 3%, but its high affinity for renin compensates the low bioavailability of the drug. Following oral administration, the peak concentration is reached within 3 to 4 hours. Its half life is 36 hours reaching its stable level in 7 days. Recent studies suggest that CYP3A4 is the enzyme responsible for aliskiren metabolism. 90% of aliskiren is purified through the feces. (Wood et al., 2003) In controlled clinical trials, aliskiren was shown to be as effective an antihypertensive drug as

**1980** Calcium antagonists, imidazoline agonists, potassium channells openers

**2000** Ouabain antagonists, urotensin II antagonists, vascular NAD(P)H oxidase

inhibitors, vaccines, renal sympathetic denervation, Rheos system **2010** Dual inhibitors of neutral endopeptidase and angiotensin II blockers

Dual antagonist of angiotensin II and endothelin A receptors

Table 1. Hystoric evolution in antihypertensive therapeutics.

**1960** Spironolactone, α 2 adrenergic receptor agonists, β blockers

Olivas & Estañ Yago, 2010)

prorenin receptors.

**Decade Antihypertensive drugs** 

agonists

monotherapy or ACE inhibitors and ARBs. (Weir et al., 2007) Aliskiren is effective and safe in its combination with thiazide diuretics, ACE inhibitors, ARBs and blockers channels of calcium (Sica et al., 2006, Drummond et al., 2007, Andersen et al., 2008, Parving et al., 2008)

With respect to the incidence of adverse events, serious and non serious, there are no statistically significant differences between placebo and therapeutic doses of aliskiren, only at doses of 600 mg of the drug showed an increase in the number of patients who had diarrhea.

A comprehensive program of clinical trials: the ASPIRE HIGHER was assigned to evaluate the influence of aliskiren on cardiovascular and renal protection beyond their antihypertensive action. This big test covers four broad areas: the cardiorenal morbility and mortality, the cardioprotective, the renoprotective and hypertension with approximately 35,000 patients in 14 studies. (ASPIRE HIGHER Clinical Trial Program) the final results of three are already known.

In the study AVOID (Aliskiren in Evaluation of Proteinuria in Diabetes) aliskiren (150-300 mg/day) was administered to diabetic hypertensive patients with proteinuria. The study found that in 6 months of treatment, the addition of aliskiren to conventional therapy in patients with losartan 100 mg per day, conditioned a further reduction of 20% in the rate of urinary albumin excretion, with a reduction greater than or equal to 50% in the urinary excretion rate of albumin in 24.7% of patients receiving aliskiren compared with 12.5% of patients receiving losartan alone. An important aspect that is worth noting is that the rate of adverse effects did not increase in percentage or statistically with the addition of aliskiren to losartan therapy. (Parving et al., 2008)

The ALOFT study (Aliskiren Observation Of Heart Failure Treatment) evaluated the effect of adding aliskiren to the standard therapy for HF in a group of patients (including an ACE inhibitor or an ARBs, but not both, as well as betablockers and diuretics if needed). The addition of 150 mg of aliskiren conditioned significant reductions in natriuretic peptide (NP), proBNP, and echocardiographic parameters related to diastolic function of patients tested, compared with the group of patients who received conventional treatment. (McMurray et al., 2008)

In the study ALLAY (Aliskiren in Left Ventricular Assessment of Hypertrophy) a group of patients with hypertension, obesity and left ventricular hypertrophy were randomized to receive: aliskiren (300 mg), losartan (100 mg), or the combination of aliskiren and losartan with the doses mentioned. The primary endpoint was the evaluation of decreased left ventricular mass after 34 weeks of treatment in the groups already defined. Aliskiren provided a 15% decrease in left ventricular mass greater than the losartan, and the association of aliskiren and losartan provided a drop of 36% higher than losartan alone. This study confirmed the good tolerability of aliskiren and its combination with losartan. (Solomon et al., 2008)

Although the rest of the clinical trials that make up the ASPIRE HIGHER are not avaible, the use of aliskiren opens a new expectation, not only in the treatment and control of hypertension, but also due to its effects on target organ damage and the reduction of cardiovascular risk.

New Therapeutics in Hypertension 5

However, repeated doses are not accompanied by plasma accumulation. A glomerular filtration rate <30 ml/min should be considered a contraindication for use. The antihypertensive efficacy of moxonidine has been shown in controlled trials in which its effect has been compared with other classes of antihypertensive drugs that have included atenolol, hydrochlorothiazide, captopril and nifedipine. In all cases the effectiveness of BP control was statistically comparable. The antihypertensive effect is due to a vasodilator effect with reduced peripheral resistance without changes in heart rate and cardiac output. The administration of moxonidine produced a significant reduction in plasma catecholamine levels and long-term use determines reducing left ventricular hypertrophy

The main advantage of moxonidine in relation to classical central agonists is given by a lower incidence of adverse reactions, even though there have been no studies comparing the two classes of drugs. Neither prospective studies have been conducted to demonstrate their protective effect on stroke, myocardial infarction, HF and kidney failure. The pharmacological characteristics of rilmenidine are very similar to those of moxonidine. Thus, experiments were made with a high number of patients in which its vasodilator effect as a result of reduced plasma concentrations of norepinephrine has been demonstrated. Another effect is the reduction of sympathetic baroreflex responses of heart and kidney, while vagal dependent cardiac baroreflex sensitivity is increased. As with moxonidine, left ventricular hypertrophy has proven reduction and be neutral on lipids and glucose levels.

In the early twenty first century vasopeptidase inhibitors were discovered as a new class of drugs for cardiovascular diseases by simultaneously inhibiting the angiotensin converting enzyme (ACE), thereby inhibiting the production of Ang such as Ang II, Ang 1-7 and Ang 2- 8, completely blocking the substrates for the activation of AT1 and AT2 receptors and neutral endopeptidase (NEP), NEP metabolizes NP into inactived molecules, blocking this enzyme determines the increased blood concentrations of NP, such as brain NP, C and D, which decreases peripheral resistance and preload. It increases venous capacitance and promotes natriuretic action. There is a reduction in sympathetic tone, inhibition of catecholamine release and activation of vagal afferent endings, suppressing the tachycardia reflex and vasoconstriction, also promoting structural changes in the myocardial

These drugs inhibit various metallopeptidases such as NEP, which catalyzes the breakdown of vasodilators and antiproliferative peptides (NP, kinins), ACE and endothelin 1. Several drugs of this group are known: omapatrilat fasidotril, mixampril, sampatrilat, CGS30440,

The most representative drug of this group is omapatrilat, a dual inhibitor of ACE and NEP. This inhibition results in an increase in vasodilator mediators (PN, adrenomedullin, kinins, prostacyclin-PGI 2, NO) and a reduction of vasoconstrictors (Ang II, sympathetic tone). Omapatrilat causes a reduction in systolic and diastolic BP higher than other antihypertensives (amlodipine, lisinopril), regardless of age, sex and race of the patient. It is well absorbed orally and reaches peak plasma concentrations of 0.5-2 h. It presents a half life

remodelling with a potent hypotensive effect. (Corti et al., 2001)

MDL100, 240, Z13752A, among others. (Sagnella, 2002)

without changing serum glucose and lipids levels.

(Pillion et al., 1994)

**4. Vasopeptidase inhibitors** 
