Renalase is a flavin adenine dinucleotide-dependent amino oxidase secreted almost entirely by the kidney. It metabolizes circulating catecholamines [2], and epinephrine is the principal substrate. The hypotensive effect of the protein has been proved in vitro and in vivo [3]. The inactive enzyme appears to circulate in blood and can be activated by circulating catecholamines or increased BP. Renalase knockout (KO) mice display elevated plasma and urinary catecholamines levels, hypertension, tachycardia, ventricular hypertrophy and inadequate cardiac and renal ischemia tolerance [4]. Animal models have shown that renalase levels increase significantly after renal denervation and this higher plasma level may mediate in part the procedure’s BP lowering effect [5]. Recombinant human renalase (hRenalase1) administered subcutaneously had a systolic and diastolic hypotensive effect, and attenuated hypertension-related cardiac damage in 5/6 nephrectomized rat [6, 7]. Administration of hRenalase1 in KO animals also improved ischemic and toxic renal injury [2]. These findings suggest that renalase represents a novel option for hypertension treatment, but human studies are needed.

Aliskiren is the first oral direct renin inhibitor available that has been commercialized in the past years. It is an effective antihypertensive drug with an adverse effect profile similar to angiotensin receptor blockers (ARBs) . Since effective drug therapy with angiotensin converting enzyme inhibitors and ARBs is standard of care in many hypertensive and cardiovascular diseases , aliskiren was evaluated as add on therapy.

In the ALTITUDE trial, aliskiren and losartan were tested against losartan alone in diabetic type 2 patients with cardiovascular and renal risk. The trial found no benefit and more hiperkalemic and hypotensive events in the aliskiren group. This chapter concluded that the addition of aliskiren to standard therapy with renin–angiotensin system blockade in type 2 diabetes patients who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. Since then, the Food and Drug Administration (FDA) has issued a warning that aliskiren should not be used in this clinical situation.

Many physicians use this drug in resistant hypertensive patients .

Renin–angiotensin system vaccines have been investigated in the past and are still under development. Renin was the first target but the product was associated with autoimmune kidney disease development. An anti-angiotensin I vaccine effectively reduced BP in animal models, but failed to prove efficacy in clinical trials. Anti-angiotensin II and anti-ATR1 vaccines are a matter of interest and current studies. Cyt-006-AngQb reduced BP in animal models and hypertensive patients [8]. Ang II-KLH-immunized mice decreased BP values and cardiac hypertrophy [9]. Anti-ATR 1 ATRQβ-001 reduced BP in Ang II-induced hypertensive mice and spontaneously hypertensive rats without evidence of immune-mediated organ damage [10]. Vaccines seem to be a feasible line of treatment for hypertension with longer dosing intervals than traditional therapies, although more clinical trials are needed and safety profile must be verified.

In humans, angiotensin II has two G protein-coupled receptors: type 1 (AT 1R) and type 2 (AT 2R). Through AT 1R, angiotensin II mediates vasoconstriction, tubular Na reabsorption, modulation of glomerular filtration rate, aldosterone release , collagen synthesis and pro-fibrotic and inflammatory effects [1]. AT 2R mediates opposite actions that lead to vasodilation, anti-proliferation and anti-inflammation via the nitric oxide (NO)/cyclic guanosine 3′,5′-monophosphate (cGMP) pathway, and also phosphatase and phospholipase A2 activation [11]. In pathological states, the expression of AT2R is upregulated in certain tissues, especially during tissular hipoxia [12]. Therefore, pharmacological stimulation of AT2R is an encouraging option for hypertension treatment. Compound 21 (C21) is the first selective nonpeptide AT 2R agonist. Animal studies have not shown BP reduction, however, it did reduce arterial stiffness, media collagen deposition, oxidative stress, fibrotic processes, hypertrophic effects on the heart and renal cortex inflammatory cell infiltration [13]. In addition, C21 produced vasodilation, and natriuretic effects, improving renal function [14]. When combined with low-dose ARB, C21 enhanced the antihypertensive effect of the former [13], while this did not occur with higher ARB doses. C21 did not show significant BP reduction as monotherapy but its potential multiple beneficial effects may promote new strategies and combinations in hypertension treatment [11].

Aldosterone mediates its effects via mineralocorticoid receptors (MR), but also in an MR-independent fashion . Therefore, in order to act on both mechanisms, aldosterone synthase inhibition has emerged as a new therapeutic target. Early in the 1990s, the nonsteroidal aromatase inhibitor fadrozole showed the potential to induce aldosterone secretion impairment without affecting the glucocorticoid response [15]. Fadrozole’s enantiomer FAD286A in animal models decreased plasma and urine aldosterone concentrations, preventing cardiac hypertrophy and fibrosis, albuminuria, renal failure and death [16]. Based on FAD286A, the first orally active aldosterone synthase inhibitor was synthesized, LCI699. In a phase II study, LCI699 was compared with eplerenone and placebo for 8 weeks in subjects with stage 1–2 essential hypertension [17]. Primary end point was reduction in diastolic BP, which was significantly lower, compared with placebo, for LCI699 1 mg once daily and eplerenone 50 mg twice daily in similar magnitude. All doses of LCI699 decreased clinic systolic BP and 24-h ambulatory BP significantly. Patients did not develop signs of hypocortisolism although ≈ 20 % of subjects had suppression of adrenocorticotropic hormone (ACTH)-induced cortisol release. Not serious, hyperkalemia or renal function impairment was reported in LCI699 or eplerenone groups [17]. LCI699 was tested in primary aldosteronism in a single-centre, single-blind, placebo-controlled, sequential, force-titration study [18]. A reduction in plasma and urinary aldosterone concentration was observed as correction of hypokalemia within the first week of treatment, accompanied by limited effects on BP and sodium-positive balance [18]. Despite clinical benefits on BP control, reduction of circulating aldosterone, enhance sodium excretion, glucocorticoid axis inhibition will limit LCI699 use [19]. More selective compounds could provide advantages; however, complete blockage of aldosterone synthesis could entail potential serious adverse consequences [19] .

Vasopeptidase inhibitors are soon to be an upcoming approach to hypertension treatment. Neutral endopeptidase (NEP) catalyzes both vasoconstrictor and vasodilator products. The beneficial effect of NEP inhibition is mediated by increased natriuretic peptide concentration [20], but inhibition of this enzyme alone did not improve clinically relevant outcomes [21]. However, benefits of NEP blockage may become evident when vasoconstrictors such as angiotensin II are reduced by concomitant use of angiotensin-converting enzyme (ACE) inhibitors or ARBs [21, 22]. The dual ACE/NEP inhibition has been associated with increased risk of angioedema [23]. LCZ696 is a combination of an angiotensin II receptor blocker (valsartan) and a neprilysin inhibitor (AHU377). Patients treated with LCZ696 had significant dose-dependent reductions in BP compared with valsartan and AHU377 monotherapy. LCZ696 improved pulse pressure and was safe and well tolerated [21].

NO -induced vasorelaxation is mediated by activation of soluble guanylyl cyclase (sGC) that increases cGMP formation and ultimately a decrease in intracellular calcium and vasodilation. In conditions associated with incremented oxidative stress, NO generation, diminished biological availability can lead to NO donor tolerance with prolonged use [24]. Two classes of compounds that activate sGC by NO-independent pathways are under investigation: sGC stimulators and sGC activators. The sGC stimulator BAY 63-2561 (Riociguat) was tested in a population with mild to moderate pulmonary hypertension and improved pulmonary hemodynamics to a greater extent than inhaled NO. Riociguat significantly reduced systolic BP and systemic vascular resistance [25]. Activators of sGC can increase sGC enzyme activity even when it is oxidized and less responsive to NO [24]. BAY 58-2667 (Cinaciguat) has been administered to patients with acute decompensated heart failure and proved to lower right atrial pressure, pulmonary and systemic vascular resistance reducing preload and afterload [26].

Both sGC stimulators and sGC activators may represent therapeutic options for pulmonary hypertension, states of chronic endothelial dysfunction such as hypertension and atherosclerosis and in patients with acute heart failure [24].

Arachidonic acid is metabolized by three principal enzymatic pathways: cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P-450 (CYP) (Fig. 5.1). Prostaglandins are produced by COX; hydroxyeicosatetraenoic acids (HETEs), lipoxins and leucotrienes by LOX; HETEs are also generated by CYP hydroxylase and epoxyeicosatrienoic acids (ETEs) are originated from CYP epoxygenase [26]. ETEs mediate vasodilation in many vascular beds including coronary, cerebral, kidney, intestine and skeletal muscle by activating large-conductance calcium-activated potassium channels in vascular smooth muscle cells [26]. They also have anti-inflammatory, anti-aggregation and angiogenic properties.