Traditionally, RAS biosynthesis is comprised of a sequential linear enzymatic cascade initiated by renin, an enzyme released from the juxtaglomerular cells in response to a reduction in blood pressure [3]. When found in the circulation, renin cleaves the zymogen angiotensinogen, which is synthesized and secreted mainly by the liver, forming the inactive decapeptide angiotensin I (Ang I). Ang I is sequentially cleaved by ACE, an enzyme mainly expressed on the surface of vascular endothelial cells, forming the octapeptide Ang II [3, 14]. Ang II demonstrates a high affinity with two distinct G protein-coupled receptors, AT1 and AT2 receptors. Under both physiological and pathological condition, AT1 receptor activation leads to blood pressure increase by stimulating vasoconstriction and sodium retention. Moreover, chronic AT1 receptor activation induces cellular proliferation, fibrosis, and inflammation [3, 15]. The relevance of Ang II/AT1 receptor actions on the cardiovascular system is underscored by the remarkable achievement of ACEi and ARBs, which inhibit Ang II formation and AT1 receptor stimulation, respectively. Nowadays, these drugs are considered the main class of pharmacotherapy in the treatment of hypertension and cardiovascular diseases [2, 15].

Ang II also binds to the AT2 receptor, producing effects that often opposite those produced by AT1, such as vasodilation and antiproliferative and anti-inflammatory actions [16, 17]. During Ang II stimulation, AT1 receptor actions mask that of the AT2 receptor, principally due to increased expression and high distribution of AT1. Although a comprehensive understanding of the role of the AT2 receptor has yet to be fully elucidated, evidence indicates that AT2 receptors may participate in mechanisms where ARBs induce cardiovascular protection [17]. This suggests that AT2 receptor agonists are a potential therapeutic tool for the treatment of cardiovascular diseases [18, 19].

The recent discovery of novel RAS components has illuminated alternative metabolic cascades and actions, thus expanding the traditional RAS paradigm [11, 12]. ACE2, an ACE homologous enzyme, acts as key enzyme by cleaving the C-terminal phenylalanine of Ang II, leading to Ang-(1–7) formation [20, 21]. Ang-(1–7) is a heptapeptide with biological actions that frequently oppose those attributed to Ang II [12, 22]. Acting via the G protein-coupled Mas receptor [23], Ang-(1–7) mediates vasodilation [11, 12], NO release [24], and antiproliferative [25], antifibrotic [26], and anti-inflammatory [27] effects. Therefore, Ang-(1–7) is well accepted in the scientific community as the primary endogenous counter-regulator of Ang II [3, 11, 12, 22]. ACE2 appears to be the major Ang-(1–7)-forming enzyme; however, additional pathways, such as neutral endopeptidase (prolylcarboxypeptidase [PCP] and prolylendopeptidase [PEP]), are also involved in the generation of Ang-(1–7) [21, 28, 29] (Fig. 5.1).

In the current scenario, RAS is regulated by two opposing axes, one deleterious branch composed of ACE/Ang II/AT1 receptor, and the other, a protective branch formed by ACE2/Ang-(1–7)/Mas receptor [11, 12]. Recent studies suggest that these two axes modulate cardiovascular homeostasis, while a chronic and sustained imbalance may contribute pathological etiologies [11]. For instance, in erectile tissues, elevated Ang II production has been observed in humans with ED [10]. Additionally, deletion of the Mas receptor gene significantly impaired erectile function and augmented collagen deposition within the corpus cavernosum in mice [13].

The RAS is highly involved in disturbances of the cardiovascular system, as well; it is considerably involved in ED pathophysiology [8, 9, 13, 30, 31]. The existence of a local RAS within the penis has been confirmed by several studies [9, 10, 13], suggesting a paracrinal modulation independent of systemic circulation. In fact, ACE, AT1 receptor, Ang I, and Ang II were detected in human corpus cavernosum [32]. In 1997, Kifor et al. found that human corpus cavernosum produces and secretes physiologically relevant amounts of Ang II [32]. Moreover, in the same study, intracavernosal injection of Ang II resulted in cavernosal smooth muscle contraction and eliminated spontaneous erection in anesthetized dog. On the other hand, when administered the Ang II receptor antagonist, losartan, a consistent and prolonged increase in cavernosal pressure was observed [32]. Interestingly, other studies have observed that human corpus cavernosum produces and secretes physiological amounts of Ang II in greater quantities than those found in the systemic plasma [8, 10], indicating an intense local modulation of erectile function by RAS. Supporting these reports, Iwamoto and coworkers demonstrated that ACE activity in canine corpus cavernosum was 30-fold higher than in canine common carotid artery [33].

Physiologically, Ang II mediates tonus contraction of the smooth muscle in the corpus cavernosum [8, 9, 30]. In fact, the local blockage of AT1 receptor by intracavernosal losartan administration increased the cavernosal pressure, suggesting the fundamental role of Ang II in the maintenance of the penile flaccid state [32]. Furthermore, Becker et al. compared the level of Ang II in blood samples acquired from the corpus cavernosum during various stages: penile flaccidity, tumescence, rigidity, and detumescence [9]. They found that Ang II cavernosal level was significantly higher in the detumescence stage, suggesting an essential role of this peptide on the detumescence process [9].

The main actions of Ang II are mediated by AT1 receptor. This receptor is expressed on the cavernosal smooth muscle and endothelial cells [3]. The activation of AT1 receptor initiates multiple intracellular signal transduction pathways that are complex and specific but converge, yielding multiple short- or long-term responses [34, 35]. One of the major pathways trigger by AT1 stimulation involves the classical phospholipase C (PLC) activation, resulting in the generation of inositol trisphosphate IP3 and diacylglycerol (DAG). IP3 and DAG regulate two distinct pathways that lead to an increase in intracellular Ca²⁺, culminating in the activation of myosin light chain kinase and smooth muscle contraction [35]. Additionally, AT1 activation may also stimulate the RhoA/Rho-kinase pathway prompting inhibition of myosin light chain phosphatase (MLCP), thereby regulating smooth muscle contraction [36]. These independent pathways make Ang II one of the most powerful endogenous vasoconstrictors. Therefore, its action on the tonus and contraction of the corpus cavernosum might be critical to erectile pathophysiology [8].

The activation of AT1 receptor also produces additional actions with critical repercussion for erectile function. Stimulation of this receptor can activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the main enzyme responsible for reactive oxygen species (ROS) production [34]. ROS is involved in the physiologic redox of cellular function; however its overproduction is closely associated with the development of vasculogenic ED [37]. In fact, Jin et al. reported that the development of hypertension-associated ED caused by Ang II infusion was associated with an increased NADPH oxidase expression and ROS production into the corpus cavernosum [38]. In addition, during long-term stimulation, AT1 activation may also induce a proinflammatory response, cell proliferation, hypertrophy, increased collagen deposition in the extracellular matrix by regulating mitogen-activated protein (MAP) kinases, and transcription factors [39, 40].

Ang II also can activate the AT2 receptor, resulting in cardiovascular consequences often opposite to that of the AT1 receptor. The AT2 receptor is highly expressed in fetal tissues, then production quickly declines following birth [16]. In light of this, the receptor still remains present and can be detected in various adult tissues. Nevertheless, its role in cardiovascular hemostasis is not completely established. To date, the role of AT2 in erectile tissues remains unknown. Previous reports have demonstrated that the specific binding of Ang II in the corpus cavernosum of rabbit was displaced by a selective AT1 antagonist, but not by an AT2 antagonist, suggesting a marginal role of AT2 in erectile tissues [30]. However, to the best of our knowledge, this is the only study addressing AT2 in the corpus cavernosum, and therefore future studies are needed to further explore the role of this receptor erection pathophysiology. Evidences point out that following injury, the AT2 receptor can be upregulated and its actions become more relevant during the pathological condition [16, 41]. Therefore, an in depth investigation of AT2 during ED would be relevant to compliment the overall understanding of RAS in this pathology.

Several reports indicate a positive correlation between increased Ang II activity and ED [8]. Indeed, Ang II plasma levels were elevated in the cavernous blood of patients with an organogenic etiology of ED [10]. This was complimented by the observation that ACE mRNA expression was upregulated in the penis of rats with arteriogenic ED [42], while Ang II-induced contraction was significantly increased in the cavernosum strips from older and diabetic rabbits [43]. Additionally, diabetic ED rats demonstrated a significant increase in Ang II intrapenile levels [44]. Reinforcing these reports, continuous subcutaneous infusion of Ang II has become a common method to produce an ED animal model, underscoring the central role of Ang II/AT1 receptor in the pathophysiology of ED [8].

The link between the ACE/Ang II/AT1 receptor axis hyperactivity and ED suggests that the application of ACEi and ARBs would be an interesting strategy to treat vasculogenic ED. In fact, several preclinical and clinical studies report beneficial outcomes on the sexual function by ACEi and ARB treatment [45–53]. In a hypertension-induced ED rat model, captopril treatment normalized both the blood pressure and erectile response, completely restoring the impaired erectile function [46]. Accordingly, in a rat model of diabetes-induced ED, losartan treatment markedly improved the erectile response [47]. Additionally, in a mouse model of hypercholesterolemia-induced ED, both telmisartan and ramipril (ARBs and ACEi respectively) restored the impaired cavernosal endothelial function by reducing the oxidative stress and normalizing the endothelial nitric oxide synthase expression [48].

Importantly, the beneficial effects produced by ACEi and ARBs on erectile function have also been documented in humans. Several antihypertensive drugs possess the undesirable adverse effect of causing or worsening ED [49], while ACEi and ARBs may have less of an effect to merely improve erectile function [50–53]. In a comparative study between different antihypertensive agents, trichlormethiazide, atenolol, and nifedipine all negatively influenced the sexual activity, with the exception of captopril [54]. Supporting that finding, a study of hypertensive men without a history of sexual dysfunction found that atenolol treatment significantly worsened erectile function, as assessed by the number of sexual intercourse episodes per month, while lisinopril showed minimal influence during the first month which was later fully recovered [55]. In a cohort of 124 diabetic patients with ED, it was observed that losartan has significantly improved sexual activity, assessed by International Index of Erectile Function-5 [45]. Interestingly, the combination of losartan and tadalafil was more effective in improving sexual satisfaction than the single use of one of these drugs [45]. In another study, 12 weeks of losartan treatment significantly improved satisfaction and frequency of sexual activity in hypertensive patients with ED [51]. Interestingly, the positive effect of ABR has also been documented in patients with ED caused by nerve-sparing radical prostatectomy. In a retrospective cohort, it was found that irbesartan treatment significantly increased sexual activity and avoided early loss of stretched penile length, an important common adverse issue in post-prostatectomy patients [56]. Contrary to these reports, a retrospective cohort study from 1990 to 2006 that was based on spontaneous reports in the Swedish adverse drug reaction database indicated a relatively high prevalence of ED in patients treated with ARBs, suggesting these drugs may have a negative effect on ED [57]. Several limitations of a retrospective exist and therefore should be taken into account, especially when interpreting data from spontaneous reports; however this contradictory finding demonstrates that large and well-controlled clinical trials are indeed necessary to clarify the benefits of ACEi and ABR use in ED.

In the last decade, Ang-(1–7) emerged as the main endogenous counter-regulatory effector of Ang II [11, 12, 22]. Acting through the Mas receptor, Ang-(1–7) produces several cardiovascular-protective actions, such as vasodilation, inhibition of oxidative stress, and anti-inflammatory, antithrombotic, antiproliferative, and antifibrotic actions [3, 11, 12, 22]. Likewise, Ang-(1–7) facilitates penile erection and preserves penile structure against pathological alterations [8].

Exogenous administration of Ang-(1–7) was able to produce concentration-dependent relaxation in isolated rabbit corpus cavernosum [43]. Also, its intracavernosal injection potentiated the erectile response induced by electrical stimulation of the major pelvic ganglion of rats and mice [13]. Nevertheless, evidence suggests that endogenous Ang-(1–7) possesses an essential role on penile physiological erection. Intracavernosal administration of A-779, a Mas receptor antagonist, was able to singly reduce erectile response [8, 13]. Moreover, rabbit corpus cavernosum contraction induced by Ang II was enlarged by coadministration of A-779 [43]. Supporting this finding, Mas receptor gene-deleted mice showed a marked reduction in erectile response [13].

Based on the protective role of Ang-(1–7)/Mas axis in erectile function, investigations have been conducted targeting and exploring the contribution of this axis in ED. Indeed, Ang-(1–7)/Mas axis activation may ameliorate or even reverse vasculogenic ED, as was demonstrated by the restoration of impaired erections in DOCA-salt hypertensive rats by acute administration of Ang-(1–7) [13]. Accordingly, treatment with an oral formulation of Ang-(1–7) [Ang-(1–7)-CyD] produced several beneficial effects against hypercholesterolemic-induced corpus cavernosum damage [58]. In particular, Ang-(1–7)-CyD chronic treatment reduced corpus cavernosum fibrosis, which is associated with an attenuation of oxidative stress. Additionally, Ang-(1–7)-CyD improved the cavernosal endothelial function and NO bioavailability [58]. Supporting these observations, Ang-(1–7) treatment was also demonstrated to prevent corpus cavernosum smooth muscle degeneration and oxidative DNA damage in a rat model of diabetic ED [59].