RAAS blockade generates alternate metabolites of Ang that can exert an anti-hypertensive effect. Vasculo-protective RAS pathways include Angiotensinase A-Ang III-Ang II type 2 (AT₂) receptor pathway and ACE 2-Ang-(1–7)-Mas receptor pathway (Te Riet et al. 2015).

Aldosterone hormone activation of mineralocorticoid receptors (MR), a member of the steroid receptor family, is known to promote vascular cell oxidative stress, inflammation, proliferation, migration and extracellular matrix production (McCurley and Jaffe 2012; Lother and Hein 2016). Vaso-deleterious effects caused by MR activation include: vasoconstriction, atherosclerosis, and vascular remodeling and fibrosis (Lother and Hein 2016; Udelson et al. 2010). Nishiyama et al. demonstrated in animal models that mineralocorticoid-induced hypertension is associated with increased vascular oxidative stress and ROS production (McCurley and Jaffe 2012; Nishiyama and Abe 2004; Iglarz et al. 2004). Subsequently, MR antagonism showed a decrease in NADPH-oxidase activity, resulting in less ROS production, and thus lower BP (Keidar et al. 2003; Sanz-Rosa et al. 2005).

Activation of MR in the vascular bed is also associated with increased expression of proinflammatory factors including ICAM1, monocyte chemoattractant protein (MCP-1), cytokines, placental growth factor (PGF), COX-2 and transcription factor NF-κB (McCurley and Jaffe 2012; Rocha et al. 2002). Aortas from patients with atherosclerosis demonstrated a decrease in PGF and connective tissue growth factor when treated with spironolactone (a MR antagonist) (Jaffe et al. 2010; Newfell et al. 2011). Furthermore, the controlled Prevention and Treatment of Hypertension With Algorithm-Based Therapy (PATHWAY)-2 clinical trial showed a decrease in blood pressure by 8.7 mmHg with spironolactone treatment in patients with resistant hypertension (Lother and Hein 2016; MacDonald et al. 2015). Such findings support the role of MR-activation induced inflammation as a contributing factor to hypertension. However, further trials exploring the use of MR antagonists as anti-hypertensive agents are required to confirm these results.

Anti-angiogenesis therapy targeting vascular endothelial growth factor (VEGF) and its receptors as treatment for anti-tumor growth has long been associated with adverse side effects of hypertension and renal toxicity manifesting as proteinuria and renal function impairment (Lankhorst et al. 2016; van den Meiracker and Danser 2016). Physiologically, VEGF mediates vasodilation through increased nitric oxide (NO) production by upregulating the NOS gene expression and increased endothelial NOS phosphorylation (Hood et al. 1998; Shen et al. 1999). The subsequent decrease in NO availability following VEGF inhibition contributes to the pathogenesis of hypertension during anti-angiogenesis therapy (van den Meiracker and Danser 2016; Facemire et al. 2009). Recent investigations of the role of the Endothelin (ET) system, specifically Endothelin-1, suggest this system as a more significant contributor to the rise in BP compared to NO deprivation. A rise in ET-1 is noted with administration of sunitinib, a receptor tyrosine kinase (RTK) inhibitor that targets VEGF receptors (Kappers et al. 2010). Endothelin-1 (ET-1) interacts with G-protein-coupled membrane bound ET_A and ET_B receptors on vascular smooth muscle to mediate vasoconstriction. Furthermore, ET_A receptor antagonism prevented anti-angiogenic induced hypertension in mice (Li et al. 2012). Currently, there is no established guideline for reversing hypertension induced by VEGF-targeted therapies (Hayman et al. 2012).

Asymmetric dimethyarginine (ADMA) is a naturally occurring amino acid synthesized when arginine residues in proteins undergo methylation by arginine methyltransferases (PRMTs) (Vallance and Leiper 2004; Vallance et al. 1992). An additional by-product of this interaction is N^G-monomethyl- L-arginine (L-NMMA), a methylarginine similar to ADMA in its biological activity. Following hydrolysis of methylated proteins ADMA and L-NMMA are released in the cytosol. ADMA is found in various tissues, circulates in plasma and is excreted in urine (Vallance and Leiper 2004). In addition to renal clearance, ADMA is extensively metabolized by dimethylarginine dimethyl aminohydrolases (DDAHs) resulting in conversion to citrulline (Achan et al. 2003).

Both ADMA and L-NMMA competitively inhibit all three isoforms NOS, thereby causing vasoconstriction, impaired endothelium-mediated vasodilatation, increased endothelial adhesiveness, and hypertension (Vallance et al. 1992; Achan et al. 2003; Hasegawa et al. 2007; Kielstein et al. 2004; Barba et al. 2000; Böger et al. 2000). Targeted deletion of DDAH gene and use of specific inhibitors of DDAH lead to accumulation of ADMA, a reduction in NO signaling and subsequent vascular dysfunction, increased systemic vascular resistance and blood pressure (Leiper et al. 2007). Transgenic mice overexpressing DDAH demonstrated reduced ADMA levels and increased cardiac NO levels. However, transgenic mice showed no changes in systemic BP compared to wild type controls under normal conditions (Hasegawa et al. 2007). Two-week treatment with angiotensin II increased ADMA levels, cardiac oxidative stress and vascular injury while DDAH overexpression attenuated these changes (Hasegawa et al. 2007). Conversely, Jacobi et al. reported no increase in ADMA levels following 4-week Ang II infusion (Jacobi et al. 2008). Overexpression of DDAH however attenuated ang-II medicated end organ damage (Jacobi et al. 2008).

Small clinical studies have noted an association between hypertension and increased ADMA levels (Surdacki et al. 1999; Perticone et al. 2005). Larger scale clinical studies have however not corroborated these findings (Meinitzer et al. 2007; Schnabel et al. 2005). Trials evaluating the effect of antihypertensive agents on ADMA levels have yielded conflicting results. Some investigators reported significant reductions in ADMA levels following treatment with RAS, (Chen et al. 2002; Delles et al. 2002; Ito et al. 2002; Napoli et al. 2004; Aslam et al. 2006) while others have failed to confirm these findings (Fliser et al. 2005; Warnholtz et al. 2007). Differences in study design, treatment regimens, methods of determining ADMA levels may account for the discrepant findings of the aforementioned studies.

ADMA has been shown to have a negative correlation with endothelial-dependent vasodilation (EDV) and a positive correlation with carotid artery intima-media thickness (IMT) in hypertensive patients with administration of salbutamol and nitroglycerine (Serg et al. 2011). Cakar and colleagues evaluated arterial stiffness markers for endothelial dysfunction and found that ADMA levels significantly correlated with augmentation index (Aix) and CRP levels. However, there was no correlation between PWV and central aortic pressure (CAP) and ADMA (Cakar et al. 2015). Similarly, the PREVENCION study showed that ADMA and NMMA did not predict carotid-femoral PWV, blood pressure or hemodynamic abnormalities (Chirinos et al. 2008). Therefore, while it is very clear that ADMA plays a role in endothelial dysfunction and can cause significant changes in vascular flow, it still remains to be seen whether ADMA directly play a role in hypertension.

Therapeutic approaches specifically targeting ADMA pathways have been studied. Increased L-citrulline supplementation overcame ADMA inhibition, resulting in improved NO production in porcine hearts (Xuan et al. 2015). The effects of L-arginine on endothelial function, blood pressure, and ADMA levels in patients with hypertension (NCT02392767) and in patients with preeclampsia are currently being evaluated (NCT00275158).

The recently concluded SPRINT trial has suggested that achieving aggressive blood pressure targets reduces cardiovascular morbidity and mortality. This will require more aggressive and complex treatment regimens, in most cases with multi-drug protocols. In order to achieve better blood pressure control, it is imperative to understand the mechanisms that lead to increased blood pressure. Knowledge of the causative mechanisms will allow informed selection of agents and combinations that are additive and even synergistic. Such an approach will in turn allow the fashioning “personalized” treatment regimens that will maximally benefit each patient individually.