Optimizing inhibition of the renin–angiotensin system in hypertension

Components of the rennin–angiotensin system (RAS) have historically been important targets for cardiovascular drug development. Renin, largely produced from juxtaglomerular cells in the kidney, converts angiotensinogen into ang I that is then converted to ang II by angiotensin converting enzyme (ACE). ACE inhibitors (ACEIs) are currently the first-line antihypertensive therapy [or angiotensin II type 1 receptor blockers (ARBs) if ACEI intolerant] in the general population and those with diabetes, atherosclerotic cardiovascular disease, or chronic kidney disease (CKD) [1,2]. However, these diseases remain the number one cause of death worldwide. In 2013, the Centers for Disease Control reported that hypertension contributed to 360 000 deaths in the United States. Hypertension increases the chance of a first heart attack, first stroke, chronic heart failure, and CKD [3]. Unfortunately, most antihypertensives result in increased reactive plasma renin possibly contributing to drug resistance in those with organ damage/failure [4]. Thus, there is great interest in optimizing renin inhibition to prevent and reverse hypertension and accompanying end-organ damage. CKD affects ∼10% of the world's population [5]. This editorial commentary focuses on the significance and limitations of the study by Barkoudah et al.[6] in this issue of the Journal. They tested the hypothesis that a novel renin inhibitor, named VTP-27999 (Methyl N-[2-[(R)-(3-Chlorophenyl)[(3R)-1-[[[(2S)-2-(methylamino)-3-[(3R)-tetrahydro-2H-pyran-3-yl]propyl]amino]carbonyl]-3-piperidinyl]methoxy]ethyl]carbamate trifluoroacetate), was more potent than aliskiren. The rationale for this stems from their previous work hinting that 150 mg/day of VTP-27999 vs. 300 mg/day aliskiren for 10 days was more potent at reducing renin activity. This was suggested by greater feedback increases in plasma levels of renin in the former group [7]. At day one and 10 of treatment, it took 4 h to achieve maximal levels of each inhibitor in the circulation whereby, on day 10 of treatment, there was 441 ± 267, 786 ± 266, and 269 ± 209 ng/ml of 150, 300 VTP, and 300 aliskiren in the circulation at 4 h, respectively [8]. The IC50 was similar for both compounds [9]. These earlier studies did not quantitate the potency of VTP-27999 on renal hemodynamics and ang II production, hence the importance of this study. Here, healthy adults were maintained on a low-salt diet regimen (10 mmol sodium daily) to endogenously increase renin activity and circulating ang II levels. Such diets are known to increase ang II-mediated regulation of renal blood flow (RBF) and tubular sodium reabsorption [10,11]. The investigators performed a comparison of the VTP compound vs. aliskiren on human renal hemodynamics by examining glomerular filtration rate and renal plasma flow and also mean arterial pressure responses. Renal vascular resistance was not determined. They quantified circulating markers of RAS activation, including plasma renin activity (PRA), prorenin receptor (PRR), and ang II. This acute-dosing study (4–5 h after intravenous bolus) showed that VTP-27999 was twice as potent when compared with aliskiren at inhibiting PRA and reducing ang II levels and increasing renal hemodynamics. There was a slight but nonsignificant reduction in blood pressure in this healthy population. This was a pilot study. Thus, the major limitations lay in its noncrossover design; small sample size; their participants maintained on a low-salt diet; and lack of inclusion of patients with hypertension and/or kidney disease, especially in the setting of diabetes. It included 24 healthy volunteers in whom the age range was 18–75 years for both sexes. There were only three women included, who were required to be postmenopausal or surgically sterilized to participate. Their ages were not specified. The data were not separated between men and women. It is known that the incidence of hypertension in women surpasses that of men following menopause [12]. However, it is unknown whether pre and/or postmenopausal women have altered sensitivity to the blood pressure-lowering and renal vasodilatory effects of renin/RAS inhibition compared with men. In support of the notion that women are more sensitive to RAS inhibition is the finding that, following 2 weeks of AT1R blockade with irbesartan, women ∼27 years of age on low-salt diet were significantly less sensitive to declines in RBF upon acute infusion of ang II compared with age-matched men [13]. Studies are necessary to determine whether younger and/or older women with cardiovascular-renal disease are more sensitive to the benefits of acute and chronic effects of renin inhibition, or other blockers of the RAS, compared with men. The study at hand was conducted in humans on low-salt diet. This diet upregulates the vasoconstrictive arm on the RAS but also the vasodilatory arm of this system as well. This includes the ang II cleavage product ang 1–7. This offsets a rise in blood pressure mediated by the increased endogenous ang II. For example, low-salt diet increased blood pressure dependence on ang 1–7 in male spontaneously hypertensive rats (SHRs) [14]. Whether this is similar in females is unknown. Although the low-salt diet model is great to assess the acute renal effects of RAS inhibition, this is not particularly clinically relevant as a Western diet typically has a salt content of 3400 mg/day. This is over the recommended 1500 mg/day [15]. A Western diet also has high-fat, protein, and/or sucrose. It is hypothesized that chronic exposure to such dietary stress promotes the development of autoimmunity, sodium reabsorption, and salt-sensitive hypertension [16,17]. High salt intake appears to be a major contributing factor to the development of hypertension in Western cultures [18]. The present study was not conducted in hypertensive patients and thus the effects of renin inhibition on salt-sensitive hypertension was not assessed. Neither were patients included that had coronary heart disease, stroke, diabetes, or CKD. Similarly, in a meta-analysis of 11 studies, including ∼11 000 individuals with hypertension without other cardiovascular or renal diseases, it was found that combining, one to another, any of the four classes of antihypertensives (not including a renin inhibitor) approximately doubled the reduction in blood pressure compared with monotherapy [19], and aliskiren plus ACEI/ARB [20] or amlodipine [21] reduced blood pressure more than either alone. However, it is important to note that patients with salt-sensitive hypertension develop more renal damage indicated by microalbuminuria over those without salt sensitivity of blood pressure [22]. Studies supporting that RAS blockade is renal protective was carried out in experimental rats with salt-sensitive hypertension (Dahl salt-sensitive rats). ACEI treatment prevented by 50% their development of hypertension, and completely prevented renal fibrosis [23]. Even more clinically relevant, in already hypertensive Dahl salt-sensitive rats, ACEI treatment significantly reduced blood pressure (tail cuff plethysmography) and renal ang II, which were even greater with aldosterone blockade [24]. Kidney damage was not examined. Adenoviral overexpression of human kallikrein significantly increased glomerular filtration rate and RBF and reversed glomerular sclerosis in male Dahl salt-sensitive rats [25]. Intriguingly, RAS blockade with losartan has been shown to increase circulating bradykinin in hypertensive patients without other cardiovascular diseases, secondary hypertension, diabetes, cardiac arrhythmia, autonomic abnormalities, or obesity [26]. Studies should address whether combining direct renin or other RAS inhibitors and dietary interventions work through the kallikrein system to protect and reverse CKD or other end-organ damage in hypertensive patients. Diabetes is the leading cause for CKD, and those with hypertension are at even greater risk [27]. Deficiency in endothelial nitric oxide synthase (NOS3) results in hypertension and exaggeration of diabetes-induced renal damage; this can be largely prevented by ACEI treatment [28], whereas data about reversal of this pathology are unknown. ARB reduces salt-sensitive hypertension accompanied by increased nitric oxide (NO) in type 2 diabetics with microalbuminura [29]. Unfortunately, many patients still progress toward kidney failure because of increased PRA, and it has been argued that renin inhibition may prove superior in this regard [30]. Experimentally, in already hypertensive transgenic (TG) rats overexpressing mouse renin (mREN) [TG(mRen-2)27 rats], streptozotocin type 1 diabetes-induced albuminuria was prevented along with reductions in blood pressure by aliskiren (10 and 30 mg/day, subcutaneous osmotic minipump infusion) even with persisting hyperglycemia [31]. Aliskiren was also shown to reverse some signs of kidney damage in this model, and in an attempt to determine if it was more beneficial to block PRR on top of aliskiren, this actually induced hyperkalemia and cardiac fibrosis. However, it is not certain whether PRR was actually inhibited or activated [32]. Intriguingly, VTP-27999, unlike aliskiren, does not increase bioavailable prorenin and its restorative effects should be examined. It is necessary to examine the potency of renin inhibition at reversing the hypertensive end-organ disease found in diabetic vs. nondiabetic models, as dual RAS inhibition has proven deleterious. It was found that combining maximal doses killed diabetic mice [33]. A meta-analysis examining blockade with aliskiren at maximal dose combined with an ACEI or ARB promoted hyperkalemia compared with monotherapy [34]. A subgroup analysis of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) trial found that aliskiren alone elicited reductions in aldosterone more effectively in heart failure patients without baseline diabetes mellitus, whereas those with diabetes had trends toward hyperkalemia with greater all-cause death [35]. More recently, Imbalzano found that aliskiren was better at reducing blood pressure and microalbuminuria in type 2 diabetic patients without heart failure [36]. In another study, aliskiren was found to have renoprotective effects when added on top of ARB treatment in type 2 diabetic patients where there was no difference in incidence of heart disease between groups [37]. Interestingly, salt restriction reduced hyperfiltration, renal enlargement, and albuminuria in streptozotocin diabetic rats [38] and potentiated the antihypertensive and antiproteinuric effects of losartan in type 2 diabetics without heart failure [39]. It is important to note that excessive RAS inhibition can promote diastolic hypotension in CKD [40]. A more potent renin inhibitor to use at lower doses may prove better in treating cardiovascular-renal disease in diabetic patients with heart failure and controlling salt intake should be considered in human studies. To determine which disease population benefits most from renin blockade, it seems that genetically ‘humanized’ rodents provide better clinical relevance. In rats overexpressing human renin and angiotensinogen, aliskiren was more potent at preventing albuminuria than valsartan [41]. This was not compared with an ACEI. It is important to note that this was associated with complete prevention in the development of hypertension; therefore, it is unclear whether these protective effects of renin inhibition were solely dependent on the prevention of the hypertension. In conclusion, there is much work to be done regarding optimal strategies to inhibit RAS in patients with hypertension and kidney disease. In this present study by Barkoudah et al. they suggest that inhibiting the rate-limiting step of this system, which is renin in humans, could be best. This is because combined RAS therapy strategies are more complicated by the presence of diabetes, heart failure or CKD when compared to treating patients with hypertension alone. There seems to be less benefit in heart failure and diabetes with possibly increased mortality with triple therapy of ACEI, ARB, and a β-adrenergic blockade [42] or ACEI/ARB with aliskiren [43], respectively. Hypertension is commonly complicated by adverse diets, diabetes, heart failure and CKD, and the use of RAS blockers seems to increase risk for hyperkalemia in this population. However, RAS blockade is still first-line defense for patients with hypertensive end-organ disease. Interestingly, in diabetics with uncontrolled hypertension and microalbuminuria, despite optimal dosing of ACEI and ARB, manidipine reduced blood pressure and albumin excretion [44]. Furthermore, recent data suggest that nonabsorbable potassium binders may prevent such hyperkalemia in such a population [45]. Finding an optimal strategy to control blood pressure is crucial in light of the recent findings from the Systolic Blood Pressure Intervention Trial (SPRINT) indicating that intensive blood pressure lowering beyond the levels currently recommended reduced total mortality in patients by ∼27% [46]. Therefore, future large clinical trials should include a crossover design; compare males and females; and screen for urinary RAS components, albuminuria, NO metabolites and potassium to: identify the patient population that may benefit from combining renin inhibition with other non-RAS antihypertensives and/or potassium binders. These trials should be conducted in conjunction with studies in appropriate animals models to gain mechanistic insights to optimally reduce blood pressure in hypertension. ACKNOWLEDGEMENTS Conflicts of interest Department of Surgery, The University of Mississippi Medical Center.