Combined Renin-angiotensin System Research Articles

Pharmacodynamic benefits of combined renin angiotensin system inhibition and alpha-1 adrenergic antagonism in the management of hypertension and cardiovascular disease in people with African ancestry

Abstract Genetic differences exist between Blacks and whites through sympathetic-vascular transduction signaling mechanisms. However, the lack of benefit of alpha-1 blockers in whites may not be applicable in Africans. The angiotensin II (Ang II) and alpha-1 receptor pathways are critical for vasoconstriction in Blacks. This article reviewed the consequence of the dual blockade among Nigerians, those with and without cardiovascular disease. Both receptors exhibited crosstalk and mutual regulations. Synergistic inhibition of Forearm vasoconstriction and hypotensive response to enalapril + prazosin (alpha-1 blocker [A1B]) occurred (P < 0.05). High efficacy of dual blockade by angiotensin converting enzyme inhibitor (ACEI) + A1B was reported in hypertensive urgency, hypertensive crises, and heart failure (HF) with reduced ejection fraction congestive HF compared to ACEI (P < 0.05). The high efficacy of dual blockade by ACEI + A1B + diuretics is beneficial for widespread use in Nigerians with cardiovascular disease.

Usefulness of Combined Renin-Angiotensin System Inhibitors and Diuretic Treatment In Patients Hospitalized with COVID-19

Antecedent use of renin-angiotensin system inhibitors (RASi) prevents clinical deterioration and protects against cardiovascular/thrombotic complications of COVID-19, for indicated patients. Uncertainty exists regarding treatment continuation throughout infection and doing so with concomitant medications. Hence, the purpose of this study is to evaluate the differential effect of RASi continuation in patients hospitalized with COVID-19 according to diuretic use. We used the Coracle registry, which contains data of hospitalized patients with COVID-19 from 4 regions of Italy. We used Firth logistic regression for adult (>50 years) cases with admission on/after February 22, 2020, with a known discharge status as of April 1, 2020. There were 286 patients in this analysis; 100 patients (35.0%) continued RASi and 186 (65%) discontinued. There were 98 patients treated with a diuretic; 51 (52%) of those continued RASi. The in-hospital mortality rates in patients treated with a diuretic and continued versus discontinued RASi were 8% versus 26% (p = 0.0179). There were 188 patients not treated with a diuretic; 49 (26%) of those continued RASi. The in-hospital mortality rates in patients not treated with a diuretic and continued versus discontinued RASi were 16% versus 9% (p = 0.1827). After accounting for age, cardiovascular disease, and laboratory values, continuing RASi decreased the risk of mortality by approximately 77% (odds ratio 0.23, 95% confidence interval 0.06 to 0.95, p = 0.0419) for patients treated with diuretics, but did not alter the risk in patients treated with RASi alone. Continuing RASi in patients concomitantly treated with diuretics was associated with reduced in-hospital mortality.

Renoprotection Provided by Additional Diuretic Treatment in Partially Nephrectomized Ren-2 Transgenic Rats Subjected to the Combined RAS and ETA Blockade.

ObjectiveOur previous study in heterozygous Ren-2 transgenic rats (TGR) demonstrated that long-term treatment with endothelin receptor A (ETA) blocker atrasentan added to the renin-angiotensin system (RAS) blockade had renoprotective effects in a model of chronic kidney disease (CKD) induced by partial nephrectomy. Since ETA blockade is known to cause edema, we were interested whether diuretic treatment added to this therapy would be beneficial.Design and MethodsPartial nephrectomy (NX) was performed at the age of 3 months in TGR rats which were subjected to: (i) RAS blockade alone (angiotensin receptor blocker losartan and angiotensin converting enzyme inhibitor trandolapril), (ii) combined RAS (losartan and trandolapril) and ETA receptor blockade (atrasentan), or (iii) diuretic (hydrochlorothiazide) added to the combined RAS + ETA blockade for 50 weeks following NX.ResultsAt the end of the study systolic blood pressure and cardiac hypertrophy were similarly decreased in all treated groups. Survival was significantly improved by ETA receptor blockade added to RAS blockade with no further effects of diuretic treatment. However, additional diuretic treatment combined with RAS + ETA blockade decreased body weight and had beneficial renoprotective effects – reductions of both kidney weight and kidney damage markers. Proteinuria gradually increased in rats treated with RAS blockade alone, while it was substantially lowered by additional ETA blockade. In rats treated with additional diuretic, proteinuria was progressively reduced throughout the experiment.ConclusionA diuretic added to the combined RAS and ETA blockade has late renoprotective effects in CKD induced by partial nephrectomy in Ren-2 transgenic rats. The diuretic improved: renal function (evaluated as proteinuria and creatinine clearance), renal morphology (kidney mass, glomerular volume), and histological markers of kidney damage (glomerulosclerosis index, tubulointerstitial injury).

SAT-179 RAS, SEH AND ETA BLOCKADE IN THE COURSE OF CHRONIC KIDNEY DISEASE IN 5/6 NEPHRECTOMIZED REN-2 TRANSGENIC RATS

Previous studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ETA) receptor blockade, retards chronic kidney disease (CKD) progression. Heterozygous TGR and age-matched Hannover-Sprague Dawley (HanSD) normotensive controls were used. Trandolapril and losartan were used as RAS blockade, cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB) as sEH blockade and atrasentan as ETA receptor blockade, administered in drinking water. 5/6 nephrectomy was done at the age of 6 weeks and 6 weeks later the appropriate treatment was started. Animals were treated with RAS blockade, a combination of RAS and sEH blockade, or a combination of RAS, sEH and ETA blockade. Survival rate, albuminuria, clearance of endogenous creatinine, glomerular damage (glomerulosclerosis index), and renal cortical tubulointerstitial injury were assessed. The addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance – all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ETA receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, abolished the beneficial effects of adding sEH inhibitor to the RAS blockade. These data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to add additional substances to this therapeutic regime should be made with extreme caution.

Addition of Endothelin A-Receptor Blockade Spoils the Beneficial Effect of Combined Renin-Angiotensin and Soluble Epoxide Hydrolase Inhibition: Studies on the Course of Chronic Kidney Disease in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats

Introduction: Previous studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ET_A) receptor blockade retards chronic kidney disease (CKD) progression. This prompted us to evaluate if this progression will be alleviated by the addition of sEH inhibitor and ET_A receptor antagonist to the standard complex blockade of RAS (angiotensin-converting enzyme inhibitor plus angiotensin II type 1 receptor blocker) in rats with established CKD. Methods: The treatment regimens were initiated 6 weeks after 5/6 NX in TGR, and the follow-up period was 60 weeks. Results: The addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance – all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ET_A receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, also abolished the beneficial effects of adding sEH inhibitor to the RAS blockade. Conclusion: These data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to further extend this therapeutic regimen should be made with extreme caution.

Moderate additive effects of endothelin receptor A blockade in Ren-2 transgenic rats subjected to various types of RAS blockade

AimsChronic endothelin receptor A (ETA) blockade lowered blood pressure (BP) by decreasing angiotensin-dependent vasoconstriction and attenuating calcium influx. We tested whether the addition of ETA blockade to renin–angiotensin system (RAS) blockade would have further effects on the principal vasoactive systems contributing to BP maintenance in Ren-2 transgenic rats (TGR). MethodsFour-week-old TGR rats were fed with normal-salt diet and given either different renin–angiotensin system (RAS) blockers [angiotensin receptor blocker losartan, angiotensin converting enzyme inhibitor captopril, direct renin inhibitor aliskiren], or ETA blocker (atrasentan) alone, or a combination of atrasentan with RAS blockers for 4weeks. At the end of the study, basal BP and acute BP responses to sequential blockade of renin–angiotensin (RAS), sympathetic nervous (SNS), and nitric oxide (NO) systems were determined in conscious rats. Thereafter, BP responses to acute inhibition of nifedipine-sensitive calcium influx through voltage-dependent calcium channels (L-VDCC) were measured. Key findingsAll RAS blockers similarly decreased BP to normotension, their effects being mediated through substantially attenuated RAS-dependent and moderately decreased SNS-dependent vasoconstriction. Atrasentan alone partially lowered BP, while BP was normalized by combination of atrasentan with either RAS blocker. In combination therapies, BP lowering effects resulted from the attenuation of both RAS- and SNS-dependent vasoconstriction. Moreover, atrasentan-treated groups had substantially reduced NO-dependent vasodilation and significantly decreased calcium influx through L-VDCC. ConclusionsAlthough the BP-lowering effect of combined ETA and RAS blockades in TGR is predominantly dependent on the effects exerted by RAS blockade, further effects are attributable to decreased calcium influx due to chronic ETA blockade.

Effects of Ramipril and Telmisartan on Plasma Concentrations of Low Molecular Weight and Protein Thiols and Carotid Intima Media Thickness in Patients with Chronic Kidney Disease.

Hypertension, a common feature in chronic kidney disease (CKD), is an independent risk factor for CKD progression and cardiovascular disease. Although inhibitors of the renin-angiotensin system (RAS) exert salutary effects on blood pressure control and proteinuria in CKD patients, their activity towards traditional and novel oxidative markers is largely unknown. We studied the effects of 6-month treatment with telmisartan versus a combination of telmisartan and ramipril on plasma concentrations of low molecular mass (LMW, including homocysteine and cysteine) and protein thiols (PSH) plasma concentration and their relationships with carotid intima media thickness (IMT), in 24 hypertensive CKD patients (age 60 ± 12 years, 8 females and 16 males). Pretreatment PSH concentrations were independently associated with IMT (r = −0.42, p = 0.039). Neither treatment affected plasma LMW thiols, in both reduced and total form. By contrast, both treatments increased PSH plasma concentrations and reduced IMT, although significant differences were only observed in the combined treatment group. Our results suggest that the beneficial effects of combined RAS inhibitor treatment on IMT in hypertensive CKD patients may be mediated by a reduction of oxidative stress markers, particularly PSH.

Effects of Combined Endothelin A Receptor and Renin‐Angiotensin System Blockade on The Regression of Chronic Kidney Disease in 5/6 Nephrectomized Ren‐2 Transgenic Rats

Study objectiveWe tested the hypothesis where the combined renin‐angiotensin system (RAS) and endothelin 1 (ETA) receptor blockade could be more effective in the slowing of progression of CKD with already established sings of renal injury than antihypertensive treatment based on isolated RAS inhibition in 5/6 nephrectomized (NX) Ren‐2 transgenic hypertensive rats (TGR).MethodsIn five groups of male rats: sham‐operated TGR; untreated 5/6 NX TGR; 5/6 NX TGR with dual RAS blockade (trandolapril 6 mg/L and losartan 100 mg/L); 5/6 NX TGR with combined treatment with RAS and ETA receptor blockade (atrasentan 5 mg/kg/day). 5/6 NX was done in age of 6 weeks and the treatments were initiated 6 weeks after 5/6 NX. Rats were placed into metabolic cages to determine albuminuria at weeks 6, 8, 12, 16, 20, 30. In other groups, concentrations of ANG II and ET1 were evaluated in the kidneys after 2 weeks of treatments.ResultsMortality of untreated 5/6 NX TGR was 100% at 17th week compared to sham‐operated rats with mortality 0% to 30th week. Mortality of 5/6 NX TGR with RAS blockade was 32 % and in group with RAS and ETA receptor blockade 37 % at the end of 30th week. In 5/6 NX TGR, both treatments reduced enhanced albuminuria, plasma and kidney ANG II and cortical ET 1 concentrations similarly.ConclusionThere is no additive effect of combined ETA receptor and RAS blockade on the regression of CKD in 5/6 NX TGR most likely due to efficient reduction of ET 1in the renal cortex by the dual RAS inhibition.

The end of the road for dual renin-angiotensin system blockade in diabetic nephropathy: which way now?

From initial promise in preclinical experimental models through the repeateddemonstration of anti-proteinuric efficacy in short-term studies to a series of failed phase 3 outcome trials, the journey of dual renin angiotensin system (RAS) blockade indiabetic nephropathyhas spanned a decade and a half. Now, with the publication of the results of the prematurely terminated Veterans Affairs Nephropathy in Diabetes (VANEPHRON-D) study (1), it seems that the endof the road for dual RAS blockade has finally arrived. Here, we review the rationale behind the concept of combination RAS inhibition as a therapeutic approach to slow renal decline in diabetes, reflect on the initial hope and the ultimate disappointment, and consider, in practical terms, what steps a physician may take when faced with a patient with diabetes and declining renal function.

0272: True antihypertensive efficacy of sequential nephron blockade in patients with resistant hypertension and confirmed medication adherence

We previously showed (Bobrie et al. J Hypertens 2012) that sequential-nephron blockade (SNB) was more effective than combined renin angiotensin system blockade (RB) for controlling BP in patients with resistant hypertension (RH). In this post-hoc analysis, we assessed medication adherence (MA) and its influence on the antihypertensive response to SNB/RB with a new combined scoring system. Pts with daytime ambulatory SBP/DBP (dASBP/dADBP) >135 and/or 85 mmHg, despite 4 week-treatment with irbesartan 300 mg+HCTZ 12.5 mg+amlodipine 5 mg, were randomised either to SNB (i.e.+spironolactone 25 mg, then +furosemide 20-40 mg, then +amiloride 5 mg, n=82) or RB (ramipril 5-10 mg, then bisoprolol 5-10 mg, RB group, n=82) for 12 weeks. MA was scored according to 4 criteria: (i) trough/peak plasma irbesartan (Irb) concentration (HPLC); (ii) urinary AcSDKP/creatinine ratio (UR) to evaluate ramipril intake; (iii) delay of last medication intake before visit (LMI); and (iv) pill counting (PC, %). One point of MA score was attributed to trough Irb >20ng/ml, UR >4nmol/mmol, LMI <24h and PC >80%. MA was defined as low (LMA, score <2), intermediate (IMA, score=3), and optimal (OMA, score=4). 82 pts among 164 had OMA (46 SNB and 36 RB); 52 pts had IMA (23 SNB and 29 RB); and 30 pts had LMA (13 SNB and 17 RB) (inter-groups difference: NS). LMA pts were younger than SMA pts (50±11 vs. 56±10 yrs, p<0.011). In OMA pts, the difference in dASBP/dADBP between SNB vs RB was significant (–11 [–17;–6]/–6 [–9;–2] mmHg, p<0.0001/p=0.0025), favoring SNB, whereas in LMA pts the significant difference between the two groups was no more observed (–6 [–19;7]/–1 [–10;7] mmHg, p=0.352/p=0.7096). The major BP lowering effect of SNB vs. RB observed in pts with OMA is lost in pts LMA. Combined methods for assessing MA allow determining the true efficacy of antihypertensive strategies in patients with RH. Reinforcement of MA in RH pts is deemed necessary.

0273: Beneficial effect of sequential nephron blockade on central pressure and large artery remodeling in resistant hypertension

We have previously shown that combined renin-angiotensin system blockade (RB) was less effective than sequential-nephron blockade (SNB) for controlling BP in resistant hypertension (RH). Whether this is accompanied with an improvement in the mechanical properties of large arteries is unknown. Pts with daytime ambulatory SBP/DBP (dASBP/dADBP) >135 and/or 85 mmHg, despite 4 week with irbesartan (Irb)+ HCTZ+amlodipine, were randomised to SNB (n=82) or RB (n=82) for 12 weeks. Central pulse pressure (CPP) and carotid-femoral pulse wave velocity (PWV) were measured by aplanation tonometry. High-resolution echotracking system (Walltrack®) was used to measure carotid artery diameter (Dcca), wall thickness (WT), circumferential wall stress (CWS), and stiffness. All parameters were measured at baseline and week 12. Baseline clinical characteristics did not differ between groups. dASBP decreased more in SNB (–19±12 mmHg) vs RB (–8±13 mmHg, p<10-6), either for CPP [SNB (–12.8±16.9 mmHg) vs RB (–1.0±9.3 mmHg, p<0.006)] after adjustment on baseline CPP and deltaMeanBP. CCA stiffness and PWV decreased similarly in both groups. Dcca decreased more in SNB (–267±46 μm) vs RB (–7.8±39 μm, p=0.01) after adjustment on baseline D and deltaASBP. WT did not differ and CWS decreased more in SNB (–15.2±16.5 kPa) vs RB (–5.2±12.6 kPa, P=0.001). In RH pts, a ttt strategy based on SNB improved CPP to a greater extent than a RB strategy. This may lead to a better target organ damage prevention and CV outcome. SNB improved CWS. Whether this effect is due aldosterone blockade or sodium depletion remains to be investigated.

Blocage combiné du système rénine angiotensine

Blockade of the renin-angiotensin system (RAS) with angiotensin-converting-enzyme (ACEI) inhibitors or angiotensin II receptor blockers (ARB) has become a major therapeutic tool. Due to internal counter-regulation, however, this system cannot be fully blocked by targeting only one of its components. Instead of increasing the doses of an ACEI, an ARB or a renin inhibitor, blocking RAS at two successive levels neutralizes the consequences of internal counter-regulation and thus provides a more complete blockade with more pronounced biological effects. Additive effects on blood pressure lowering and on renin secretion during combined administration of RAS blockers were first demonstrated in normotensive subjects and in various experimental models of hypertension, heart failure and renal failure. Although combined RAS blockade provided an additional hemodynamic response and more complete neutralization of the cellular effects of angiotensin II, no benefit was observed in terms of cardiovascular or renal protection in heart disease (heart failure, post-myocardial infarction, high vascular risk) or kidney disease (diabetic nephropathy). Moreover, more complete RAS blockade is risky in conditions where blood pressure and renal perfusion are renin-dependent (renal failure and hypotension) and also in hypoaldosteronism (hyperkalemia). The European, French and US. health agencies have contraindicated combined RAS blockade because of its unfavorable risk-benefit balance, especially in patients with diabetes or renal failure.

Addition of ETA receptor blockade increases renoprotection provided by renin–angiotensin system blockade in 5/6 nephrectomized Ren-2 transgenic rats

AimsThere is evidence that in addition to hypertension and hyperactivity of the renin–angiotensin system (RAS), enhanced intrarenal activity of endothelin (ET) system contributes to the pathophysiology and progression of chronic kidney disease (CKD). This prompted us to examine if this progression would be alleviated by addition of type A ET receptor (ETA) blockade to the standard blockade of RAS. Main methodsRen-2 transgenic rats (TGR) after 5/6 renal ablation (5/6 NX) served as a model of CKD. For RAS inhibition a combination of angiotensin-converting enzyme inhibitor (trandolapril, 6mg/L drinking water) and angiotensin II type 1 receptor blocker (losartan, 100mg/L drinking water) was used. Alternatively, ETA receptor blocker (atrasentan, 5mg·kg−1·day−1 in drinking water) was added to the combined RAS blockade. The follow-up period was 44weeks after 5/6 NX, and the rats' survival rate, systolic blood pressure (SBP), proteinuria and indices of renal glomerular damage were evaluated. Key findingsThe survival rate was at first improved, by either therapeutic regime, however, the efficiency of RAS blockade alone considerably decreased 36weeks after 5/6 NX: final survival rate of 65% was significantly lower than 91% achieved with combined RAS and ETA receptor blockade. SBP was not affected by the addition of ETA blockade while proteinuria and renal glomerular damage were further reduced. SignificanceOur data show that a combined RAS and ETA receptor blockade exhibits additional beneficial effects on survival rate and the progression of CKD in 5/6 NX TGR, as compared with RAS inhibition alone.

The Angiotensin-Melatonin Axis

Accumulating evidence indicates that various biological and neuroendocrine circadian rhythms may be disrupted in cardiovascular and metabolic disorders. These circadian alterations may contribute to the progression of disease. Our studies direct to an important role of angiotensin II and melatonin in the modulation of circadian rhythms. The brain renin-angiotensin system (RAS) may modulate melatonin synthesis, a hormone with well-established roles in regulating circadian rhythms. Angiotensin production in the central nervous system may not only influence hypertension but also appears to affect the circadian rhythm of blood pressure. Drugs acting on RAS have been proven effective in the treatment of cardiovascular and metabolic disorders including hypertension and diabetes mellitus (DM). On the other hand, since melatonin is capable of ameliorating metabolic abnormalities in DM and insulin resistance, the beneficial effects of RAS blockade could be improved through combined RAS blocker and melatonin therapy. Contemporary research is evidencing the existence of specific clock genes forming central and peripheral clocks governing circadian rhythms. Further research on the interaction between these two neurohormones and the clock genes governing circadian clocks may progress our understanding on the pathophysiology of disease with possible impact on chronotherapeutic strategies.

Combination renin–angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions

The RAS (renin-angiotensin system) is activated after MI (myocardial infarction), and RAS blockade with ACEis [ACE (angiotensin-converting enzyme) inhibitors] or ARBs (angiotensin receptor blockers) slows but does not completely prevent progression to heart failure. Cardiac ACE is increased after MI and leads to the formation of the vasoconstrictor AngII (angiotensin II). The enzyme ACE2 is also activated after MI and degrades AngII to generate the vasodilator Ang-(1-7) [angiotensin-(1-7)]. Overexpression of ACE2 offers cardioprotective effects in experimental MI, but there is conflicting evidence as to whether the benefits of ACEis and ARBs are mediated through increasing ACE2 after MI. In the present study, we assessed the effect of an ACEi and ARB, alone and in combination, on cardiac ACE2 in a rat MI model. MI rats received vehicle, ACEi (ramipril; 1 mg/kg of body weight), ARB (valsartan; 10 mg/kg of body weight) or combination (ramipril at 1 mg/kg of body weight and valsartan at 10 mg/kg of body weight) orally for 28 days. Sham-operated rats were also studied and received vehicle alone. MI increased LV (left ventricular) mass (P<0.0001), impaired cardiac contractility (P<0.05) and activated cardiac ACE2 with increased gene (P<0.05) and protein expression (viable myocardium, P<0.05; border zone, P<0.001; infarct, P<0.05). Ramipril and valsartan improved remodelling (P<0.05), with no additional effect of dual therapy. Although ramipril inhibited ACE, and valsartan blocked the angiotensin receptor, neither treatment alone nor in combination augmented cardiac ACE2 expression. These results suggest that the cardioprotective effects of ramipril and valsartan are not mediated through up-regulation of cardiac ACE2. Strategies that do augment ACE2 after MI may be a useful addition to standard RAS blockade after MI.

Trientine and renin–angiotensin system blockade ameliorate progression of glomerular morphology in hypertensive experimental diabetic nephropathy

A comparison of the efficacy of the copper chelator, trientine, with combined renin angiotensin system (RAS) blockade on the progression of glomerular pathology in the diabetic (mREN-2)27 rat is reported. Animals were treated for 2 months with trientine, combined RAS blockers, combined trientine plus RAS blockers or none. Treatments began after inducing diabetes with streptozotocin. Physiological data were recorded monthly and light microscopic glomerular features were scored. Plasma allantoin and both plasma and renal protein carbonyls were measured as markers of oxidative stress. Trientine and RAS blockade decreased proteinuria and albuminuria and prevented an increase in creatinine clearance and kidney weight. Both reduced the diabetes-related glomerular features of mesangiolysis and glomerular segmental hypocellularity and trientine prevented severe tuft-to-capsule adhesion and reduced tubularization. Hypertension-related severe mesangial matrix expansion and global hypercellularity were increased by both treatments, which may reflect repair of mesangiolysis. Trientine reduced plasma but not renal protein carbonyls or plasma allantoin. In this model, trientine prevented the development of many diabetes-specific features similarly to RAS blockade. Amelioration of oxidative stress and features commonly observed in human diabetic nephropathy (DN), support a diabetes-related defect in copper (Cu) metabolism. The addition of Cu(II) chelation may improve current DN therapy.

Efficacy of Sevikar® compared to the combination of perindopril plus amlodipine on central arterial blood pressure in patients with moderate-to-severe hypertension: Rationale and design of the SEVITENSION study

Background and rationale To date, few studies have investigated the effects of combined renin-angiotensin system blockade/calcium channel blockade on central aortic blood pressure. The Conduit Artery Function Evaluation (CAFE) sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) investigated the effects of amlodipine/perindopril and atenolol/bendroflumethiazide on central aortic blood pressure (CABP). Similar brachial blood pressure levels were achieved; however, there was a significant difference, in favor of the amlodipine/perindopril combination, on the effects of CABP. No study has investigated the effects of a combination of an angiotensin receptor blocker/calcium channel blocker compared to those of a calcium channel blocker/angiotensin-converting enzyme inhibitor combination. To confirm and support previous findings, the SEVITENSION study will assess the effects on CABP of treatment with the high dose combination of perindopril plus amlodipine as used in ASCOT–CAFE compared with the high dose combination of olmesartan/amlodipine in patients with moderate-to-severe hypertension uncontrolled on amlodipine monotherapy. Objective To demonstrate non-inferiority of fixed-dose olmesartan/amlodipine combination therapy compared with the combination of perindopril plus amlodipine on the mean change from baseline in central aortic systolic blood pressure. Design A multicenter, double-blind, parallel-group, non-inferiority study comprising a 2–4-week open-label run-in period with amlodipine and a 24-week active treatment period. CABP will be measured by the SphygmoCor® Vx Pulse Wave Velocity System. Patients 720 moderate-to-severe hypertensive patients aged ≥ 40 to ≤ 80 years and ≥ 3 additional risk factors will be enrolled. Interventions Study treatment will comprise orally-administered combination of olmesartan/amlodipine (40/10 mg) or perindopril (8 mg) plus amlodipine (10 mg), and matching placebos. (EudraCT number: 2009-012966-30; ClinicalTrials.gov identifier: NCT01101009).

Cross-talk Between Statins and the Renin-angiotensin System

Hypercholesterolaemia and hypertension are major public health problems that are frequently treated with statins and renin-angiotensin system (RAS) blockades. Although the mechanisms of action for these two classes of drugs differ, both classes have beneficial effects on the vasculature. Experimental and clinical studies demonstrated that combined statins and RAS blockades improve endothelial function as reflected by improved flow-mediated dilation, improved fibrinolysis potential and reduced oxidant stress, inflammatory markers and insulin sensitivity. There is a strong scientific rationale for recommending combination therapy, especially statins and RAS blockades, to treat or prevent atherosclerosis and coronary heart disease. In this article, we address the mechanisms on the cross-talk between statins and RAS and discuss the rationale and importance of combination therapy with statins and RAS blockades in treating and preventing cardiovascular events.

Central Pressure and Biomarker Responses to Renin Inhibition with Hydrochlorothiazide and Ramipril in Obese Hypertensives: The ATTAIN Study

Background/Aims: In obese, hypertensive subjects, the renin-angiotensin system (RAS) is enhanced and natriuresis impaired, suggesting a role for combination RAS blockade with diuretics. Data suggest that renin inhibition may attenuate diuretic-induced RAS activation and oxidative stress. Methods: In this 8-week, double-blind study of 386 obese individuals (mean body mass index: 35.3) with stage 2 hypertension (mean age: 54.9 years; mean sitting systolic blood pressure, SBP: ≧160 but <200 mm Hg), we compared the efficacy of aliskiren + hydrochlorothiazide (HCTZ) in reducing blood pressure (BP), plasma renin activity (PRA), and a urinary marker of oxidative stress to ramipril. Subjects were randomized to aliskiren/HCTZ 150/12.5 mg or ramipril 5 mg for 1 week, and after the 1st week force titrated to aliskiren/HCTZ 300/25 mg or ramipril 10 mg for 7 weeks. Results: After 8 weeks, aliskiren/HCTZ provided greater reductions in office BP than ramipril (–28.1/–10.1 vs. –16.6/–3.6 mm Hg, p < 0.0001) as well as 24-hour ambulatory and central pressure measures. Aliskiren/HCTZ also lowered PRA (–45 vs. +83%) and the urinary F2-isoprostane/creatinine ratio (–18 vs. +7%) to a greater extent than ramipril. Adverse events (AEs) were similar in the two groups (35.8% with aliskiren/HCTZ vs. 37.3% on ramipril reporting at least one AE). Conclusions: Our findings suggest that the aliskiren/HCTZ combination reduced BP, PRA, and isoprostanes to a greater extent than did ramipril in obese patients with stage 2 hypertension.

Recent changes in the landscape of combination RAS blockade

The renin–angiotensin system (RAS) is a prime target for cardiovascular drug therapy. Inhibition of the RAS lowers blood pressure and confers protection against cardiovascular and renal events. These latter benefits cannot be entirely attributed to blood pressure lowering. Angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) have been studied extensively and, while there is irrefutable evidence that these agents mitigate the risk for cardiovascular and renal events, their protection is incomplete. In outcomes studies that have employed ACE-inhibitors or ARBs there has been a relatively high residual event rate in the treatment arm and this has been ascribed, by some, to the fact that neither ACE-inhibitors nor ARBs completely repress RAS. For this reason, combined RAS blockade with an ACE-inhibitor and ARB has emerged as a therapeutic option. In hypertension, combined RAS blockade elicits only a marginal incremental drop in blood pressure and it does not further lower the risk for cardiovascular events. In chronic heart failure and proteinuric renal disease, combining these agents in carefully selected patients is associated with a reduction in clinical events. Irrespective of the setting, dual RAS blockade is associated with an increase in the risk for adverse events, primarily hyperkalemia and worsening renal function. The emergence of the direct renin inhibitor, aliskiren, has afforded clinicians a new strategy for RAS blockade. Renin system blockade with aliskiren plus another RAS agent is the subject of ongoing large-scale clinical trials and early studies suggest promise for this strategy. Currently, combined RAS blockade with an ACE-inhibitor and an ARB should not be routinely employed for hypertension; however, the combination of an ACE-inhibitor or ARB with aliskiren might be considered in some patients given the more formidable blood pressure-lowering profile of this regimen. In carefully selected patients with heart failure or kidney disease, combination therapy with two RAS inhibitors should be considered.