Angiotensin II Receptor Blockade Research Articles

Sacubitril/valsartan versus valsartan in regressing myocardial fibrosis in hypertension: a prospective, randomized, open-label, blinded endpoint clinical trial protocol.

Diffuse interstitial myocardial fibrosis is a key common pathological manifestation in hypertensive heart disease (HHD) progressing to heart failure (HF). Angiotensin receptor-neprilysin inhibitors (ARNi), now a front-line treatment for HF, confer benefits independent of blood pressure, signifying a multifactorial mode of action beyond hemodynamic regulation. We aim to test the hypothesis that compared with angiotensin II receptor blockade (ARB) alone, ARNi is more effective in regressing diffuse interstitial myocardial fibrosis in HHD. Role of ARNi in Ventricular Remodeling in Hypertensive LVH (REVERSE-LVH) is a prospective, randomized, open-label, blinded endpoint (PROBE) clinical trial. Adults with hypertension and left ventricular hypertrophy (LVH) according to Asian sex- and age-specific thresholds on cardiovascular magnetic resonance (CMR) imaging are randomized to treatment with either sacubitril/valsartan (an ARNi) or valsartan (an ARB) in 1:1 ratio for a duration of 52 weeks, at the end of which a repeat CMR is performed to assess differential changes from baseline between the two groups. The primary endpoint is the change in CMR-derived diffuse interstitial fibrosis volume. Secondary endpoints include changes in CMR-derived left ventricular mass, volumes, and functional parameters. Serum samples are collected and stored to assess the effects of ARNi, compared with ARB, on circulating biomarkers of cardiac remodeling. The endpoints will be analyzed with reference to the corresponding baseline parameters to evaluate the therapeutic effect of sacubitril/valsartan vs. valsartan. REVERSE-LVH will examine the anti-fibrotic potential of sacubitril/valsartan and will offer mechanistic insights into the clinical benefits of sacubitril/valsartan in hypertension in relation to cardiac remodeling. Advancing the knowledge of the pathophysiology of HHD will consolidate effective risk stratification and personalized treatment through a multimodal manner integrating complementary CMR and biomarkers into the conventional care approach.Clinical Trial Registration: ClinicalTrials.gov, identifier, NCT03553810.

Biology of mitral valve prolapse: from general mechanisms to advanced molecular patterns-a narrative review.

Mitral valve prolapse (MVP) represents the most frequent cause of primary mitral regurgitation. For several years, biological mechanisms underlying this condition attracted the attention of investigators, trying to identify the pathways responsible for such a peculiar condition. In the last ten years, cardiovascular research has moved from general biological mechanisms to altered molecular pathways activation. Overexpression of TGF-β signaling, for instance, was shown to play a key role in MVP, while angiotensin-II receptor blockade was found to limit MVP progression by acting on the same signaling pathway. Concerning extracellular matrix organization, the increased valvular interstitial cells density and dysregulated production of catalytic enzymes (matrix metalloproteinases above all) altering the homeostasis between collagen, elastin and proteoglycan components, have been shown to possibly provide a mechanistic basis contributing to the myxomatous MVP phenotype. Moreover, it has been observed that high levels of osteoprotegerin may contribute to the pathogenesis of MVP by increasing collagen deposition in degenerated mitral leaflets. Although MVP is believed to represent the result of multiple genetic pathways alterations, it is important to distinguish between syndromic and non-syndromic conditions. In the first case, such as in Marfan syndrome, the role of specific genes has been clearly identified, while in the latter a progressively increasing number of genetic loci have been thoroughly investigated. Moreover, genomics is gaining more interest as potential disease-causing genes and loci possibly associated with MVP progression and severity have been identified. Animal models could be of help in better understanding the molecular basis of MVP, possibly providing sufficient information to tackle specific mechanisms aimed at slowing down MVP progression, therefore developing non-surgical therapies impacting on the natural history of this condition. Although continuous progress has been made in this field, further translational studies are advocated to improve our knowledge of biological mechanisms underlying MVP development and progression.

Effect of Angiotensin receptor blockade on Plasma Osmolality and Neurohumoral Responses to High Environmental Temperature in Rats Fed a High Salt Diet

Plasma osmolality (pOsmol) and neurohumoral signals play important roles in the pathophysiology of cardiovascular diseases. Our study investigated the effect of high environmental temperature (HET) on neurohumoral responses and pOsmol in rats fed a high salt diet (HSD), with and without angiotensin II receptor blockade (ARB), using telmisartan. Fifty-six male 8-week old Sprague-Dawley rats (95-110g) were randomly assigned into seven groups of 8 rats. These included control rats (I) fed with 0.3% NaCl diet (normal diet, ND); salt-loaded rats (II) fed with 8% NaCl (high salt) diet; ND rats (III) exposed to HET (38.5±0.5oC ) 4 hours daily per week; rats (IV) fed with 8% NaCl diet and exposed to HET daily. Others included rats (V) fed with 8% NaCl diet and treated with telmisartan (30mg/kg); ND rats (VI) exposed to HET and treated with telmisartan; rats (VI) fed with 8% NaCl diet, exposed to HET and treated with telmisartan. Plasma angiotensin II, aldosterone, vasopressin and norepinephrine (NE) concentrations were determined by ELISA technique; pOsmol from plasma K+, Na+ and Urea. HSD combined with HET in rats synergistically increased pOsmol (P<0.001) with an associated non-synergistic rise in fluid intake (P<0.001), fluid balance (P<0.001), plasma angiotensin II (P<0.01) and aldosterone (P<0.05), NE (P<0.001) and vasopressin (P<0.05) concentrations compared to control. Telmisartan did not alter pOsmol in all the treated-rats, but normalized fluid intake levels and plasma vasopressin in the rats exposed to either HSD or HEt alone. Prolonged exposure of rats to hot environment exacerbated the effect of excess dietary salt on pOsmol, with no effect on angiotensin II-mediated neurohumoral responses

Effect of Angiotensin receptor blockade on Plasma Osmolality and Neurohumoral Responses to High Environmental Temperature in Rats Fed a High Salt Diet.

Plasma osmolality (pOsmol) and neurohumoral signals play important roles in the pathophysiology of cardiovascular diseases. Our study investigated the effect of high environmental temperature (HET) on neurohumoral responses and pOsmol in rats fed a high salt diet (HSD), with and without angiotensin II receptor blockade (ARB), using telmisartan. Fifty-six male 8-week old Sprague-Dawley rats (95-110g) were randomly assigned into seven groups of 8 rats. These included control rats (I) fed with 0.3% NaCl diet (normal diet, ND); salt-loaded rats (II) fed with 8% NaCl (high salt) diet; ND rats (III) exposed to HET (38.5±0.5oC ) 4 hours daily per week; rats (IV) fed with 8% NaCl diet and exposed to HET daily. Others included rats (V) fed with 8% NaCl diet and treated with telmisartan (30mg/kg); ND rats (VI) exposed to HET and treated with telmisartan; rats (VI) fed with 8% NaCl diet, exposed to HET and treated with telmisartan. Plasma angiotensin II, aldosterone, vasopressin and norepinephrine (NE) concentrations were determined by ELISA technique; pOsmol from plasma K+, Na+ and Urea. HSD combined with HET in rats synergistically increased pOsmol (P<0.001) with an associated non-synergistic rise in fluid intake (P<0.001), fluid balance (P<0.001), plasma angiotensin II (P<0.01) and aldosterone (P<0.05), NE (P<0.001) and vasopressin (P<0.05) concentrations compared to control. Telmisartan did not alter pOsmol in all the treated-rats, but normalized fluid intake levels and plasma vasopressin in the rats exposed to either HSD or HEt alone. Prolonged exposure of rats to hot environment exacerbated the effect of excess dietary salt on pOsmol, with no effect on angiotensin II-mediated neurohumoral responses.

High-sensitivity Troponin T in hemodialysis patients: a randomized placebo-controlled sub-study investigating angiotensin-II-blockade, variation over time and associations with clinical outcome

BackgroundTroponin T (TnT) is a well-known risk factor for negative outcome in hemodialysis (HD) patients, but little is known about variation over time, and the impact of clinical and dialysis specific factors. This study investigated the effect of angiotensin II receptor blockade (ARB), short and long-term variation in TnT and associations with clinical parameters.MethodsIn this analysis based on the SAFIR-cohort (Clinical Trials ID: NCT00791830) 81 HD patients were randomized double-blind for placebo (n = 40) or angiotensin II receptor blocker (ARB) treatment (n = 41) with irbesartan (150–300 mg) and followed for 12 months with six serial measurements of TnT using a high-sensitivity assay.ResultsFifty-four patients (67%) completed follow-up. Baseline TnT-medians (min-max) were (placebo/ARB): 45(14–295)/46(10–343) ng/L. ARB-treatment did not significantly affect mean TnT-levels over the 12-month study period. Median week-to-week and one-year TnT-variation (5th–95th-percentile range) using all samples regardless of intervention were: 0(− 14–10) ng/L (week-to-week) and 3(− 40–71) ng/L (12 months). Median TnT-amplitude, capturing the change from the lowest to the highest TnT-value observed during the one-year study period was 38% or 20.5 ng/L. Median ratios with 95% limits of agreement were: 1.00(0.73–1.37); P = 0.92 (1 week/baseline; n = 77) and 1.07(0.52–2.25); P = 0.19 (12 months/baseline; n = 54). Baseline TnT was positively correlated with diabetes, ultrafiltration volume, arterial stiffness, change in intradialytic total peripheral resistance and N-terminal pro b-type natriuretic peptide (NT-proBNP) and negatively correlated with hematocrit, residual renal function and change in intradialytic cardiac output. High baseline TnT was associated with a higher risk of admission and cardiovascular (CV) events during follow-up. Increase in TnT over time (ΔTnT = 12-months-baseline) was significantly associated with increase in left ventricular (LV) mass and NT-proBNP and decrease in LV ejection fraction and late intradialytic stroke volume. ΔTnT was not significantly associated with admissions, CV or intradialytic hypotensive events during follow-up. Admissions were significantly more likely with a high (TnT-amplitude> 20.5 ng/L) than a low TnT-amplitude. Peaks in TnT were less frequent in aspirin-treated patients.ConclusionARB-treatment had no significant effect on TnT-levels. Week-to-week variation was generally low, yet over 12 months individual patients had considerable TnT fluctuations. Rise in TnT over time was significantly correlated with markers of cardiac deterioration.Trial registrationClinicalTrials.gov Identifier: NCT00791830. Date of registration: November 17, 2008. EudraCT no: 2008–001267-11.

The Effects of Pregnancy on the Sympathoexcitatory and Pressor Responses to Nanoinjection of Angiotensin II into the Arcuate Nucleus

Pregnancy induces profound increases in sympathetic nerve activity (SNA). Angiotensin II (AngII) may contribute, since systemic or central blockade of AngII production or receptors (AT1aR) decreases SNA in pregnant animals. However, the brain sites involved are unknown. One possibility is the arcuate nucleus (ArcN), since AngII binds to ArcN AT1aR to increase SNA, and the ArcN is a well‐established reproductive integrating center. To begin to test this hypothesis, we measured the changes in SNA and mean arterial pressure (MAP) in response to bilateral nanoinjections of AngII (30 pmol in 30 nL) into the ArcN of α‐chloralose anesthetized pregnant rats and virgin rats throughout the estrus cycle. ArcN AngII slowly increased (P&lt;0.05) lumbar SNA (LSNA) in pregnant rats (by 50±10 % after 90 min; n=6), and the rise was larger than in proestrus rats (‐1±8 %; n=5; P&lt;0.05), similar to diestrus rats (40±9 %; n=4), but less than estrus rats (72±12 %; n=6; P&lt;0.05). ArcN AngII rapidly increased (P&lt;0.05) MAP by ~10 mmHg (after 10 min) in all groups, but after 90 min the increase was sustained (P&lt;0.05) only in pregnant (13±2 mmHg) and estrus (11±4 mmHg) rats. A cohort of ArcN neurons projects to and stimulates vasopressinergic neurons in the hypothalamic paraventricular and supraoptic nuclei. Therefore, to test if the initial or sustained increases in MAP were mediated by vasopressin, another set of estrus and pregnant rats were pretreated with the Manning Compound (V1x; 5 μg iv) 15 min before ArcN AngII. In estrus rats (n=4), V1x had no effects on baseline LSNA or MAP, but completely blocked the initial rise in MAP induced by ArcN AngII (2±3 mmHg). Nevertheless, the increase in MAP at 90 min was unchanged (13±3 mmHg; P&lt;0.05). The LSNA response to ArcN AngII (83±9 %) was also not altered. In pregnant rats pretreated with V1x (n=4), baseline MAP decreased (P&lt;0.05) by 10±1 mmHg, and again ArcN AngII failed to increase MAP initially (2±1 mmHg). However, the increase in MAP 90 min after ArcN AngII (7±2 mmHg) was the same as the increase 90 min after injection of artificial cerebrospinal fluid into the ArcN of V1x‐treated pregnant rats (5±2 mmHg). Again, the increase in LSNA to ArcN AngII was unchanged (30±6 %). Finally, RNAScope was used to assay AT1aR mRNA expression in the ArcN in diestrus, proestrus, and pregnant rats. ArcN AT1aR were undetectable in proestrus rats and were expressed at low but detectable levels in diestrus rats. In contrast, pregnancy markedly increased the expression of AT1aR in the ArcN. In summary, during pregnancy, ArcN AngII produces substantial increases in LSNA in association with elevated AT1aR expression. Moreover, the increase in MAP in response to ArcN AngII was reduced or eliminated in estrus and pregnant rats pretreated with a vasopressin V1 receptor blocker. In conclusion, these data highlight the ArcN as a potential site at which AngII increases SNA during normal pregnancy. The data also suggest that AngII can elicit an increase in vasopressin secretion via an action in the ArcN and that vasopressin contributes to the pressor responses induced by ArcN AngII in both estrus and pregnant rats.Support or Funding InformationHL128181

12. Angiotensin-II type-1 receptor blockade decreased T2 signal intensity in spinal cord compression in symptomatic cervical spondylotic myelopathy

BACKGROUND CONTEXT Cervical spondylosis may lead to spinal cord compression, poor vascular perfusion, and ultimately cervical myelopathy. The process whereby chronic compression may cause spinal cord damage has not been fully understood. However, multiple mechanisms such as inflammation, apoptosis, and vascular variations, are thought to be responsible for the neuronal loss, axonal degeneration, and myelin impairment seen in cervical spondylotic myelopathy (CSM). Studies reported a beneficial effect of renin-angiotensin system (RAS) blockers in the central nervous system, particularly in brain inflammation and stroke, but data on their influence on the spinal cord are limited. PURPOSE We aimed to determine if RAS blockers are correlated with preoperative functional status and radiological markers of spinal cord damage secondary to compression in patients with CSM. STUDY DESIGN/SETTING Retrospective cohort study. PATIENT SAMPLE Symptomatic cervical spondylosis patients. OUTCOME MEASURES Functional status (including modified Japanese Orthopedic Association [mJOA] and Nurick grading scales) and imaging characteristics (including % maximum canal compromise [MCC], % maximum spinal cord compromise [MSCC], increased signal intensity [ISI], signal intensity ration [SIR] and ISI surface area), all of which were evaluated on midsagittal T2-weighted MRIs. METHODS Adults with symptomatic degenerative cervical stenosis patients were included. Demographic data, comorbidities, antihypertensive medications (particularly RAS blockers), and functional status were collected. We assessed % canal compromise, % cord compromise, surface area of T2 signal cord change, and pixel intensity of signal cord change compared to normal cord on T2-weighted MRI sequences. RESULTS Of the 267 patients, 41.6% were female and 58.1% male; median age of 57.2 years; 20.6% smokers; 24.7% diabetics. One hundred forty-nine patients (55.8%) had hypertension, of which 142 (95.3%) were taking antihypertensive medications: 37 angiotensin-II receptor blockers [ARBs], 44 angiotensin-converting enzyme inhibitors [ACEIs], and 61 other medications). Patients treated with ARBs displayed a higher signal intensity ratio (lower signal intensity change in the compressed cord area) compared to those untreated non-hypertensive patients (p=.004). Hypertensive patients had worse preoperative mJOA and Nurick scores compared to non-hypertensive patients (p CONCLUSIONS In cervical spinal cord compression patients, hypertensive subjects treated with RAS inhibitors were associated with less signal intensity change (higher SIR) than untreated non-hypertensive patients. Also, hypertensive subjects under any antihypertensive medication displayed worse mJOA and Nurick scores compared to untreated non-hypertensive individuals. Further studies are warranted to verify the effect of RAS inhibitors in spinal cord damage. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Bioactive Signaling in Next-Generation Pharmacotherapies for Heart Failure

The standard pharmacotherapy for heart failure (HF), particularly HF with reduced ejection fraction (HFrEF), is primarily through the use of receptor antagonists, notably inhibition of the renin-angiotensin system by either angiotensin-converting enzyme inhibition or angiotensin II receptor blockade (ARB). However, the completed Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial identified that the use of a single molecule (sacubitril/valsartan), which is an ARB and the neutral endopeptidase inhibitor (NEPi) neprilysin, yielded improved clinical outcomes in HFrEF compared with angiotensin-converting enzyme inhibition alone. This review examined specific bioactive signaling pathways that would be potentiated by NEPi and how these would affect key cardiovascular processes relevant to HFrEF. It also addressed potential additive/synergistic effects of ARB. A number of biological signaling pathways that may be potentiated by sacubitril/valsartan were identified, including some novel candidate molecules, which will act in a synergistic manner to favorably alter the natural history of HFrEF. This review identified that activation rather than inhibition of specific receptor pathways provided favorable cardiovascular effects that cannot be achieved by renin-angiotensin system inhibition alone. Thus, an entirely new avenue of translational and clinical research lies ahead in which HF pharmacotherapies will move beyond receptor antagonist strategies.

Angiotensin II/Angiotensin II Receptor Blockade Affects Osteoporosis via the AT1/AT2-Mediated cAMP-Dependent PKA Pathway

Animal studies have reported on the benefits of ARB on bone mass. However, the underlying mechanism for angiotensin II (AngII)/AngII receptor blockade (ARB) in regulating bone mass remains elusive. Since high levels of plasma and urine cAMP are observed in osteoporotic and hypertensive patients, we hypothesized that cAMP may be an important molecule for the downstream events of the activation of AT receptors, members of the G-protein-coupled receptor family, in regulating bone turnover. In this study, micro-CT and X-ray analyses indicated that AngII decreased bone mass via biasing bone resorption over bone formation in osteoporotic mice. However, these adverse effects were blocked by olmesartan and PD123319. In vitro, AngII was shown to downregulate osteogenic differentiation and matrix mineralization, but to upregulate osteoclastic activity by mainly affecting osteoblasts producing osteoclastogenesis-associated key soluble factors, including M-CSF and RANKL. Similarly, ARB treatment exhibited antagonistic effects on AngII. In conclusion, osteoblasts are the directly targeted cells. ARB1 exhibits a greater capacity to increase bone mass than ARB2. The cAMP-dependent PKA pathway plays an important role in AngII/ARB on changing bone mass.

The effects of angiotensin II signaling blockade on platelet activity in subjects with hypertension.

To investigate the effects of Angiotensin II receptor blockade (ARB) and angiotensin converting enzyme (ACE) inhibition on platelet reactivity in patients with mild to moderate hypertension. PFA-100 evaluates platelet function (expressed in seconds as closure time, CT) in anti-coagulated whole blood in vitro at high shear rates. The test cartridge is impregnated with either collagen and epinephrine (Col/Epi) or collagen and ADP (Col/ADP). 33 patients were randomized to perindopril 4mg (n = 9), valsartan 80mg/d (n = 9) and for lifestyle modification (n = 15) for 4 weeks. Platelet reactivity was measured at baseline and after 4 weeks by PFA-100. Normotensive controls (n = 11) were also tested at baseline to standardize PFA-100 CT. Haematocrit, platelet count and plasma vWF antigen levels were measured. There was no difference in baseline haematocrit, platelet count or vWF antigen level between the groups. The vWF antigen levels measured after 4 weeks showed no significant difference either. Significant blood pressure reduction was seen in the treated group (SBP P = 0.002 and DBP P = 0.005) when compared to the life style modification group (SBP P = 0.06 and DBP P = 0.04) after 4 weeks. There was no significant statistical difference in Col/ADP CT in treated and non-treated groups but increase in CT (P = 0.05) in treated group with Col/Epi seen after 4 weeks. In patients with mild to moderate hypertension, valsartan and perindopril compared to life style modification demonstrate a significant decrease in platelet reactivity.

A Low-Salt Diet Increases the Estimated Net Endogenous Acid Production in Nondiabetic Chronic Kidney Disease Patients Treated with Angiotensin Receptor Blockade

Background/Aims: An acid-base imbalance precedes renal disease progression in patients with chronic kidney disease (CKD). Little is known about the effects of a low-salt diet (LSD) on net endogenous acid production (NEAP) levels in CKD patients using angiotensin receptor blockade. Methods: We enrolled a total of 202 nondiabetic CKD patients who underwent an 8-week treatment with olmesartan from the original trial [Effects of Low Sodium Intake on the Antiproteinuric Efficacy of Olmesartan in Hypertensive Patients with Albuminuria (ESPECIAL) trial: NCT01552954]. The patients were divided into good- and poor-LSD-compliance groups. Results: During the interventional 8 weeks, the NEAP in the good-compliance group increased compared to the control group (12.9 ± 32.0 vs. -2.0 ± 35.0 mmol/day, p = 0.002). NEAP was positively associated with the good-LSD-compliance group in the fully adjusted analyses (r = 0.135, p = 0.016). The additional reduction of 2.39 g/day of protein intake with a reduction of 1 g/day of salt intake did not increase the NEAP under angiotensin II receptor blockade (ARB) treatment with an LSD (r = 0.546, p < 0.001). Conclusion: We found that an LSD may increase the NEAP in nondiabetic CKD patients using ARB, which suggests that additional acid producing-protein restriction should be required to prevent the NEAP from rising.

Proteinuria and Histopathological Change of Everolimus Based Immunosuppression On De Novo Kidney Transplantation With 5 Years Follow-Up in Protocol Biopsies.

Purpose: The impact of everolimus (EVR) based immunosuppression in De Novo Kidney Transplantation was evaluated in safety profile, focusing proteinuria and histopathological change through the protocol biopsy findings compared with mycophenolate mofetile (MMF) based immunosuppression. Method: During March 2008 and August 2009, we enrolled 24 living donor kidney transplant patients in a 2-year, multicenter, randomized phase 3 study (RAD001A1202 study) to compare the safety and efficacy with protocol biopsy data between EVR based and MMF based immunosuppression. We extended further 3 years and evaluated clinical outcome in a single center. EVR group received reduced-exposure cyclosporine (target C0 25-50ng/ml after 6 months), and EVR-C0 were adjusted 3-8ng/ml. MMF group received standard-exposure cyclosporine (target C0 100-250ng/ml). Both group received basiliximab induction. We evaluated in safety profile, focusing proteinuria and histopathological change through the protocol biopsy findings. Protocol biopsies were performed at 1hour, 3 weeks, 6 months and 12 months after transplantation. Result: All patients continued in each regimen. With a mean observation period of 60.1 months, current patient and graft survival is 100% in both groups (EVR; n=13, MMF; n=11). eGFR (ml/min/1.73m2) was similar 40.7 in EVR group and 37.4 in MMF group. None of both groups was treated for clinical acute rejection, similar incidence of Banff borderline change on protocol biopsies were observed in 7.7% of EVR group and 18.2% of MMF group. Calcineurin inhibitor nephrotoxicity was observed less in EVR group (7.7%) than in MMF group (27.3%) in biopsies over 12 months. Proteinuria were observed more in EVR group (76.9%) than in MMF group (54.5%) respectively. There were two patients whose proteinuria developed over 2g/day at 12 months or later in EVR group. We could not find any particular glomerular lesion in the biopsies, however neovascular hyalinosis at glomerular vascular pole was noticeable. The proteinuria in EVR group was successfully treated with angiotensin-II receptor blockade. Conclusion: EVR based immunosuppression does not provide particular histological change at the glomerular level even though proteinuria was observed.

Efficacy and Safety of Everolimus Based Immunosuppression On De Novo Kidney Transplantation With 5 Years Follow-Up Especially in Protocol Biopsy Findings and Donor Specific Antibody Production.

Purpose: The impact of everolimus (EVR) based immunosuppression in De Novo Kidney Transplantation was evaluated in clinical outcomes, protocol biopsies findings and donor specific antibody (DSA) production.Methods: During 2008 and August 2009, we enrolled twenty-four living donor kidney transplant patients in a 2-year, multicenter, randomized phase 3 study (RAD001A1202 study) to compare the safety and efficacy between EVR based and mycophenolate mofetile (MMF) based immunosuppression. We extended further three years and evaluated clinical outcome in a single center.EVR group received reduced-exposure cyclosporine (target C0 25-50ng/ml after 6 months) + steroid, and EVR-C0 were adjusted 3-8ng/ml. MMF group received standard-exposure cyclosporine (target C0 100-250ng/ml after 6 months) + steroid. Both group received basiliximab induction.Results: All patients continued in each regimen. With a mean observation period of 60.1 (43.8-69.4) months, current patient and graft survival is 100% in both groups (EVR; n=13, MMF; n=11). Renal function expressed as eGFR (ml/min/1.73m2) was similar 40.7±14.6 in EVR group and 37.4±8.6 in MMF group. Significant proteinuria, more than 300mg/day, were observed more in EVR group (76.9%) than in MMF group (54.5%), however the proteinuria in EVR group was successfully treated with angiotensin-II receptor blockade. None of EVR and MMF group was treated for clinical T cell mediated rejection, similar incidence of Banff borderline change on 6 or 12 months protocol biopsies were observed in 7.7% of EVR group and 18.2% of MMF group, but none of both groups revealed peritubular capillaritis. Luminex solid phase assay revealed the similar incidence of class II DSA production in both groups, 7.7% of EVR group at 2 years after transplant and 15.4% of MMF group at 3 years. Protocol oral glucose tolerance test at 6 and 12 months revealed more, but no significantly, worsen profile in 46.1% of EVR group to 18.2% in MMF group.Conclusions: EVR based immunosuppression provides equivalent clinical outcomes as well as the incidence of De Novo DSA production with MMF based immunosuppression with 5 years follow-up.

Synergistic protective effects of mizoribine and angiotensin II receptor blockade on cyclosporine A nephropathy in rats

Chronic cyclosporine A (CsA) nephrotoxicity is manifested by renal dysfunction, progressive histopathological kidney lesions characterized by afferent arteriolopathy, and tubulointerstitial fibrosis. In addition to the direct toxic effect of CsA, many other etiological factors such as angiotensin II, transforming growth factor (TGF)-β, and macrophage infiltration are involved in this pathogenesis. This study investigated the hypothesis that concomitant administration of mizoribine (MZR) and angiotensin II receptor blockade (ARB) may prevent CsA nephrotoxicity in rats. Sprague-Dawley male rats were divided into the following seven groups: group 1, treated with CsA; group 2, treated with CsA + MZR; group 3, treated with CsA + valsartan (Val); group 4, treated with CsA + MZR + Val; group 5, treated with MZR; group 6, treated with Val; and group 7, controls (n = 5 each). Renal histopathology and the effect of CsA-induced nephrotoxicity on inflammatory mediators were evaluated. Results of this study demonstrated that ARB administration significantly decreased arteriolopathy and that in comparison with monotherapy, concomitant administration of MZR and ARB further decreased arteriolopathy, fibrosis, macrophage infiltration, and TGF-β1 mRNA expression associated with CsA nephrotoxicity. These findings indicate that MZR and ARB combination treatment provides synergistic protective effects against chronic CsA nephrotoxicity.

Alport syndrome: the effects of spironolactone on proteinuria and urinary TGF-β1

Alport syndrome (AS) is a progressive hereditary glomerular disease. Recent data indicate that aldosterone promotes fibrosis mediated by the transforming growth factor-β1 (TGF-β1) pathway, which may worsen proteinuria. Spironolactone (SP) antagonizes aldosterone and this study aimed to evaluate the efficacy of SP in reducing proteinuria and urinary TGF-β1 excretion in proteinuric AS patients. The study involved ten children with AS, normal renal function, and persistent proteinuria (>6 months; uPr/uCr ratio >1). SP 25 mg once a day for 6 months was added to existing ACE inhibitor treatment with or without angiotensin-II receptor blockade. Urine and blood samples were examined monthly. Urinary TGF-β1 levels were measured twice before and three times during SP treatment. Plasma renin activity (PRA) and serum aldosterone levels were also measured. In eight patients, uProt/uCreat was also assessed after 9 months and 12 months of SP treatment. After beginning SP therapy, all patients showed significant decrease in mean uProt/uCreat ratio (1.77 ± 0.8 to 0.86 ± 0.6; p < 0.001) and mean urinary TGF-β1 levels (104 ± 54 to 41 ± 20 pg/mgCreatinine; p < 0.01), beginning after 30 days of treatment and remaining stable throughout SP administration. PRA remain unchanged, and mean serum aldosterone increased from 105 ± 72 pg/ml to 303 ± 156 pg/ml (p < 0.001). The only side effect was gynecomastia in an obese boy. After 1 year of therapy, mean uProt/uCreat remains low (0.82 ± 0.48). Addition of SP to ACE-I treatment with or without angiotensin II receptor blokers (ARB) significantly reduced proteinuria. This was mediated by decreased urinary TGF-β1 levels and not associated with major side effects.

The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease

Mineralocorticoid receptor blockade (MRBs) in combination with angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor blockade (ARBs) improve prognostic markers of cardiovascular and renal disease in early stage chronic kidney disease (CKD). Concerns relating to the safety and tolerability of MRBs in CKD may limit their use in a non clinical trial setting. METHODS In the Chronic Renal Impairment in Birmingham II study, 115 patients with non-diabetic early stage CKD (eGFR 30-89ml/min/1.73m(2) ) received 25mg daily of spironolactone for 4 weeks before randomization to continuing treatment or placebo for a further 36 weeks. All patients were on ACE inhibitors and/or ARB therapy. Potassium and renal function were checked at weeks 1, 2, 4, 8, 16, 28 and 40. The incidence of hyperkalaemia, significant renal dysfunction (reduction eGFR ≥25%) and adverse effects was assessed. After 40 weeks of treatment the incidence of serious hyperkalaemia (K(+) ≥6.0mmol/L) was <1%. A potassium 5.5-5.9mmol/L occurred on ≥1 occasion over follow-up in 11 patients (nine on spironolactone) and was predicted by baseline potassium ≥5.0mmol/L and eGFR ≤45 ml/min/1.73m(2) . Over follow-up, three patients experienced significant renal dysfunction but no patients withdrew due to intolerance or side effects. Changes in potassium, eGFR and systolic blood pressure were most apparent in the first 4 eeks. Spironolactone was well tolerated in selected patients with early stage CKD. Strict monitoring over the first month of treatment followed by standard surveillance as for ACE inhibitors and ARBs is suggested.

Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF) Trial

Unlike antiarrhythmic drugs, the safety and beneficial effects of angiotensin II receptor blockade (ARB) in patients with structural heart disease is well established. The clinical efficacy of ARBs to prevent atrial fibrillation (AF) so far only has been shown in patients with structural heart disease. Here, we report the primary outcome of the Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF) trial, which investigated the effect of olmesartan medoxomil compared with placebo on AF burden in patients with paroxysmal AF without structural heart disease. The ANTIPAF trial was a prospective, randomized, placebo-controlled, multicenter trial analyzing the AF burden (percentage of days with documented episodes of paroxysmal AF) during a 12-month follow-up as the primary study end point. Four hundred thirty patients with documented paroxysmal AF without structural heart disease were randomized to placebo or 40 mg olmesartan per day. Concomitant therapy with ARBs, angiotensin-converting enzyme inhibitors, and antiarrhythmic drugs was prohibited. Patients were followed using daily transtelephonic ECG (tele-ECG) recordings independent of symptoms. The intention-to-treat population of the trial encompassed 425 patients (placebo group, n=211; olmesartan group, n=214). A total of 87 818 tele-ECGs were analyzed in these patients during follow-up (placebo group, 44 888 ECGs; olmesartan group, 42 930 ECGs). Thus, a mean of 207 tele-ECGs were recorded per patient. The primary end point (AF burden) was not different between the 2 groups (P=0.770). Secondary outcome parameters, including quality of life, also were not different. In particular, time to first AF recurrence, time to persistent AF, and number of hospitalizations were not different between the 2 groups. The time to prescription of recovery medication (amiodarone) was the only parameter showing an intergroup difference, with earlier prescription of amiodarone in the placebo group (P=0.022). One year of ARB therapy per se does not reduce the number of AF episodes in patients with documented paroxysmal AF without structural heart disease. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00098137.

Differential effects of angiotensin II-receptor blockade on vascular and skeletal manifestations of Marfan syndrome

Differential effects of angiotensin II-receptor blockade on vascular and skeletal manifestations of Marfan syndrome

Renal medullary effects of transient prehypertensive treatment in young spontaneously hypertensive rats

Transient angiotensin II receptor blockade (ARB) leads to prolonged blood pressure (BP) lowering, but the underlying mechanism remains uncertain. Long-term BP control is regulated by the medullary microcirculation with the pericyte as contractile cell. We hypothesize that the prolonged BP effect is caused by increased medullary blood flow (MBF) associated with structural alterations based on reduced medullary pericyte number. Four-week-old spontaneously hypertensive rats (SHR) were treated for 4 weeks with losartan (SHR-Los: 20 mg kg(-1) day(-1)), hydralazine (SHR-Hyd: 15 mg kg(-1) day(-1)), losartan and pan-caspase inhibitor zVAD (SHR-Los + 1 mg kg(-1) day(-1) zVAD), losartan and glycogen synthase kinase-3beta (GSK) inhibitor valproate (SHR-Los + 10 mg kg(-1) day(-1) Val) or placebo. BP, MBF and pericyte number were determined under and after treatment (8 and 12 weeks). Apoptotic pericytes were determined with alpha-actin and TUNEL double staining. Sodium concentration was determined in renal medulla and urine. Antihypertensive treatment equipotently reduced BP at 8 weeks of age. After drug withdrawal (12 weeks of age) BP reduction was restricted to SHR-Los (SHR-Los: 153 +/- 5, SHR-Hyd: 177 +/- 2, SHR: 184 +/- 3 mmHg). Simultaneously, MBF was increased and pericyte number reduced, while medullary and urinary sodium concentration increased. Transient ARB in combination with zVAD or valproate resulted in more medullary pericytes and higher BP (SHR-Los/zVAD: 164 +/- 7; SHR-Los/Val: 168 +/- 6 mmHg) compared with transient ARB alone. After drug withdrawal, transient ARB leads to increased MBF and is associated with a reduction in medullary pericytes. This may be associated with pericyte apoptosis as anti-apoptosis during transient ARB increases pericyte number and BP.

Bradykinin stimulates renal collecting duct prorenin

Elevated plasma prorenin (PR) is a predictor of diabetic (DM) microvascular complications. We recently identified the renal collecting duct (CD) as the major source of PR in DM and showed that angiotensin II (ANGII) receptor blockade, effectively reduces renal and plasma PR levels. We aimed to compare the effects of the ANGII receptor 1 blocker telmisartan (ARB, T), and the angiotensin converting enzyme inhibitor (ACEI), ramipril (R), on CD PR. PR content in the intact kidney was visualized in control (C) and STZ‐DM MWF rats using in vivo multi‐photon fluorescence microscopy. DM‐rats were treated for 28 days with T (ARB, 3mg/kg/day) or R (ACEI, 1mg/kg/day). Direct effects of ANGII and bradykinin (B,10nM each) on CD PR synthesis were measured using renin immunocytochemistry. STZ‐DM caused a 3‐fold increase in CD PR content which was completely abolished by T, but not by R. Also, immunoblot and renin activity measurements found that renal tissue and plasma PR levels increased 2‐fold in STZ‐DM which were prevented by T (0.8‐fold of C), but not by R (2.2‐fold). Similarly to ANGII, B increased immunoreactive PR content in cultured CD cells 35‐fold which was prevented by the B B2 receptor blocker HOE‐140. In conclusion, elevated CD PR content in DM is most effectively inhibited by ANGII receptor blockade using T and not by the blockade of the ACE using R, which effect is at least in part due to the direct stimulatory effect of B on CD PR.