BACKGROUND: -The frequency of sudden unexpected death is highest in the early post-myocardial infarction (MI) period; nevertheless, 2 recent trials showed no improvement in mortality with early placement of an implantable cardioverter-defibrillator after MI. Methods and Results-To better understand the pathophysiological events that lead to sudden death after MI, we assessed autopsy records in a series of cases classified as sudden death events in patients from the VALsartan In Acute myocardial infarctioN Trial (VALIANT). Autopsy records were available in 398 cases (14% of deaths). We determined that 105 patients had clinical circumstances consistent with sudden death. On the basis of the autopsy findings, we assessed the probable cause of sudden death and evaluated how these causes varied with time after MI. Of 105 deaths considered sudden on clinical grounds, autopsy suggested the following causes: 3 index MIs in the first 7 days (2.9%); 28 recurrent MIs (26.6%); 13 cardiac ruptures (12.4%); 4 pump failures (3.8%); 2 other cardiovascular causes (stroke or pulmonary embolism; 1.9%); and 1 noncardiovascular cause (1%). Fifty-four cases (51.4%) had no acute specific autopsy evidence other than the index MI and were thus presumed arrhythmic. The percentage of sudden death due to recurrent MI or rupture was highest in the first month after the index MI. By contrast, after 3 months, the percentage of presumed arrhythmic death was higher than recurrent MI or rupture (chi(2)=23.3, P<0.0001). Conclusions-Recurrent MI or cardiac rupture accounts for a high proportion of sudden death in the early period after acute MI, whereas arrhythmic death may be more likely subsequently. These findings may help explain the lack of benefit of early implantable cardioverter-defibrillator therapy.

Valsartan, a water-insoluble drug, is mainly used in the treatment of hypertension albeit with reduced oral bioavailability. The aim of work was to develop a valsartan:beta-cyclodextrin (VAL:beta-CD) pharmaceutical composition in order to improve its water solubility and bioavailability. The VAL:beta-CD complexes were prepared by the kneading, solid dispersion and freeze-drying methods, of which the freeze-drying method (FDY) was found to be the best to prepare an inclusion complex. A physical mixtyure PM was also prepared. Complexes were characterized by thermal analysis, Fourier transformed- infrared (FTIR) spectroscopy, Powder X-ray diffractometry, intrinsic dissolution and NMR (2D-ROESY). Phase-solubility analysis showed A(L)-type diagrams with beta-cyclodextrin (beta-CD). Microcalorimetric titrations suggested the formation of 1:1 inclusion complex between VAL and beta-CD. The apparent stability constants K(1:1) calculated from phase-solubility plots were 165.4 M(-1 )(298 K), 145.0 M(-1 )(303 K) and 111.3 M(-1 )(310 K). In vivo experiments in rats showed that reduction in arterial pressure for the FDY complex is better than with valsartan used alone. The better activity of FDY can be attributed to the higher solubility of valsartan after inclusion in the cyclodextrin cavity, as suggest by the intrinsic dissolution studies.

Administration of valsartan at bedtime as opposed to upon wakening improves the sleep-time relative blood pressure (BP) decline towards a more normal dipper pattern without loss of 24-h efficacy. Amlodipine, however, has been shown to be effective in reducing BP throughout the day and night, independent of dosing time. A large proportion of hypertensive subjects cannot be properly controlled with a single medication. However, no study has yet investigated the potential differing effects of combination therapy depending of the time-of-day of administration. Accordingly, the authors investigated the administration-time-dependent BP-lowering efficacy of valsartan/amlodipine combination. The authors studied 203 hypertensive subjects (92 men/111 women), 56.7 +/- 12.5 yrs of age, randomized to receive valsartan (160 mg/day) and amlodipine (5 mg/day) in one of the following four therapeutic schemes: both medications on awakening, both at bedtime, either one administered on awakening and the other at bedtime. BP was measured by ambulatory monitoring for 48 consecutive hours before and after 12 wks of treatment. Physical activity was simultaneously monitored every min by wrist actigraphy to accurately determine the beginning and end of daytime activity and nocturnal sleep. BP-lowering efficacy (quantified in terms of reduction of the 48-h mean of systolic/diastolic BP) was highest when both hypertension medications were ingested at bedtime, as compared to any one of the three other tested therapeutic schemes (17.4/13.4 mm Hg reduction with both medications on awakening; 15.1/9.6 mm Hg with valsartan on awakening and amlodipine at bedtime; 18.2/12.3 mm Hg with valsartan at bedtime and amlodipine on awakening; 24.7/13.5 mm Hg with both medications at bedtime; p < .018 between groups). The sleep-time relative BP decline was significantly increased towards a more normal dipper pattern only when both medications were jointly ingested at bedtime (p < .001). Bedtime dosing of the combination of the two medications also resulted in the largest percentage of controlled subjects among all the assessed therapeutic schemes (p = .003 between groups). In subjects requiring combination therapy to achieve proper BP control, the association of amlodipine and valsartan efficiently reduces BP for the entire 24 h independent of dosing time. However, the greater proportion of controlled patients, improved efficacy on lowering asleep BP mean, and increased sleep-time relative BP decline suggest valsartan/amlodipine combination therapy should be preferably administered at bedtime. (Author correspondence: rhermida@uvigo.es ).

In the present study, the combined effect of mobile phase polarity and pH on retention behavior of some ARA-IIs (irbesartan, losartan, valsartan and telmisartan) is investigated. The linear relationships established between retention factors of the species and the polarity parameter of the mobile phase has proved to predict accurately retention in LC as a function of the acetonitrile content (50%, 55%, 60%, v/v). The suggested model uses the pH value in the acetonitrile-water mixture as mobile phase instead of pH value in water and takes into account the effect of activity coefficients. Moreover, correlation between retention and the mobile phase pH can be established allowing prediction of the retention behavior as a function of the mobile phase pH. The model can be used to estimate the pK(a) in an acetonitrile percentage between 50% and 60%, at 30 degrees C. The developed method was successfully applied to both the simultaneous separation of these drug-active compounds and individual determination in their commercial pharmaceutical dosage forms.

A simple, precise, accurate stability-indicating gradient reverse phase ultra-performance liquid chromatographic (RP-UPLC) method was developed for the quantitative determination of purity of Valsartan drug substance and drug products in bulk samples and pharmaceutical dosage forms in the presence of its impurities and degradation products. The method was developed using Waters Aquity BEH C18 (100mmx2.1mm, 1.7mum) column with mobile phase containing a gradient mixture of solvents A and B. The eluted compounds were monitored at 225nm, the run time was within 9.5min, which Valsartan and its seven impurities were well separated. Valsartan was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. Valsartan was found to degrade significantly in acid and oxidative stress conditions and stable in base, hydrolytic and photolytic degradation conditions. The degradation products were well resolved from main peak and its impurities, proving the stability-indicating power of the method. The developed method was validated as per international conference on harmonization (ICH) guidelines with respect to specificity, linearity, limit of detection, limit of quantification, accuracy, precision and robustness. This method was also suitable for the assay determination of Valsartan in pharmaceutical dosage forms.

Visible T-wave alternans (TWA), a beat-to-beat alternation in the morphology and amplitude of the ST segment or T wave, has been observed for over a century to occur in association with life-threatening arrhythmias in patients with acute coronary syndrome, heart failure, and cardiac channelopathies. This compelling linkage prompted development of quantitative techniques leading to FDA-cleared commercial methodologies for measuring nonvisible levels of TWA in the frequency and time domains. The first aim of this review is to summarize evidence from more than a hundred studies enrolling a total of >12,000 patients that support the predictivity of TWA for cardiovascular mortality and sudden cardiac death. The second focus is on the usefulness of TWA in guiding therapy. Until recently, TWA has been used primarily in decision making for cardioverter-defibrillator implantation. Its potential utility in guiding pharmacologic therapy has been underappreciated. We review clinical literature supporting the usefulness of TWA as an index of antiarrhythmic effects and proarrhythmia for different drug classes. Beta-adrenergic and sodium channel-blocking agents are the most widely studied drugs in clinical TWA investigations, with both reducing TWA magnitude; the exception is patients in whom sodium channel blockade discloses the Brugada syndrome and provokes macroscopic TWA. An intriguing possibility is that TWA may help to detect beneficial effects of nonantiarrhythmic agents such as the angiotensin II receptor blocker valsartan, which indirectly protects from arrhythmia through improving myocardial remodeling. We conclude that quantitative analysis of TWA has considerable potential to guide pharmacologic intervention and thereby serve as a therapeutic target. Ann Noninvasive Electrocardiol 2010;15(3):276-288.

A sensitive, selective and high throughput liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS) method has been developed for the determination of teriflunomide, an active metabolite of leflunomide in human plasma. Plasma samples were prepared by liquid-liquid extraction of teriflunomide and valsartan as internal standard (IS) in ethyl acetate from 200muL human plasma. The chromatographic separation was achieved on an Inertsil ODS-3 C18 (50mmx4.6mm, 3mum) analytical column using isocratic mobile phase, consisting of 20mM ammonium acetate-methanol (25:75, v/v), at a flow-rate of 0.8mL/min. The precursor-->product ion transition for teriflunomide (m/z 269.0-->82.0) and IS (m/z 434.1-->350.3) were monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring (MRM) and negative ion mode. The method was validated over a wide dynamic concentration range of 10.1-4001ng/mL. Matrix effect was assessed by post-column infusion experiment and the mean process efficiency were 91.7% and 88.2% for teriflunomide and IS respectively. The method was rugged and rapid with a total run time of 2.0min and is applied to a bioequivalence study of 20mg leflunomide (test and reference) tablet formulation in 12 healthy Indian male subjects under fasting condition.

The adaptive changes that develop in the pressure-overloaded left ventricular myocardium include cardiac hypertrophy and interstitial fibrosis. The objectives of the present study were to evaluate the effects of Tanshinone II-A, a bioactive diterpene quinone isolated from Danshen, on cardiac fibrosis and collagen metabolism in rats with renovascular hypertension. Male Sprague-Dawley rats were subjected to two-kidney two-clip (2K2C) or sham operation (sham) and treated with Valsartan (Val, 26.7mg/kg/d), Tanshinone II-A (Tsn, 70, 35mg/kg/d) or vehicle. Six weeks later, systolic blood pressure (BP), LV weight, collagen abundance, cardiac function parameters, hydroxyproline content and mRNA levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were evaluated. Both high-dose (Tsn-H, 70mg/kg/d) and low-dose (Tsn-L, 35mg/kg/d) of Tsn failed to attenuate 2K2C-induced BP elevation but significantly attenuated the attendant interstitial fibrosis. Val suppressed elevations of BP and left ventricular systolic pressure (LVSP) in 2K2C rats. Val and Tsn-H exerted comparable suppressive effects on the gene expression of MMP-9 and TIMP-1, while Val decreased the MMP-2 mRNA level without affecting the transcript levels of TIMP-2. Both Val and Tsn-H attenuated cardiac dysfunction, while Tsn-L showed slight improvement. These data demonstrate for the first time, that Tsn prevented cardiac fibrosis and improved cardiac function in a rat model of renovascular hypertensive independent of hypotensive effect. Tsn conferred its beneficial effects on the collagen metabolism probably through its regulation of transcript levels of the MMPs/TIMPs balance.

BACKGROUND AND AIMS: We undertook this study to investigate the effect of mesangial cells stimulated by immunoglobin A1 from IgAN on transforming growth factor-beta1 synthesis in podocytes. METHODS: Jacalin affinity chromatography and Sephacryl S-200 molecular sieve chromatography were used to isolate IgA1 from blood of IgAN patients, which was then used as aggregated IgA1 (aIgA1). Podocytes were incubated with special mesangial medium. Real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) were used, respectively, to measure TGF-beta1 mRNA expression and its protein concentration in medium. RESULTS: TGF-beta1 mRNA and its protein concentration in the medium of podocytes increased when exposed to the medium of mesangial cells, which were stimulated by IgA1 from IgAN patients. Angiotensinogen and angiotensin-converting enzyme (ACE) mRNAs, as well as angiotensin II, were also increased by the medium (p <0.05). Enalaprilat and valsartan partly lowered overproduction of TGF-beta1 mRNA and excreted protein of podocytes, whereas enalaprilat plus valsartan completely restored them to the level as control. CONCLUSIONS: These data suggest that mesangial cells stimulated by IgA1 from IgAN patients may excrete some material to facilitate TGF-beta1 synthesis in podocytes through activating renin-angiotensin system by cross-talk.

Gender-specific determinants of blood pressure (BP) values and control have not been the focus of clinical hypertension research. The purpose of this analysis was to identify gender-specific and multi-level (physician and patient) determinants of BP values and predictors of uncontrolled BP. We completed a subgroup analysis comparing men and women who participated in the Belgian PREVIEW study of second-line treatment effectiveness of valsartan, applying two-level hierarchical modelling of 90-day BP values and guideline-defined BP control. In total, 1665 women and 1525 men were treated by 504 general practitioners. Fewer women than men reached systolic BP (SBP) (P=0.015) and combined BP targets at 90 days (P=0.007). More than 26% of the variance in 90-day SBP (intra-class correlation coefficient (ICC)=0.270) and diastolic BP (DBP) (ICC=0.262) was attributable to physician-level factors for men; the physician-level ICCs for SBP and DBP were 0.259 and 0.268, respectively, for women. Determinants of 90-day BP values and predictors of uncontrolled BP varied considerably by gender. Many of the multi-level determinants of BP by gender are amenable to intervention, and the remainder can serve as warning signs to clinicians that patients may remain vulnerable to poor outcomes associated with sub-optimal BP control.Journal of Human Hypertension advance online publication, 15 July 2010; doi:10.1038/jhh.2010.71.

Amlodipine besylate (AML) is a long-acting calcium channel blocker used as an antihypertensive agent. Valsartan (VAL) is also used to treat hypertension, either alone or in combination with other agents. Two-component mixtures of AML and VAL were analyzed by HPLC and the ratio spectra of the first derivative spectrophotometric technique. The spectrophotometric method depends on the first derivative of the ratio-spectra by measurements of the amplitudes at 234.0 nm for VAL and 351.0 nm for AML. Calibration graphs were established for 0.5-20 microg/mL AML and 1-32 microg/mL VAL using the ratio spectra of the first derivative spectrophotometric method. In the HPLC method, an ACE 5 C18 (4.6 x 150 mm, 5 microm) RP column at 30 degrees C with the mobile phase methanol-acetonitrile-NaH2PO4.H2O buffer, including 5 mL/L triethylamine and adjusted to pH 3.0 (42 + 18 + 40, v/v/v) at 2.0 mL/min flow rate was used to separate both compounds with detection at 254.0 nm. Linearity was obtained in the concentration range of 0.5-500 microg/mL for AML and 5.0-900 microg/mL for VAL. The proposed methods have been extensively validated. These methods allow a number of cost- and time-saving benefits. They were successfully applied to the determination of AML and VAL in synthetic mixtures and in a pharmaceutical dosage form. There was no significant difference between the performance of the proposed methods regarding the mean and SD values. The proposed methods are simple, rapid, and suitable for QC applications.

Early initiation of rational and effective combination therapy consisting of antihypertensive drugs with two different and complementary mechanisms of actions is increasingly becoming accepted in clinical practice and by guidelines as a first-line approach to control blood pressure (BP) and prevent cardiovascular outcomes in patients with hypertension. Once-daily combination therapy provides more rapid control of BP, which is important for preventing cardiovascular events, with similar or improved tolerability compared with the component monotherapies, and improved adherence because of regimen simplification. Combination therapy with a calcium channel antagonist (calcium channel blocker [CCB]) and an inhibitor of the renin-angiotensin-aldosterone system (RAAS) is a rational approach to achieve BP goals and provide protection against renal and cardiovascular morbidity and mortality. A number of CCB/RAAS inhibitor combinations, including CCB/angiotensin-converting enzyme (ACE) inhibitor and CCB/ angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]) combinations are available as fixed-dose formulations. There is substantial evidence for the BP-lowering efficacy of CCB/RAAS inhibitor combinations in diverse patient populations, and their use in combination is associated with favourable tolerability and fewer adverse metabolic effects than some other combination therapies. Recent evidence from large outcome trials supports the use of CCB/RAAS inhibitor combinations for reducing the risk of cardiovascular and renal events, particularly in high-risk patients, together with evidence that the benefits of CCB/RAAS inhibitor combinations may extend beyond their efficacy in lowering BP in terms of protecting against fatal and nonfatal stroke, myocardial infarction and cardiovascular-related deaths. The efficacy of the CCB amlodipine and the ARB valsartan in lowering BP and protecting against cardiovascular events and stroke across a range of hypertensive patient populations has been established over many years. Fixed-dose amlodipine/valsartan combinations are available in many countries and have shown greater BP reductions and better BP control than the respective monotherapies in diverse patient populations, together with a favourable tolerability profile. Once-daily amlodipine/valsartan is a rational and convenient treatment option for the effective management of patients with hypertension, improving adherence to antihypertensive medication and protecting against cardiovascular and renal morbidity and mortality.

BACKGROUND: A potential contribution of local activation of the renin-angiotensin system (RAS) to the pathogenesis of renal injury has been indicated by evidence for blood pressure-independent renoprotective effects of angiotensin II (AngII) receptor blockers (ARBs). The present study was performed to test the hypothesis that urinary angiotensinogen provides a specific index of intrarenal RAS status in patients with immunoglobulin A (IgA) nephropathy. METHODS: This paper is a survey of urine specimens from three groups: healthy volunteers, patients with IgA nephropathy and patients with minor glomerular abnormality (MGA). Patients with hypertension, diabetes, reduced glomerular filtration rate and/or who were under any medication were excluded from this study. Urinary angiotensinogen levels were measured by a sandwich enzyme-linked immunosorbent assay system. RESULTS: Urinary angiotensinogen levels were not different between healthy volunteers and patients with MGA. However, urinary angiotensinogen levels, renal tissue angiotensinogen expression and AngII immunoreactivity were significantly higher in patients with IgA nephropathy than in patients with MGA. Baseline urinary angiotensinogen levels were positively correlated with renal angiotensinogen gene expression and AngII immunoreactivity but not with plasma renin activity or the urinary protein excretion rate. In patients with IgA nephropathy, treatment with an ARB, valsartan (40 mg/day), significantly increased renal plasma flow and decreased filtration fraction, which were associated with reductions in urinary angiotensinogen levels. CONCLUSION: These data indicate that urinary angiotensinogen is a powerful tool for determining intrarenal RAS status and associated renal derangement in patients with IgA nephropathy.

BACKGROUND: Myocardial rupture is a relatively rare and usually fatal complication of myocardial infarction (MI). Early recognition of patients at greatest risk of myocardial rupture provides an opportunity for early intervention. METHODS: VALIANT was a double-blind, randomized, controlled trial comparing valsartan, captopril, and their combination in high-risk patients post-MI. Myocardial rupture was identified by autopsy (available in 138/589 patients dying within 30 days of index MI), echocardiography, direct surgical visualization, or presence of hemopericardium. An independent clinical end points committee reviewed medical records for all deaths or suspected nonfatal cardiovascular events. RESULTS: Rupture was identified in 45 (0.31%) patients enrolled in VALIANT, occurring 9.8 +/- 6.0 days after the qualifying MI. Rupture accounted for 7.6% (45/589) of all deaths occurring in the first 30 days of follow-up and 24% (33/138) of deaths in which autopsies were obtained. Compared with survivors, rupture was associated with increased age, hypertension, increased Killip class, lower estimated glomerular filtration rate, and Q wave MI, and inversely related to beta-blocker and diuretic use. Compared with patients who died of other causes within 30 days, patients with myocardial rupture were more likely to have had an inferior MI, Q wave MI, or hypertension; to have used oral anticoagulants; or to have received thrombolytic therapy. CONCLUSIONS: Although rare, myocardial rupture accounted for nearly one fourth of all deaths within the first 30 days after high-risk MI, suggesting an estimated incidence of approximately 1% within the first 30 days. A number of clinical characteristics may identify post-MI patients at higher risk of myocardial rupture.

High dietary potassium stimulates the renal expression of cytochrome P450 (CYP) epoxygenase 2C23, which metabolizes arachidonic acid (AA). Because the AA metabolite 11,12-epoxyeicosatrienoic acid (11,12-EET) can inhibit the epithelial sodium channel (ENaC) in the cortical collecting duct, we tested whether dietary potassium modulates ENaC function. High dietary potassium increased 11,12-EET in the isolated cortical collecting duct, an effect mimicked by inhibiting the angiotensin II type I receptor with valsartan. In patch-clamp experiments, a high potassium intake or treatment with valsartan enhanced AA-induced inhibition of ENaC, an effect mediated by a CYP-epoxygenase-dependent pathway. Moreover, high dietary potassium and valsartan each augmented the inhibitory effect of 11,12-EET on ENaC. Liquid chromatography/mass spectrometry showed that the rate of EET conversion to dihydroxyeicosatrienoic acids (DHET) was lower in renal tissue obtained from rats on a high-potassium diet than from those on a control diet, but this was not a result of altered expression of soluble epoxide hydrolase (sEH). Instead, suppression of sEH activity seemed to be responsible for the 11,12-EET-mediated enhanced inhibition of ENaC in animals on a high-potassium diet. Patch-clamp experiments demonstrated that 11,12-DHET was a weak inhibitor of ENaC compared with 11,12-EET, whereas 8,9- and 14,15-DHET were not. Furthermore, inhibition of sEH enhanced the 11,12-EET-induced inhibition of ENaC similar to high dietary potassium. In conclusion, high dietary potassium enhances the inhibitory effect of AA and 11,12-EET on ENaC by increasing CYP epoxygenase activity and decreasing sEH activity, respectively.

J Clin Hypertens (Greenwich). 2010;12:414-421. ((c))2010 Wiley Periodicals, Inc. This was a systematic assessment of the efficacy and safety of telmisartan and valsartan for the management of blood pressure (BP) in patients with essential hypertension. The authors reviewed randomized controlled trials (RCTs) and quasi-RCTs comparing telmisartan and valsartan for the management of essential hypertension in which the participants were followed for at least 6 weeks. When a metaanalysis was possible, included studies were analyzed by Review Manager 5.0 provided by Cochrane Collaboration Group. Statistics were calculated as weight mean differences (WMDs) and relative risk with a random-effect model. A total of 6 RCTs with 3762 patients were included in this metaanalysis. When the authors combined data from all treatment categories as a group, no difference was found between telmisartan and valsartan in reduction of systolic BP and diastolic BP. In subgroup analysis, telmisartan showed a significant benefit on lowering systolic BP and diastolic BP (WMD, -2.88; 95% confidence interval [CI], -5.03 to -0.73; P<0.01; and WMD,-1.73; 95% CI, -2.47 to -0.98; P<0.01; respectively). It was found that telmisartan had a higher rate of management of clinical BP compared with valsartan (relative risk, 1.09; 95% CI, 1.00-1.19; P=0.05). No difference was found in the incidence of adverse events. Telmisartan's BP-lowering capabilities were comparable to those of valsartan in monotherapy. When combined with hydrochlorothiazide, telmisartan was more effective than valsartan. Telmisartan had the same safety in the treatment of essential hypertensive patients in comparison with valsartan.

At the age of three yr, a male patient had surgical treatment for bilateral vesicoureteral reflux (VUR), and at the age of 19 yr, he developed nephrotic syndrome because of focal segmental glomerulosclerosis (FSGS). His renal function deteriorated despite treatment with temocapril and aspirin, and dialysis treatment was started when he was 19. After nine yr of dialysis, he received a living kidney transplantation from his 58-yr-old father, who had a long history of hypertension. A graft biopsy before perfusion showed moderate arteriolosclerosis. As urine protein increased to 2.15 g/d at 16 months after kidney transplantation, the graft biopsy was performed again. FSGS lesion with severe arteriosclerosis was recognized under light microscope, while the effacement of podocyte foot processes was seldom observed. The alteration of calcineurin inhibitor from cyclosporine to tacrolimus, combined with the new administration of angiotensin receptor antagonist (valsartan) and aldosterone receptor blocker, successfully decreased the amount of urine protein to 0.8 g/d within two wk. We considered that the present case showed two distinct types of FSGS lesions--one because of VUR and the other because of cyclosporine arteriolopathy--in each native kidney and transplanted kidney.

Background/Aims: Klotho gene, a new anti-aging gene, is mainly expressed in the kidney tubules. Several studies have found the relationship between klotho and emergence and development of renal diseases. This study set out to explore the role of fosinopril (Fos) and valsartan (Val) on klotho expression induced by angiotensin II (Ang II) in rat renal tubular epithelial cells (NRK-52E). Methods: NRK-52E cells were divided into five groups according to the treatment of Ang II, Fos and Val. Transforming growth factor-beta(1) (TGF-beta(1)), p38, phospho-p38 (p-p38), p53, and Sp1 protein expression were determined by immunohistochemical and Western blotting analysis. Klotho expression was detected by reverse transcription-polymerase chain reaction and Western blotting analysis. Results: Ang II upregulated TGF-beta(1), p-p38 and p53 expression, and inhibited Sp1 and klotho expression in NRK-52E cells. After the intervention of Fos and/or Val, TGF-beta(1), p-p38 and p53 expression were downregulated, Sp1 and klotho expression were upregulated. TGF-beta(1) and p53, Sp1 and klotho expression exhibited a positive linear correlation, respectively. Conclusion: We conclude that Fos and Val have a protective role in Ang II-induced renal damage, and it may be through mechanism of inhibiting TGF-beta(1), p-p38 and p53 expression, thus upregulating Sp1 and klotho expression.

The cardiovascular and cardiorenal disease continuum comprises the transition from cardiovascular risk factors to endothelial dysfunction and atherosclerosis, to clinical complications such as myocardial infarction (MI) and stroke, to the development of persistent target-organ damage and, ultimately, to chronic congestive heart failure (CHF), end-stage renal disease or premature death. The renin-angiotensin-aldosterone system (RAAS) is involved in all steps along this pathway, and RAAS blockade with ACE inhibitors or angiotensin AT(1)-receptor antagonists (angiotensin receptor blockers; ARBs) has turned out to be beneficial for patient outcomes throughout the disease continuum. Both ACE inhibitors and ARBs can prevent or reverse endothelial dysfunction and atherosclerosis, thereby reducing the risk of cardiovascular events. These drugs have further been shown to reduce end-organ damage in the heart, kidneys and brain. Aldosterone antagonists such as spironolactone and eplerenone are increasingly recognized as a third class of RAAS inhibitor with potent risk-reducing properties, especially but not solely with respect to the inhibition of cardiac remodelling and the possible prevention of heart failure. In secondary prevention, head-to-head comparisons of ACE inhibitors and ARBs, such as the recent ONTARGET study, provided evidence that, in addition to better tolerability, ARBs are non-inferior to ACE inhibitors in the prevention of clinical endpoints such as MI and stroke in cardiovascular high-risk patients. However, the combination of both ramipril and telmisartan at the maximally tolerated dosage achieved no further benefits and was associated with more adverse events such as symptomatic hypotension and renal dysfunction. In acute MI complicated by heart failure, the VALIANT trial has shown similar effects of ACE inhibition with captopril and ARB treatment with valsartan, but dual RAAS blockade did not further reduce events. In CHF, meta-analyses of RESOLVD, ValHeFT and CHARM-ADDED have shown that combined RAAS inhibition with an ACE inhibitor and ARB significantly reduced the morbidity endpoint in certain patient subgroups compared with standard therapy. However, in clinical practice, dual RAAS blockade is rarely employed, as seen, for instance, in the CORONA trial. The RALES and EPHESUS trials, investigating the effects of aldosterone blockade on cardiovascular outcomes in CHF patients, revealed that the addition of an aldosterone antagonist to standard heart failure therapy conferred powerful relative risk reductions for both morbidity and mortality. Future studies will elucidate whether this also holds true for patients who are asymptomatic or who have heart failure with preserved ejection fraction. In selected patients with renal disease, several studies have suggested that combined RAAS blockade brings about additional renoprotective antiproteinuric effects independent of blood pressure reduction, and large trials with robust endpoints are underway. In summary, combined therapy with several RAAS inhibitors is not recommended for all patients along the cardiorenovascular continuum. Patients with CHF with incomplete neuroendocrine blockade, as indicated, for example, by repetitive cardiac decompensation or refractory symptoms, might benefit from dual therapy as long as safety issues are well controlled. Finally, novel pharmacological agents such as the direct renin inhibitor aliskiren may provide additional therapeutic tools, but their role has yet to be established.

Abstract Objectives: To investigate the effect of nebivolol, a third generation beta-blocker, on blood pressure (BP) reduction and polysomnographic parameters in hypertensive patients with mild-to-moderate obstructive sleep apnoea (OSA). Methods: In this double-blind, parallel group study, patients were randomized to nebivolol 5 mg or valsartan 80 mg once daily following a 14-day, placebo run-in period during which any antihypertensive medication were discontinued. BP and heart rate measurements and overnight polysomnography were performed at baseline and after 6 weeks of treatment. Safety and tolerability were assessed. Results: Thirty-one patients were randomized to nebivolol (n = 16) or valsartan (n = 15). After six weeks both systolic and diastolic BP were effectively reduced by both treatments. Reductions in BP were not statistically significant different between agents, but mean heart rate was significantly decreased with nebivolol (compared with valsartan (p < 0.001). There was no statistically significant difference between both treatments for the change from baseline to treatment end for mean (+/-SD) Apnoea Hypopnoea Index (AHI) (nebivolol: 23.0 +/- 9.2 to 27.9 +/- 21.2 events/h; valsartan: 23.8 +/- 6.6 to 22.5 +/- 18.0 events/h; p = 0.48) or for any other sleep-related parameters. Both agents were well tolerated. Conclusion: Nebivolol has a significant BP reduction effect in patients with OSA that is similar to valsartan and reduces heart rate to a greater extent which may prove beneficial in selected patients.