Additional Blood Pressure Lowering Effect Research Articles

Development and Validation of a New Stability Indicating Liquid Chromatographic Method for the Simultaneous quantification of Hydrochlorthiazide and Telmisartan

Telmisartan is an angiotensin receptor blocker and Hydrochlorothiazide is used to treat edema caused by various heart, kidney and liver diseases. Telmisartan is used in combination with a thiazide-type diuretic such as Hydrochlorothiazide by which an additive blood pressure lowering effect was proved. A new stability indicating liquid chromatographic method has been developed for the simultaneous estimation of Telmisartan and Hydrochlorthiazide in tablets. Chromatographic separation was achieved by using a X Bridge shield RP C-18 (150mm × 3.0mm, 3.5µm) column of Waters HPLC with Empower2 software and PDA detector, maintained at 45 ºC. Gradient mode of elution was performed and the flow rate of the mobile phase was 0.8 mL/min (Detector wavelength 235nm). Forced degradation studies were performed and the proposed method was found to be selective and specific.

LCZ696, Angiotensin II Receptor-Neprilysin Inhibitor, Ameliorates High-Salt-Induced Hypertension and Cardiovascular Injury More Than Valsartan Alone.

LCZ696, an angiotensin receptor-neprilysin inhibitor, has recently been demonstrated to exert more beneficial effects on hypertensive or heart failure patients than conventional renin-angiotensin system blockers. However, the mechanism underlying the benefit of LCZ696 remains to be understood. The present study was undertaken to examine the effect of LCZ696 compared with valsartan on hypertension and cardiovascular injury. (i) Using telemetry, we compared the hypotensive effect of LCZ696 and valsartan in spontaneously hypertensive rats (SHR) that were fed a high-salt diet followed by a low-salt diet. (ii) We also examined the comparative effect of LCZ696 and valsartan on salt loaded SHRcp, a model of metabolic syndrome. (i) LCZ696 exerted a greater blood pressure (BP) lowering effect than valsartan in SHR regardless of high-salt or low-salt intake. Additive BP reduction by LCZ696 was associated with a significant increase in urinary sodium excretion and sympathetic activity suppression. (ii) LCZ696 significantly ameliorated cardiac hypertrophy and inflammation, coronary arterial remodeling, and vascular endothelial dysfunction in high-salt loaded SHRcp compared with valsartan. LCZ696 caused greater BP reduction than valsartan in SHR regardless of the degree of salt intake, which was associated with a significant enhancement in urinary sodium excretion and sympathetic activity suppression. Furthermore, an additive BP lowering effect of LCZ696 led to greater cardiovascular protection in hypertensive rats.

Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial

Conflicting blood pressure-lowering effects of catheter-based renal artery denervation have been reported in patients with resistant hypertension. We compared the ambulatory blood pressure-lowering efficacy and safety of radiofrequency-based renal denervation added to a standardised stepped-care antihypertensive treatment (SSAHT) with the same SSAHT alone in patients with resistant hypertension. The Renal Denervation for Hypertension (DENERHTN) trial was a prospective, open-label randomised controlled trial with blinded endpoint evaluation in patients with resistant hypertension, done in 15 French tertiary care centres specialised in hypertension management. Eligible patients aged 18-75 years received indapamide 1·5 mg, ramipril 10 mg (or irbesartan 300 mg), and amlodipine 10 mg daily for 4 weeks to confirm treatment resistance by ambulatory blood pressure monitoring before randomisation. Patients were then randomly assigned (1:1) to receive either renal denervation plus an SSAHT regimen (renal denervation group) or the same SSAHT alone (control group). The randomisation sequence was generated by computer, and stratified by centres. For SSAHT, after randomisation, spironolactone 25 mg per day, bisoprolol 10 mg per day, prazosin 5 mg per day, and rilmenidine 1 mg per day were sequentially added from months two to five in both groups if home blood pressure was more than or equal to 135/85 mm Hg. The primary endpoint was the mean change in daytime systolic blood pressure from baseline to 6 months as assessed by ambulatory blood pressure monitoring. The primary endpoint was analysed blindly. The safety outcomes were the incidence of acute adverse events of the renal denervation procedure and the change in estimated glomerular filtration rate from baseline to 6 months. This trial is registered with ClinicalTrials.gov, number NCT01570777. Between May 22, 2012, and Oct 14, 2013, 1416 patients were screened for eligibility, 106 of those were randomly assigned to treatment (53 patients in each group, intention-to-treat population) and 101 analysed because of patients with missing endpoints (48 in the renal denervation group, 53 in the control group, modified intention-to-treat population). The mean change in daytime ambulatory systolic blood pressure at 6 months was -15·8 mm Hg (95% CI -19·7 to -11·9) in the renal denervation group and -9·9 mm Hg (-13·6 to -6·2) in the group receiving SSAHT alone, a baseline-adjusted difference of -5·9 mm Hg (-11·3 to -0·5; p=0·0329). The number of antihypertensive drugs and drug-adherence at 6 months were similar between the two groups. Three minor renal denervation-related adverse events were noted (lumbar pain in two patients and mild groin haematoma in one patient). A mild and similar decrease in estimated glomerular filtration rate from baseline to 6 months was observed in both groups. In patients with well defined resistant hypertension, renal denervation plus an SSAHT decreases ambulatory blood pressure more than the same SSAHT alone at 6 months. This additional blood pressure lowering effect may contribute to a reduction in cardiovascular morbidity if maintained in the long term after renal denervation. French Ministry of Health.

Effects of hormone replacement therapy with drospirenone on cardiovascular system in postmenopausal hypertensive women with abdominal obesity

Objective. To evaluate effects of hormone replacement therapy with drospirenone on cardiovascular system in postmenopausal hypertensive women. Design and methods. Sixty-three postmenopausal women with hypertension I–II degree, abdominal obesity and climacteric syndrome were examined. During the first month all patients received telmisartan, then women were randomized into two groups — the first group (n = 30) continued treatment with telmisartan, participants of the second group (n = 33) took hormone replacement therapy: estradiol hemihydrates 2 mg + drospirenone 1 mg (HRT) in addition to antihypertensive therapy. Weight, anthropometric measurements, blood pressure (BP), diastolic function were evaluated. Results. There were additional BP lowering effect, significant decrease in weight and abdominal obesity parameters in group treated with HRT. Improved diastolic function of the left ventricle was more marked in HRT group, but there were no significant differences between two groups. Conclusions. HRT with drospirenone has beneficial effects on cardiovascular system in postmenopausal hypertensive women with abdominal obesity.

Additive beneficial effects of valsartan combined with rosuvastatin in the treatment of hypercholesterolemic hypertensive patients.

Background and ObjectivesWe compared the efficacy and safety of valsartan and rosuvastatin combination therapy with each treatment alone in hypercholesterolemic hypertensive patients.Subjects and MethodsPatients who met inclusion criteria were randomized to receive 1 of the following 2-month drug regimens: valsartan 160 mg plus rosuvastatin 20 mg, valsartan 160 mg plus placebo, or rosuvastatin 20 mg plus placebo. The primary efficacy variables were change in sitting diastolic blood pressure (sitDBP) and sitting systolic blood pressure (sitSBP), and percentage change in low-density lipoprotein-cholesterol (LDL-C) in the combination, valsartan, and rosuvastatin groups. Adverse events (AEs) during the study were analyzed.ResultsA total of 354 patients were screened and 123 of them were finally randomized. Changes of sitDBP by least squares mean (LSM) were -11.1, -7.2, and -3.6 mm Hg, respectively, and was greater in the combination, as compared to both valsartan (p=0.02) and rosuvastatin (p<0.001). Changes of sitSBP by LSM were -13.2, -10.8, and -4.9 mm Hg, and was greater in the combination, as compared to rosuvastatin (p=0.006) and not valsartan (p=0.42). Percentage changes of LDL-C by LSM were -52, -4, and -47% in each group, and was greater in the combination, as compared to valsartan (p<0.001), similar to rosuvastatin (p=0.16). Most AEs were mild and resolved by the end of the study.ConclusionCombination treatment with valsartan and rosuvastatin exhibited an additive blood pressure-lowering effect with acceptable tolerability, as compared to valsartan monotherapy. Its lipid lowering effect was similar to rosuvatatin monotherapy.

Blood pressure lowering efficacy of partial agonist beta blocker monotherapy for primary hypertension.

Partial agonists are a subclass of beta blockers used to treat hypertension in many countries. Partial agonist act by stimulating beta receptors when they are quiescent and blocking beta receptors when they are active. The blood pressure (BP) lowering effect of partial agonist beta blockers has not been quantified. To quantify the dose-related effects of various partial agonists beta blockers on systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate versus placebo in patients with primary hypertension. We searched the Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, EMBASE and ClinicalTrials.gov for randomized controlled trials up to October 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Group's Specialised Register. Randomized double-blinded placebo-controlled parallel or cross-over trials. Studies must contain a partial agonist monotherapy arm with fixed dose. Patients enrolled into the studies must have primary hypertension at baseline (defined as SBP/DBP > 140/90 mmHg). Duration of studies must be between three to 12 weeks. Two authors (GW and HB) confirmed the inclusion of studies and extracted the data independently. Thirteen randomized double-blinded placebo-controlled trials that examined the blood pressure lowering efficacy of six partial agonists in 605 hypertensive patients were included in this review. Five of the included studies were parallel studies and the other eight were cross-over studies. The overall risk of bias is high in this review due to the small sample size and high risk of detection bias. Pindolol, celiprolol and alprenolol lowered SBP and DBP compared to placebo. Acebutolol lowered SBP but there was no clear evidence that it lowered DBP. There was no clear evidence that pindolol and oxprenolol lowered SBP or DBP. Other than for celiprolol, sample sizes were generally small increasing the uncertainty in findings for individual agents versus placebo. In patients with moderate to severe hypertension, partial agonists (considered as a subclass) lowered peak BP by an average of 8 mmHg systolic (95% CI, -10 to -6, very low quality evidence), 4 mmHg diastolic (95%CI, -5 to -3, very low quality evidence) and reduced heart rate by five beats per minute (95%CI, -6 to -4, very low quality evidence). Higher dose partial agonists did not appear to provide additional BP lowering effects compared to lower dose. The maximum BP lowering effect of the overall subclass occurred at the starting dose. Partial agonists reduced pulse pressure by 4 mmHg (95% CI, -5 to -2, very low evidence). Only one study reported withdrawal due to adverse effects, the risk ratio (95% confidence interval) was 0.72 (0.07, 7.67). There was very low quality evidence that in patients with moderate to severe hypertension, partial agonists lowered peak BP by an average of 8/4 mmHg and reduced heart rate by five beats per minute. There was no evidence of a greater effect at doses higher than the initial doses. This estimate was probably exaggerated as it was subject to a high risk of bias. Based on the indirect comparison of the results in this review and two Cochrane reviews on angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which also used similar inclusion criteria as this review, the BP lowering effect appeared to be less than the effect in patients with mild to moderate elevated BP who were taking ACE inhibitors and ARBs based on an indirect comparison. Withdrawals due to adverse effects were only reported in one trial so it is impossible to assess the harm of these drugs.

Blood pressure lowering efficacy of nonselective beta-blockers for primary hypertension.

Beta-blockers are one of the classes of drugs frequently used to treat hypertension. Quantifying the blood pressure (BP) lowering effects of nonselective beta-blockers provides important information that aids clinical decision making. To quantify the dose-related effects of nonselective beta-adrenergic receptor blockers (beta-blockers) on systolic blood pressure (SBP) and diastolic blood pressure (DBP) as compared with placebo in people with primary hypertension. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ClinicalTrials.gov for randomized controlled trials up to October 2013. Randomized, double-blind, placebo-controlled, parallel or cross-over trials. Studies had to contain a nonselective beta-blocker monotherapy arm with a fixed dose. Participants enrolled into the studies had to have primary hypertension at baseline. Duration of studies had to be between three and 12 weeks. Two review authors (GW and AL) independently confirmed the inclusion of studies and extracted the data. We included 25 RCTs that evaluated the BP lowering effects of seven nonselective beta-blockers in 1264 people with hypertension. Among the 25 RCTs, four were parallel studies and 21 were cross-over studies. Overall, nonselective beta-blockers lowered systolic BP and diastolic BP compared with placebo. Nonselective beta-blockers, in the recommended dose range, did not showed a convincing dose-response relationship by direct comparison. The once (1x) and twice (2x) starting dose subgroups contained the largest sample size. The estimate of BP lowering efficacy for nonselective beta-blockers by combining the 1x and 2x starting dose subgroup was -10 mmHg (95% CI -11 to -8) for systolic BP and -7 mmHg (95% CI -8 to -6) for diastolic BP (low-quality evidence). Nonselective beta-blockers starting at the 1x recommended starting doses lowered heart rate by 12 beats per minute (95% CI 10 to 13) (low-quality evidence). The dose-response relationship in heart rate was evident by both direct and indirect comparison. Due to imprecision, there was no clear evidence of an effect of nonselective beta-blockers on pulse pressure in any dose subgroups except for a small reduction with the 2x starting dose (-2.2 mmHg, 95% CI -3.7 to -0.7) (very low quality evidence). The point estimates in the 1x, four times (4x) and eight times (8x) starting dose subgroups were similar to the 2x starting dose subgroup. Therefore, it would appear that if nonselective beta-blockers do lower pulse pressure, the magnitude is likely to be about 2 mmHg. There were very limited data (two studies) on withdrawals due to adverse effects (risk ratio (RR) 0.84; 95% CI 0.38 to 1.82). In people with mild-to-moderate hypertension, nonselective beta-blockers lowered peak BP by a mean of -10/-7 mmHg (systolic/diastolic) and reduced heart rate by 12 beats per minute. Propranolol and penbutolol were the two drugs that contributed to most of the data for nonselective beta-blockers. This estimate is likely exaggerated due to the presence of extreme outliers and other sources of bias. If we removed the extreme outliers from the analysis, the estimate for non-selective beta-blockers was lower (-8/-5 mmHg (systolic/diastolic)). Nonselective beta-blockers did not show a convincing graded dose-response in the recommended dose range for systolic BP and diastolic BP, while higher dose nonselective beta-blockers provided greater reduction of heart rate. Using higher dose nonselective beta-blockers might cause more side effects, such as bradycardia, without producing an additional BP lowering effect. The effect of nonselective beta-blockers on pulse pressure was likely small, at about 2 mmHg.

Model-Supported Development of CS-8635: A Fixed-Dose Combination of Olmesartan, Amlodipine, and Hydrochlorothiazide.

CS-8635, a fixed-dose triple combination of olmesartan, amlodipine, and hydrochlorothiazide, was developed to address the growing need for additional blood pressure (BP) reduction in patients not controlled with dual-combination therapies. Prior to Phase III, modeling and simulation (M&S) was conducted to estimate the additional BP lowering effect of CS-8635 compared to the respective dual combinations. The Phase III study evaluated CS-8635 BP lowering effects only at the highest dose strength among the five dose strengths to be developed. Post-trial M&S was performed using an integrated dataset from three Phase III programs; CS-8635 plus two prior dual combinations. M&S robustly estimated and described the BP lowering effects of CS-8635 evaluated in a clinical setting. Furthermore, M&S evaluated BP lowering effects of the additional four dose strengths not studied. In summary, M&S aided the development of the clinical study and full characterization of the BP lowering effects of CS-8635 across intermediate doses.

Effects of Bacillus Natto Products on Blood Pressure in Patients with Lifestyle Diseases

The fermented soybean product natto is a popular traditional food in Japan and is considered a health supplement. To investigate the effect of supplements derived from natto on blood pressure in patients with lifestyle diseases, a cross-over, double-blind study was performed. The substances used were fermented soya (natto) extract and NKCP®, with main components of subtilisin NAT and bacillopeptidase F, respectively. A four-week course of NKCP® significantly decreased average systolic blood pressure from 130.9 to 120.5 mmHg (p=0.001) and diastolic blood pressure from 72.9 to 68.6 mmHg (p=0.024). However, after a four-week treatment with fermented soya (natto) extract, no significant changes in systolic or diastolic blood pressure were found (126.8 to 126.4 mmHg, and 70.9 to 68.3 mmHg, respectively). The difference in the effect on blood pressure between these two substances is considered as owing to the differences of the in vitro experimental results on blood fluidity. The use of dietary supplements, especially NKCP®, from natto provides additional blood pressure lowering effects in patients already receiving medical care.

Olmesartán con diuréticos o con antagonistas del calcio: ¿a qué perfil de paciente hipertenso?

The combination of olmesartan both with a thiazide diuretic or with amlodipine has been shown to confer an additional blood pressure-lowering effect, with good tolerability and fewer adverse effects. Few studies have evaluated differences among therapeutic regimens that include olmesartan in association with diuretics or amlodipine. These differences are due mainly to effects unrelated to the blood pressure-lowering effects of drugs used in combination with olmesartan, since both combinations are similar in their antihypertensive efficacy.This article reviews the effects of both combinations, bearing in mind several factors such as the metabolic risk of hypertensive patients, their age, blood pressure variability, and central blood pressure.

Clinical Implications

HomeHypertensionVol. 60, No. 6Clinical Implications Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBClinical Implications Originally published1 Dec 2012https://doi.org/10.1161/HYP.0b013e31827adfa9Hypertension. 2012;60:1367NHE3-Inhibition in the Gut and Hypertension (page 1560)High intestinal sodium absorption is 1 mechanism of hypertension and constipation. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of sodium absorption in the gut. SAR218034 is an orally nonabsorbable specific NHE3 inhibitor. Inhibition of intestinal NHE3 by SAR218034 increased feces sodium-excretion and reduced urinary sodium-excretion, while absolute sodium balance and serum sodium-concentration was not changed. Reduced intestinal sodium absorption by SAR218034-treatment was associated with increased feces water content and reduction in systolic blood pressure. Angiotensin-converting enzyme inhibition by ramipril plus NHE3 inhibition resulted in an additive blood pressure lowering effect. Selective inhibition of NHE3-mediated sodium absorption in the gut has the potential to reduce high blood pressure and can be safely combined with angiotensin-converting enzyme inhibitor treatment. In addition, NHE3 inhibition in the gut may display a laxative effect in elderly patients suffering from constipation. These results show that SAR218034 inhibiting intestinal NHE3-mediated sodium absorption has potential as a representative of a new class of antihypertensive drugs. Intestinal NHE3 inhibitors may be particularly useful as an adjunct to other therapies. The real potential of the NHE3 inhibitor is to help accomplish a truly low salt-intake from the gut, because it is difficult to sufficiently reduce salt in the human diet.Quality of Life After Renal Denervation (page 1479)Recent studies have demonstrated the effectiveness of radiofrequency ablation of the renal sympathetic nerves in reducing blood pressure in patients with treatment resistant hypertension. In this issue of Hypertension, Lambert et al present data indicating that subjective health-related quality of life, as assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey, is markedly diminished in patients with treatment resistant hypertension. Three months after renal denervation, the 36-Item Short-Form Health Survey mental component summary score improved, with the change being driven by increases in the vitality, social function, role emotion, and mental health domains. No change occurred in the physical component summary score. The changes in 36-Item Short-Form Health Survey scores were not related to the magnitude of blood pressure reduction. Although the authors could not exclude the possibility of a placebo effect, the potential mechanisms underlying their observations are intriguing. Preclinical studies have demonstrated that sensory renal afferent nerves can influence the firing rate of medullary and hypothalamic neurones and that renal afferent denervation prevents the development of hypertension and an increase in norepinephrine turnover in the posterior and lateral hypothalamic nuclei and the locus coeruleus. The majority of brain norepinephrine is located in the locus coeruleus, which, together with its hypothalamic and amygdala projections, is linked with behavioral responses involving autonomic activation. Whether the improvement in health-related quality of life that occurred after renal denervation is sustained and has a biological basis associated with reduction in sympathetic tone remains unknown but does merit further attention.Blood Pressure Tracking Over the Life Course (page 1393)Although prior studies have shown that blood pressure steadily increases with age, there are limited longitudinal data characterizing the pattern of blood pressure tracking over the life course. Furthermore, the extent to which risk factors influence blood pressure tracking is not well understood. Therefore, we used multilevel modeling to analyze blood pressure measurements performed serially, over a period of up to 28 years, in participants of the Framingham Heart Study. On the basis of data collected from >21 700 person-observations, we observed that risk factors such as greater body mass index and higher heart rate were associated with an increase in all component measures of blood pressure. However, dyslipidemia was primarily associated with increased mean arterial pressure, a measure of steady-state load, whereas diabetes mellitus and smoking were predominantly associated with higher pulse pressure, representing pulsatile load. Notably, age-related increases in pulse pressure were more pronounced in women compared with men overall. The differential impact of select risk factors on elevation in the individual components of blood pressure underscores distinct regulation of these measures over the life course. Further research is needed to investigate the mechanisms underlying these observations and, in turn, the extent to which targeted interventions may attenuate the typical trajectory of blood pressure progression with aging. Previous Back to top Next FiguresReferencesRelatedDetails December 2012Vol 60, Issue 6 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/HYP.0b013e31827adfa9 Originally publishedDecember 1, 2012 PDF download Advertisement

Antihypertensive and Laxative Effects by Pharmacological Inhibition of Sodium-Proton-Exchanger Subtype 3–Mediated Sodium Absorption in the Gut

High intestinal sodium absorption is one mechanism of hypertension and constipation. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of sodium absorption in the gut. SAR218034 (SAR) is an orally nonabsorbable specific NHE3 inhibitor. The effect of SAR (1 mg/kg per day in chow) on feces sodium excretion, systolic blood pressure via tail cuff, and gene expression of NHE3 in the gut were studied in senescent lean hypertensive rats (spontaneously hypertensive rats-lean, loaded with NaCl 0.7% in drinking water) and in hypertensive, obese, and hyperinsulinemic rats (spontaneously hypertensive rats-obese, not loaded with NaCl). In spontaneously hypertensive rats-lean, inhibition of intestinal NHE3 by SAR increased feces sodium excretion and reduced urinary sodium excretion, whereas absolute sodium balance and serum sodium concentration were not changed. This suggests reduced intestinal sodium absorption in SAR-treated animals and was associated with increased feces water content (58% versus 42% in placebo treated animals; P=0.0001) and reduction in systolic blood pressure from 222 ± 7 to 198 ± 2 mm Hg (P=0.0001). Angiotensin-converting enzyme inhibition by ramipril plus NHE3 inhibition resulted in an additive blood pressure-lowering effect. In spontaneously hypertensive rats-obese, SAR lowered systolic blood pressure but did not modify serum insulin or cholesterol levels. Gene expression of NHE3 was upregulated in the ileum and colon but not in the jejunum of SAR-treated rats. Reduction of intestinal sodium absorption by selective NHE3 inhibition in the gut reduces high blood pressure and increases feces water excretion. Intestinal NHE3 blockade could be a new treatment strategy for elderly patients suffering from high blood pressure and constipation.

Olmesartan/amlodipine: blood pressure lowering and beyond in special populations

Clinical studies and population-based analyses show that in patients with hypertension, the majority cannot control their blood pressure (BP) by treatment with a single antihypertensive agent. Combining agents from different antihypertensive classes with complementary modes of action significantly increases efficacy and is a treatment strategy recommended by European treatment guidelines, particularly in patients at high cardiovascular risk. The combinations of antihypertensive agents recommended by the European guidelines include an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB). The single-pill combination formulation of the ARB olmesartan medoxomil plus the CCB amlodipine is an effective and well-tolerated treatment that provides greater blood pressure lowering and control than the component monotherapies and favours compliance by not increasing pill burden. Importantly, the efficacy and tolerability of olmesartan plus amlodipine is not affected by age, gender, hypertension severity, diabetes status, race or body mass index. Additional blood pressure lowering effects are observed with stepwise uptitration of olmesartan plus amlodipine with or without hydrochlorothiazide, with more patients achieving blood pressure goals. In addition, olmesartan plus amlodipine has demonstrated effects beyond BP lowering by showing beneficial effects on markers of inflammation, endothelial dysfunction and oxidative stress, as well as metabolic improvements and a reduction in new-onset diabetes incidence in hypertensive patients with metabolic syndrome.

Direct Angiotensin II Type 2 Receptor Stimulation in N ω -Nitro- l -Arginine-Methyl Ester–Induced Hypertension

Pulse wave velocity (PWV), a direct marker of arterial stiffness, is an independent cardiovascular risk factor. Although the angiotensin II type 1 receptor blockade belongs to major antihypertensive and cardioprotective therapies, less is known about the effects of long-term stimulation of the angiotensin II type 2 receptor. Previously, compound 21, a selective nonpeptide angiotensin II type 2 receptor agonist improved the outcome of myocardial infarction in rats along with anti-inflammatory properties. We investigated whether compound 21 alone or in combination with angiotensin II type 1 receptor blockade by olmesartan medoxomil could prevent PWV increase and aortic remodeling in N(ω)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension. Male adult Wistar rats (n=65) were randomly assigned to control, L-NAME, L-NAME+compound-21, L-NAME+olmesartan, and L-NAME+olmesartan+compound-21 groups and treated for 6 weeks. We observed that L-NAME hypertension was accompanied by enhanced PWV, increased wall thickness, and stiffness of the aorta, along with elevated hydroxyproline concentration. Olmesartan completely prevented hypertension, PWV and wall thickness increase, and the increase of aortic stiffness and partly prevented hydroxyproline accumulation. Compound 21 partly prevented all of these alterations, yet without concomitant prevention of blood pressure rise. Although the combination therapy with olmesartan and compound 21 led to blood pressure levels, PWV, and wall thickness comparable to olmesartan-alone-treated rats, only in the combination group was complete prevention of increased hydroxyproline deposition achieved, resulting in even more pronounced stiffness reduction. We conclude that chronic angiotensin II type 2 receptor stimulation prevented aortic stiffening and collagen accumulation without preventing hypertension in rats with inhibited NO synthase. These effects were additive to angiotensin II type 1 receptor blockade, yet without additional blood pressure-lowering effect, and they seem to be NO and blood pressure independent.

Possible beneficial effects of amlodipine, lisinopril, and their Combination on lipid profile in hypertensive patients

It is well known that monotherapy does not provide therapeutic response in all hypertensive. Somepatients show an excellent response, while in others there is a poor response. Combinationantihypertensive therapy is administered when blood pressure is inadequately controlled bymonotherapy to achieve a balanced and additive antihypertensive effect with minimum adverse effects.Both angiotensin converting enzyme (ACE) inhibitors and dihydropyridine type of calcium antagonistsare well established and widely used in monotherapy. An understanding of differences in themechanism of action of these agents allows a logical approach for the use of these agents as acombination therapy. This study was designed to evaluate the possible beneficial effects of long actingcalcium channel blocker, amlodipine and the long acting Angiotensin converting enzyme (ACE)inhibitor, lisinopril given either alone or in combination in patients with essential hypertension on lipidprofile (LDL-C and HDL-C) and on other parameters using a randomized double blind, crossoverstudy. The study includes 150 patients with systolic blood pressure (SBP)&gt;140 mmHg and diastolicblood pressure (DBP) &gt;90 mmHg received amlodipine 5 mg, lisinopril 5 mg and their combinationprior randomization schedule. Systolic, diastolic blood pressure and pulse rate were recorded at weeklyintervals while, serum levels of urea, creatinine, LDL-C and HDL-C where recorded at monthlyintervals, the duration of this study was 3 months. Results were obtained using paired students t-test,differences were considered significant with (p&lt;0.05).A significant decline in SBP and DBP in all treatment groups (p&lt;0.05) was recorded, the reductiontend to be more pronounced in the combination group. Moreover, there was a significant effect ofcombination on the heart rate, serum level of urea and creatinine, beside that, the level of HDL wassignificantly elevated with amlodipine and combination. We concluded that combination had additionalblood pressure lowering effect when compared either with amlodipine or lisinopril alone, in addition tothe greater effect on lipid profile which demonstrated that this combination is potentialantiatherosclerotic agent.

Dual blockade versus single blockade of the renin–angiotensin system in the light of ONTARGET

Angiotensin II plays an important role in the cardiovascular continuum starting with risk factors and progressing to atherosclerosis, target organ damage, and ultimately to heart failure, stroke, or death. Inhibiting the renin-angiotensin-aldosterone system (RAAS) represents a cornerstone for the treatment of hypertension and heart failure. In patients with heart failure, the single RAAS blockade with angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce morbidity and mortality, increase life expectancy, and preserve the renal function. AT1 receptor blockers (ARBs) are equally effective in reducing mortality and morbidity in patients with impaired left ventricular function. The combination of ACE inhibitors with ARBs leads to an additive blood pressure lowering effect, better reduction in proteinuria, and to additive benefits in heart failure and left ventricular hypertrophy. But combination therapy is also associated with more side effects. Further investigations evaluating the effect of dual RAAS blockade on fatal and nonfatal cardiovascular events are needed.

Aliskiren: An Oral Direct Renin Inhibitor for the Treatment of Hypertension

Aliskiren is the first member of the new class of orally active direct renin inhibitors to receive approval from the United States Food and Drug Administration for the treatment of hypertension. In patients with hypertension, aliskiren can be used either as monotherapy or in combination with other antihypertensive agents. By inhibiting renin, aliskiren blocks the conversion of angiotensinogen to angiotensin I, which subsequently results in a reduction in angiotensin II concentrations. Unlike the angiotensin-converting enzyme inhibitors and the angiotensin II receptor blockers (ARBs), which reactively stimulate an increase in plasma renin activity, aliskiren suppresses the effects of renin and leads to a reduction in plasma renin activity. In clinical trials involving patients with mild-to-moderate hypertension, aliskiren provided antihypertensive efficacy that was comparable to that of an ARB. Combination therapy with aliskiren and an ARB may provide additional blood pressure-lowering effects compared with the respective monotherapies with each of the agents. The results from surrogate outcome studies have also alluded to the potential for aliskiren to prevent target organ damage. Because aliskiren does not significantly affect the cytochrome P450 system, it has been associated with few drug interactions. In clinical studies, aliskiren was well tolerated, and its adverse-effect profile was similar to that of placebo. Fatigue, headache, dizziness, diarrhea, nasopharyngitis, and back pain were the most commonly reported adverse events. Overall, aliskiren appears to be a reasonable treatment option for patients with mild-to-moderate hypertension who are intolerant of first-line antihypertensive therapies. Aliskiren may also be a promising renoprotective strategy in patients with concomitant hypertension and diabetes mellitus. Its potential as a first-line antihypertensive agent will have to be further examined once studies evaluating its effects on long-term clinical outcomes are completed.

Prescribing angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers in chronic kidney disease (Review Article)

In Australia the number of patients developing end-stage kidney disease is growing. Almost 70% of new cases of treated end-stage kidney disease are due to diabetes, hypertension or glomerulonephritis. The majority of these patients have a chronic decline of renal function over many years before dialysis is required, even when the initial insult is no longer present. Hypertension and the degree of proteinuria are the most important determinants for this progression and ample evidence suggests that angiotensin II is the key player in sustaining both hypertension and proteinuria. Angiotensin II mediates not only haemodynamic changes but also profibrotic and pro-inflammatory processes. Blockade of the renin-angiotensin system decreases proteinuria and slows the progression of both diabetic and non-diabetic proteinuric renal disease. Angiotensin-converting enzyme (ACE) inhibitors are first-line therapy in patients with type 1 diabetes mellitus and nephropathy, whereas angiotensin receptor blockers (ARB) are first-line therapy in patients with type 2 diabetes mellitus and microalbuminuria or overt nephropathy. Finally, treatment with ACE inhibitors delays the progression of proteinuric nephropathy in non-diabetic patients. Combination therapy with ACE inhibitors and ARB may allow a more complete blockade of the renin-angiotensin system and clinical trials show that ACE inhibitor-ARB combinations have an additive antiproteinuric effect of up to 40% compared with ACE inhibitor or ARB alone, without additional blood pressure-lowering effect. Finally, it is important to emphasize that progressive lowering of blood pressure to 120 mmHg is associated with improved renal outcome and that this effect is independent of baseline renal function.

Efficacy and safety of combination therapy with losartan and hydrochlorothiazide in elderly hypertension

We examined the effect and safety of combination therapy with low-dose diuretics (hydrochlorothiazide: HCTZ) and angiotensin II receptor antagonist (losartan) in elderly cases of hypertension, using ambulatory blood pressure monitoring (ABPM). Elderly hypertensive patients (mean age 75 +/- 2 years) were treated with either losartan (25-50 mg/day) or HCTZ (12.5 mg/day) for at least 4 weeks, and then 24-hour blood pressure (BP) was measured by ABPM. Combination therapy with addition of other drug was initiated in 14 patients whose 24-hour systolic BP or daytime systolic BP was over 140 mmHg (160 mmHg for the patients of 80 years or older). After 4 weeks of the combination therapy, ABPM was repeated. Blood cell count and blood chemistry were also done before and after initiation of combination therapy. In the losartan-preceding group (n = 9), the combination therapy with HCTZ reduced 24-hour BP by 19.3 +/- 2.3/6.6 +/- 2.3 mmHg. Similarly, daytime and nighttime BP decreased by 21.4 +/- 4/8.4 +/- 2.8 mmHg and 15.2 +/- 4/4.2 +/- 2.4 mmHg, respectively. In the HCTZ-preceding group, the combination with losartan also decreased 24-hour BP by 12.2 +/- 4.8/3.4 +/- 1.4 mmHg. The decreases of daytime and nighttime BP were 13.8 +/- 6.6/4 +/- 1.1 mmHg and 10 +/- 4.7/3 +/- 2.4 mmHg, respectively. Heart rate did not change with combination therapy in the losartan-preceding group, while heart rate during daytime tended to decrease by addition of losartan in the HCTZ-preceding group (3.8 +/- 1.7/min). Serum electrolytes, uric acid, lipids, renal function and body weight did not change during the study period. Thus, combination therapy of losartan/hydrochlorothiazide seems useful in the treatment of elderly hypertension, showing additive BP lowering effect without metabolic adverse effects.

Evaluation of amlodipine, lisinopril, and a combination in the treatment of essential hypertension

Angiotensin converting enzyme (ACE) inhibitors and dihydropyridine calcium antagonists are well established and widely used as monotherapy in patients with mild to moderate essential hypertension. Earlier studies combining short acting...