Blood Pressure-independent Effects Research Articles

Blood pressure-dependent and independent effects of amlodipine and angiotensin receptor blockers on the risk of stroke

Calcium channel blockers (CCBs) by the use of amlodipine substantially reduce the risk of stroke, and the benefit of initial treatment with this drug versus other antihypertensive drugs could be largely, though not entirely, explained by blood pressure differences between randomized groups of trials [1]. When contrasted with a long-acting CCB, amlodipine, angiotensin receptor blockers (ARBs) are less effective in lowering blood pressure and also demonstrate inferiority for the prevention of stroke [1]. It remains uncertain, however, whether mechanisms independent of blood pressure also affect the size of the treatment benefit, and there have been few formal attempts to investigate any such classand drug-specific effects. Using data from trials of amlodipine or ARBs that were included in recent meta-analyses [2,3], we conducted analyses to determine the relative contribution of blood-pressure-dependent and independent mechanisms to the reduction in risk of stroke produced by these drugs. Instead of comprehensive electronic and manual searches, we identified 10 and 17 odds ratios (ORs) for stroke from randomized controlled trials of amlodipine (77,093 individuals) and ARBs (104,360 individuals), respectively, from the comprehensive metaanalyses [2,3] (Table 1). We used sophisticated methods designed by the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) [4]. For each trial, the mean difference in follow-up systolic blood pressure levels between the randomized groups was sought. The association between the difference in follow-up systolic blood pressure levels and the log OR for stroke was investigated using random-effects meta-regression analysis with inverse variance weighting. Initially, using a single regression model, separate regression lines were fitted for trials in which amlodipine or ARBs were the treatment. The slopes of these lines were compared, so as to test for a differential effect of blood pressure reduction on risk in trials of amlodipine compared with ARBs. If these slopes were not significantly different (pN0.05), a parallel lines regression model was fitted, which assumes equal effects of blood pressure reduction with amlodipine and ARBs. Using this model, the null hypothesis of no separation between the 2 parallel lines was tested to explore whether there was evidence of a differential effect of amlodipine and ARBs independent of blood pressure lowering. Assumptions of linear associations between differences in follow-up blood pressure levels and log ORs were tested using standard graphical methods. Analyses were carried out using the metareg routine in STATA version 8.0 (Stata Corporation, College Station, Texas). In the single regression model, the association between the magnitude of reduction in blood pressure and the size of relative risk reduction were similar for amlodipine and ARBs (p=0.326). In the parallel lines regression model, treatment with amlodipine or ARBs achieved a 4.0% (95% confidence interval [CI]; 1.2% to 7.0%; p=0.007) reduction in the risk for each 1 mm Hg reduction in blood pressure (Fig. 1). At zero blood pressure reduction, the estimated relative risk reduction with amlodipine was 11.9% (95% CI, 4.4% to 18.7%; p=0.004). However, ARBs did not confer any additional protection beyond that conferred by blood pressure reduction alone. There was a significant difference between amlodipine and ARBs in terms of their likelihood of providing protection independent of blood pressure lowering (p=0.010), suggesting greater protection with amlodipine than ARBs. The size of blood pressure reduction achieved with amlodipine or ARBs was directly associated with the size of the reductions in the risk of stroke. In addition, although treatment with amlodipine provided an additional 11.9% relative risk reduction beyond that explained by the observed blood pressure differences, no such effect was observed for ARBs. This cerebroprotective effect of amlodipine was significantly greater than any such effect produced by ARBs. These findings extend those previously reported by Wang et al. [1], who plotted only 5 ORs for amlodipine trials and 5 ORs for ARB trials and performed meta-regression analyses separately for trials involving amlodipine and ARB groups. The present analyses provide much more reliable information about the blood pressure-dependent and independent effects of amlodipine and ARBs. The analyses included 10 ORs for amlodipine trials and 17 ORs for ARB trials and involved more sophisticated statistical methods (parallel lines regression model) specifically aimed at the identification of blood pressure-dependent and independent components of the treatment effects. For the risk of stroke, metaregression analyses by the BPLTTC [4] showed similar blood pressure-dependent effects of angiotensin-converting enzyme inhibitors and ARBs but no blood pressure-independent effects for both drug classes. Maximization of the benefit for stroke may be achieved with a regimen that includes amlodipine together with other drugs in an effort to optimize the size of the blood pressure reduction achieved. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology (Shewan and Coats 2010;144:1–2).

How to use marginal structural models in randomized trials to estimate the natural direct and indirect effects of therapies mediated by causal intermediates

Although intention-to-treat analysis is a standard approach, additional supplemental analyses are often required to evaluate the biological relationship among interventions, intermediates, and outcomes. Therefore, we need to evaluate whether the effect of an intervention on a particular outcome is mediated by a hypothesized intermediate variable. To evaluate the size of the direct effect in the total effect, we applied the marginal structural model to estimate the average natural direct and indirect effects in a large-scale randomized controlled trial (RCT). Method The average natural direct effect is defined as the difference in the probability of a counterfactual outcome between the experimental and control arms, with the intermediate set to what it would have been, had the intervention been a control treatment. We considered two marginal structural models to estimate the average natural direct and indirect effects introduced by VanderWeele (Epidemiology 2009) and applied them in a large-scale RCT - the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J trial) - that compared angiotensin receptor blockers and calcium-channel blockers in high-risk hypertensive patients. There were no strong blood pressure-independent or dependent effects; however, a systolic blood pressure reduction of about 1.9 mmHg suppressed all events. Compared to the blood pressure-independent effects of calcium channel blockers, those of angiotensin receptor blockers contributed positively to cardiovascular and cardiac events, but negatively to cerebrovascular events. There is a particular condition for estimating the average natural direct effect. It is impossible to check whether this condition is satisfied with the available data. We estimated the average natural direct and indirect effects through the achieved systolic blood pressure in the CASE-J trial. This first application of estimating the average natural effects in an RCT can be useful for obtaining an in-depth understanding of the results and further development of similar interventions.

Valsartan and Amlodipine: Safety and Efficacy in Stroke Prevention

Stroke is one of the leading causes of death and disability worldwide. Controlling hypertension is known to be the most important treatment in preventing stroke. Reduction of blood pressure (BP) even below the normal range continues to reduce stroke risk. However, there are also thought to be blood pressure-independent effects of antihypertensive treatments, which differ between antihypertensive classes. Calcium channel blocker, amlodipine, and angiotensin receptor blocker, valsartan, represent the two antihypertensive drugs with supportive evidence for the prevention of stroke. Amlodipne and valsartan have favorable effects on stroke outcome as monotherapy, particularly in patients with high cardiovascular risk. There has been no study in which evaluated the effectiveness of the combination of these two agents, however, the combination of amlodipine and valsartan is well tolerated and the large BP reductions with this combination therapy would suggest that this might be an effective approach for stroke prevention.

Blood pressure-independent effect of candesartan on cardio-ankle vascular index in hypertensive patients with metabolic syndrome

Angiotensin receptor blockers (ARBs) are known to reduce the cardiovascular risk in hypertensive patients. This study was designed to examine the effect of an ARB candesartan on subclinical atherosclerosis assessed by cardio-ankle vascular index (CAVI) in comparison with calcium channel blockers (CCBs) alone in hypertensive patients with metabolic syndrome (MetS). A total of 53 consecutive hypertensive patients with MetS were randomly assigned to the candesartan group, in which candesartan was added on, or the CCBs group, in which CCBs were added on. Clinical and biological parameters were obtained before and after the 12-month treatment period. The primary measure of efficacy was the %change in CAVI. When treated with candesartan, but not CCBs, CAVI significantly decreased from 8.7 to 7.7 by 11%. Blood pressure (BP) significantly decreased with both treatments, but the differences between groups were not significant. The changes in other parameters remained unchanged in both the groups. Analysis of covariance found that both the BP reduction and the therapy difference contributed to the decrease in CAVI, but the BP reduction was not involved in the decrease in CAVI caused by the difference in the therapy. Candesartan may be a better antihypertensive drug than CCBs to improve subclinical atherosclerosis of patients with MetS.

Prorenin, Renin, and Their Receptor

In addition to its well-known role in regulating blood pressure and fluid balance, the renin-angiotensin-aldosterone system (RAAS) has continued to fascinate both researchers and clinicians because of the several additional functions that it has been proposed to carry out. Disruption of the production or action of angiotensin II (Ang II) during development, either by gene mutation or by pharmacological blockade, results in tubular agenesis and anemia in the fetus (humans) or offspring (laboratory animals) and is most often lethal.1,2 Some of the suspected, but still unproven, roles of angiotensin peptides include effects on energy metabolism,3 longevity,4 memory,5 autoimmune diseases,6,7 and a direct, blood pressure-independent effect on tissue damage. This latter role is extremely hard to prove, because the effects of Ang II on blood pressure are hard to separate from its potential direct effects on tissues both in the laboratory and in clinical trials. The most recent developments in RAAS research have led to the suggestion that tissue damage may not be solely attributable to the action of angiotensin peptides but may also involve a direct effect of renin and its protein precursor, prorenin. The concept that prorenin and renin play a direct role in vascular pathologies is largely built on 4 lines of evidence. First is the finding that elevations of circulating prorenin were associated (and may even precede) diabetic microvascular disease.8,9 Second is the report that transgenic rats engineered to have a 400-fold increase in circulating prorenin developed severe cardiac remodeling and renal lesions in the absence of hypertension,10 raising the possibility that prorenin was not only associated with tissue damage but that it may even be responsible for the damage by a mechanism that did not require Ang II generation. Third is the discovery of the so-called (pro)renin receptor ((P)RR), …

Are There Effects of Renin–Angiotensin System Antagonists Beyond Blood Pressure Control?

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are recognized to reduce cardiovascular and renal morbidity and mortality, which is primarily attributed to their antihypertensive effects. Activation of the renin-angiotensin system (RAS) may also play an important role in the pathogenesis of cardiovascular and renal disease through blood pressure-independent mechanisms mediated by angiotensin II. Thus, inhibiting the RAS with either an ARB or an ACE inhibitor may confer additional benefit in people with advanced nephropathy that cannot be explained totally by reductions in blood pressure. Preclinical evidence suggests that blood pressure lowering is not solely responsible for the organ and tissue protective effects of ACE inhibitors or ARBs. Furthermore, clinical studies evaluating effects on end organs and surrogate markers have shown that these agents have blood pressure-independent effects. There is also intriguing evidence that agents in the same class may differ in their effects on renal function despite similar blood pressure control. Support for blood pressure-independent effects comes from outcome studies. Agents evaluated in such studies and that appear to have effects independent of blood pressure lowering include irbesartan, losartan, ramipril, and telmisartan. Taken together, this body of evidence indicates that the clinical benefits of ARBs and ACE inhibitors in patients with advanced nephropathy extend beyond blood pressure reduction. Therefore, although antihypertensive efficacy is of primary importance in choosing a treatment to provide cardiovascular and renal protection, consideration should be given to the effects of an agent that extend beyond blood pressure.

Angiotensin receptor blockers: baseline therapy in hypertension?

The provocative editorial by Verma and Strauss in the BMJ 5 years ago1 stating that angiotensin receptor blockers (ARBs) ‘may increase myocardial infarction—and patients may need to be told’ caused a tempest in the teapot and led to extensive scrutiny of outcome data with this drug class. In 2007 the blood pressure-lowering treatment trialists collaboration found that there were similar blood pressure-dependent effects of angiotensin-converting enzyme (ACE) inhibitors and ARBs for the risk of stroke, coronary heart disease, and heart failure.2 The authors cautioned, however, that only for ACE inhibitors but not for ARBs, was there evidence of a blood pressure-independent effect on the risk of major coronary disease events. Also, ONTARGET, a thorough, double-blind prospective randomized trial, documented equal outcome efficacy of an ARB and an ACE inhibitor in a high-risk population, although there was a trend for better stroke prevention in the ARB (telmisartan) arm and better coronary artery disease prevention in the ACE inhibitor (ramipril) arm.3 When analysing these studies and including the most recent ARB trials such as TRANSCEND,4 PRoFESS,5 CASE-J trial,6 HIJ-CREATE,7 JIKEI,8 and KYOTO,9 we found, in a database of ∼100 000 patients from 26 randomized non-heart failure trials of ARBs, a 13% reduction in the risk of stroke ( P = 0.022) ( Figure 1 ) but a trend towards increased risk of myocardial infarction, especially when compared with active treatment ( P = 0.06) ( Figure 2 ). Figure 1 Odds ratio for stroke. There was a significant reduction in the risk of stroke with …

Blood pressure-independent effects of enhanced NO/cGMP signalling and gender on aortic remodelling in experimental renal hypertension

Results SNX led to increases in systolic blood pressure, with lower levels in F rats (F-SNX 129 ± 13 mmHg vs. M-SNX 140 ± 11 mmHg). Bay 41-8543 and hydralazine reduced blood pressure to control levels. Aortic remodelling was characterized by marked media thickening in both SNX groups, with a more pronounced increase in M versus F (127 ± 9 vs. 108 ± 6% of control; p < 0.001). Intima-media ratio was reduced in both uremic groups, with significant sex differences (M-SNX 66 ± 7% vs. F-SNX 80 ± 8% of control; p < 0.01). Furthermore, gender differences were observed in media-to-lumen ratio as indicator of aortic hypertrophy. The ratio was significantly higher in SNX males only (M-SNX 131 ± 9% vs. F-SNX 107 ± 15% of control; p < 0.001). Bay 41-8543 significantly ameliorated media thickness (111 ± 10 vs. 127 ± 9% of control in M; 101 ± 7 vs. 108 ± 6% of control in F; p < 0.05), intima-media ratio (85 ± 10 vs. 66 ± 7% of control in M; 91 ± 6 vs. 80 ± 8% of control in F, p < 0.01) and media-to-lumen ratio (107 ± 9 vs. 131 ± 9% of control in M; p < 0.001). Despite a similar reduction in blood pressure, hydralazine treatment did not alter aortic wall remodelling. These morphological changes were accompanied by elevated collagen I and reduced elastin protein expression at the level of aortic media, with decreased elastin/collagen ratio in untreated SNX groups, as marker of aortic wall stiffening. Bay 41-8543 treatment successfully prevented these molecular alterations (collagen I protein expression: 9.4 ± 0.3 vs. 14.5 ± 1.1% in females and 9.6 ± 0.4 vs. 16.1 ± 1.0% in males), while hydralazine showed no effects. SNX was characterized by increased extracellular matrix turnover with up-regulation of MMP2 and TIMP1 genes, more pronounced in males than in females (M-SNX 1.8 ± 0.1 vs. F-SNX 1.1 ± 0.1 for MMP2; M-SNX 4.2 ± 0.8 vs. F-SNX 2.7 ± 0.6 for TIMP1; both expressed as relative values vs. controls). In the male Bay 41-8543-treated group, expression of these genes was significantly lower (1.4 ± 0.1 MMP2from 4th International Conference of cGMP Generators, Effectors and Therapeutic Implications Regensburg, Germany. 19–21 June 2009

Antihypertensive treatment and stroke prevention: are angiotensin receptor blockers superior to other antihypertensive agents?

Stroke remains a common vascular event with high mortality and morbidity. After heart disease, stroke is the second leading cause of death worldwide in adult persons. Silent or subclinical stroke is likely to occur with even greater frequency than clinical stroke and increases the risk of subsequent cerebrovascular events. Hypertension is by far the single most important controllable risk factor for stroke. The relationship between blood pressure (BP) and stroke mortality is strong, linear, and continuous in subjects with levels of BP higher than 115/75 mm Hg. Blood pressure reduction by antihypertensive treatment is clearly efficacious in the prevention of stroke (both primary and secondary). Although meta-analyses suggest that BP reduction, per se, is the most important determinant for stroke risk reduction, the question is if specific classes of antihypertensive drugs offer special protection against stroke is still controversial. Some studies have suggested that angiotensin receptors blockers (ARBs) appear to offer additional protection against stroke. This has been hypothesized in studies in hypertensives, such as LIFE and SCOPE, and especially in the only comparative trial focused on secondary stroke prevention. In the MOSES trial, the comparison of eprosartan versus nitrendipine in patients with a previous stroke resulted, despite a similar BP reduction, in a significant reduction in the primary composite endpoint of total mortality plus cardiovascular and cerebrovascular events, including recurrent events. These results may suggest a blood pressure-independent effect of ARBs, which can be mediated through several mechanisms, including their ability to counteract other markers of target organ damage, but also through a direct neuroprotective effect.

High salt intake induces left ventricular interstitial fibrosis by a blood pressure and angiotensin II type 1 receptor‐independent mechanism

ObjectiveTo evaluate the mechanisms of left (LV) and right (RV) ventricular hypertrophy induced by salt overload.Methods18‐week‐old Wistar rats were fed normal (NS: 1.3% NaCl), high 1 (HS1 4%) or high 2 (HS2 8%) salt diet since weaning. Starting on the 7th week of age, two HS2 subgroups received hydralazine or losartan (HZ 15 and LOS 20 mg/kg/day). Tail cuff blood pressure (BP), myocyte transverse diameter (TD), interstitial fibrosis (IF) and angiotensin II type 1 (AT1) receptor and collagen type I (COL 1) protein expression were measured.Results (mean±SEM ‐ p&lt;0.05, n=7‐8/group)At 18th week of age, BP (mmHg) was higher on HS1 (146±2) and HS2 (147±1) than on NS (121±2). BP on HS2+HZ (123±1) and HS2+LOS (120±2) did not differ from NS. TD in the LV was higher on HS1 (14±0.2), HS2 (16±0.5) and HS2+HZ (15±0.2) than on NS (12±0.4) and HS2+LOS (12±0.1). TD in the RV was higher on HS2 (15±0.5) and HS2+HZ (15±0.5) than on NS (12±0.3), HS1 (13±0.5) and HS2+LOS (11±0.1). IF and COL 1 (AU) in the LV and RV were higher on HS1, HS2 and HS2+LOS than on NS and HS2+HZ (COL 1 LV: HS1 1.04±0.05, HS2 1.10±0.01, HS2+HZ 0.91±0.04, HS2+LOS 1.02±0.02 and NS 0.87±0.02). AT1 (AU) in the LV and RV was higher on HS2, HS2+HZ than NS, HS1 and HS2+LOS (AT1 LV: HS2 1.1±0.02, HS2+HZ 1.1±0.01, HS2+LOS 0.9±0.02 and NS 0.9±0.08).ConclusionsHS leads to LV hypertrophy by a BP independent effect. It can be speculated that the effect of HS on TD and IF is due to different mechanisms.FAPESP

Protective effects of renin–angiotensin blockade beyond blood pressure control

Antihypertensive drugs exert a number of blood pressure-independent benefits. However, demonstrating the clinical significance of these effects may be difficult for a number of reasons. First, blood pressure can be measured in the clinic, at home and over the 24-h period by ambulatory monitoring. Second, differences between these measures mean that achieving equivalent blood pressure reductions in two treatment arms may be difficult, if not impossible. Furthermore, even small differences in blood pressure can translate into significant effects on cardiovascular risk, especially in the later stages of the cardiovascular continuum. In large clinical trials, other errors limiting the sensitivity to treatment differences include high patient dropouts and unplanned crossover. In addition, as so many patients fail to achieve blood pressure goals even in clinical trials where patient's and physician's motivation is high, the need for cardiovascular protection beyond blood pressure control is unequivocal. Clinical trials of angiotensin II receptor blockers have suggested significant effects beyond blood pressure control, which are observed throughout and with greater consistency in the early phases of the cardiovascular continuum. There may also be differences between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors. Conclusive demonstration that these blood pressure-independent effects do exist will require, however, a much more accurate and extended assessment of the blood pressure effects of the drugs.

Hypertension

The field of hypertension has enjoyed some remarkable successes in recent years. Better blood pressure management has been an important contributor to the recent rapid decline in the age-adjusted death rates for coronary heart disease (CHD) and stroke.1 Yet, there is yet so much more that could be accomplished through better blood pressure management. CHD and stroke remain the first and third leading causes of death in the United States.2 And only slightly more than a third of those with hypertension in the United States achieve recommended treatment goal blood pressure levels.3 Control rates are even worse in most other countries.4 Better blood pressure management can save many lives. Here, some pathways to success are considered. Few measurements in medicine are done as poorly and inconsistently as blood pressure measurement. Methods used today in clinical practice and in clinical trials are little changed from the earliest days of measurement.5 Though there is a clear recognition of biological variability, we continue to make decisions largely on measurements taken at random times under poorly controlled conditions. The measurement process is less regulated than measurement of most other major risk factors. Just compare the quality control process for glucose or cholesterol measurement with that for blood pressure measurement in your own local setting. There are not readily available solutions for this issue. Substantial investments in research in this area should be made by government and commercial entities. We must have reliable, reproducible, convenient, and precise measurement tools for blood pressure. These tools should allow for measurement of the important components of blood pressure and mechanisms for integrating and interpreting influence of time of day, activity, …

Angiotensin II Blockade and Total Cardiovascular Risk

Hypertension is one of the world's largest public health problems and it is both a disease and a risk factor for cardiovascular disease (CVD). The heart, the endothelium and the kidneys are the target organs of hypertension. Recently, several antihypertensive drugs have been introduced to the market; therefore, the choice is mainly determined by the patients' features. In particular, ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) demonstrate a larger reduction in cardiovascular risk than other antihypertensive treatments because of the existence of blood pressure-independent effects. In fact, the angiotensin II pathway plays a major role in metabolic, haemodynamic and endothelial homeostasis. For these reasons, ACE inhibitors and ARBs have primary indications in patients with obesity, hypercholesterolaemia and diabetes mellitus because of their favourable metabolic properties. Furthermore, several large trials have demonstrated that they have favourable effects also in patients with left ventricular dysfunction or systolic heart failure, as well as other forms of heart disease. Drugs affecting the angiotensin II pathway may reduce endothelial dysfunction through several mechanisms including reduction of vascular permeability and oxidative stress. Another important effect of these drugs is neuroprotection. This is an important effect because in the near future, due to an aging population, an important goal for optimal antihypertensive treatment will be the prevention of cognitive decline. ACE inhibitors and ARBs are very important drugs in the modern management of the total cardiovascular risk in hypertensive patients.

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n = 28) were treated with 1.0 microg kg(-1) min(-1) ANG II, 3.0 microg kg(-1) min(-1) ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage.

Pathophysiology of Target‐Organ Disease: Does Angiotensin II Remain the Key?

Basic research provides an increasingly compelling rationale for renin-angiotensin system (RAS) blockade in hypertension treatment and cardiovascular risk reduction. Clinical trials addressing blood pressure-independent effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, however, have yielded mixed results, in part because of incomplete RAS blockade. Animal studies have shed new light on the complexity of RAS pathways involved in the induction of target-organ damage. New outcomes trials are under way to explore the full potential of more complete RAS blockade with regard to cardiovascular target-organ protection.

Prevention of Stroke in Patients with Hypertension

Despite the substantial evidence of the benefits of lowering blood pressure, conventional treatment does not normalize the burden of major cardiovascular events in patients with hypertension. Data now suggest that the nature of the antihypertensive agent used may have an important impact on long-term cardiovascular outcomes, including stroke. Optimal treatment should provide powerful 24-hour blood pressure control, including during the early morning hours when the risk of stroke is highest. In addition, antihypertensive therapies selected should have positive blood pressure-independent effects on stroke risk. In contrast to angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers (ARBs) provide consistent benefits in stroke protection beyond blood pressure lowering. The ARB telmisartan has a particularly interesting profile for stroke management. Selective angiotensin II type 1 receptor blockade and 24-hour blood pressure control with telmisartan provide the potential for improved stroke prevention. This will be investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) study.

Complications of hypertension and the role of angiotensin receptor blockers in hypertension trials

Hypertension is a high-prevalence disease that may affect several organs. In recent years, data have accumulated indicating that angiotensin II receptor blockers (ARBs) may have a supplementary effect beyond lowering blood pressure. The aim of this review is to evaluate the impact of ARBs on the most important complications of hypertension – heart, cerebrovascular and renal diseases, and metabolic complications – based on the findings from large clinical hypertension trials. The results may indicate that ARBs have a superior effect compared with placebo or other antihypertensive drugs in order to prevent left ventricular hypertrophy, atrial fibrillation, stroke, renal disease and diabetes mellitus, while there appears to be no blood pressure-independent superior effect of ARBs regarding prevention of myocardial infarction or heart failure.

Blood pressure-dependent and independent effects of agents that inhibit the renin–angiotensin system

To evaluate the blood pressure-dependent and independent effects of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) on major cardiovascular events. Using data from 26 large-scale trials comparing an ACEI or an ARB with placebo or another drug class, meta-regression analyses were conducted in which treatment-specific relative risks for major cause-specific outcomes [stroke, major coronary heart disease (CHD) events and heart failure] were regressed against follow-up blood pressure differences. From a total of 146 838 individuals with high blood pressure or an elevated risk of cardiovascular disease, 22 666 major cardiovascular events were documented during follow-up. The analyses showed comparable blood pressure-dependent reductions in risk with ACEI and ARB (P >or= 0.3 for all three outcomes). The analyses also showed that ACEI produced a blood pressure-independent reduction in the relative risk of CHD of approximately 9% (95% confidence interval 3-14%). No similar effect was detected for ARB, and there was some evidence of a difference between ACEI and ARB in this regard (P = 0.002). For both stroke and heart failure there was no evidence of any blood pressure-independent effects of either ACEI or ARB. There are similar blood pressure-dependent effects of ACEI and ARB for the risks of stroke, CHD and heart failure. For ACEI, but not ARB, there is evidence of blood pressure-independent effects on the risk of major coronary disease events.

Endothelin-receptor antagonists in arterial hypertension: Further indications?

Endothelin-1 exerts vasoactive, pro-inflammatory, hypertrophic, and profibrotic properties on the heart, kidney, and blood vessels. Hence, endothelin-receptor antagonists hold the potential to reduce blood pressure and to prevent complications of hypertension, atherosclerosis, and diabetes through blood pressure-independent effects on cardiovascular growth, inflammation, and fibrosis. These potentially important effects of endothelin antagonism may contribute to its therapeutic potential in hypertension and other cardiovascular disorders, including chronic renal failure and diabetes. First clinical trial evidence demonstrates a moderate reduction in blood pressure in studies of patients with mild-to-moderate essential hypertension and patients with resistant hypertension. Future large-scale randomized clinical trials will provide more insight into whether the blood-pressure reduction and promising pleiotropic effects observed with several members of this novel class of drugs, which are already established therapy in pulmonary hypertension, will translate into clinical benefit in patients with arterial hypertension.

Spironolactone improves structure and increases tone in the cerebral vasculature of male spontaneously hypertensive stroke-prone rats

Background Previous studies show that ischemic cerebral infarct size is related to cerebral vessel structure. Spironolactone, a mineralocorticoid receptor antagonist, decreases ischemic cerebral infarct size in male spontaneously hypertensive stroke-prone rats (SHRSP). Therefore, we hypothesized that chronic spironolactone treatment would improve cerebral artery structure in the SHRSP. Methods Six-week-old male SHRSP were treated with spironolactone (2.5 mg/day) for 6 weeks and were compared to untreated control SHRSP and normotensive Wistar Kyoto (WKY) rats. Using a pressurized arteriograph, structural measurements of the middle cerebral artery (MCA) were taken under passive (calcium-free), zero-flow conditions. Myogenic tone was calculated from active and passive measurements taken at 75 and 125 mmHg. Mean arterial pressure was measured using radiotelemetry. Results Myogenic tone was increased only at 75 mmHg in the spironolactone-treated SHRSP compared to control rats. The MCA lumen and outer diameters were increased in the spironolactone-treated SHRSP compared to control SHRSP, but were not different from WKY rats, indicating a decrease in vascular remodeling. There was no effect of spironolactone on blood pressure, suggesting that this is a blood pressure-independent effect. Conclusion Increased myogenic tone and lumen diameter in the spironolactone-treated SHRSP may be responsible for the protective role of spironolactone in ischemic stroke.