Aminopeptidase A inhibitors as potential central antihypertensive agents

Overactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental models, such as spontaneously hypertensive rats and transgenic mice expressing both human renin and human angiotensinogen transgenes. We recently reported that, in the murine brain, angiotensin II (AngII) is converted to angiotensin III (AngIII) by aminopeptidase A (APA), whereas AngIII is inactivated by aminopeptidase N (APN). If injected into cerebral ventricles (ICV), AngII and AngIII cause similar pressor responses. Because AngII is metabolized in vivo into AngIII, the exact nature of the active peptide is not precisely determined. Here we report that, in rats, ICV injection of the selective APA inhibitor EC33 [(S)-3-amino-4-mercaptobutyl sulfonic acid] blocked the pressor response of exogenous AngII, suggesting that the conversion of AngII to AngIII is required to increase blood pressure (BP). Furthermore, ICV injection, but not i.v. injection, of EC33 alone caused a dose-dependent decrease in BP by blocking the formation of brain but not systemic AngIII. This is corroborated by the fact that the selective APN inhibitor, PC18 (2-amino-4-methylsulfonyl butane thiol), administered alone via the ICV route, increases BP. This pressor response was blocked by prior treatment with the angiotensin type 1 (AT1) receptor antagonist, losartan, showing that blocking the action of APN on AngIII metabolism leads to an increase in endogenous AngIII levels, resulting in BP increase, through interaction with AT1 receptors. These data demonstrate that AngIII is a major effector peptide of the brain RAS, exerting tonic stimulatory control over BP. Thus, APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors as central antihypertensive agents.

Genetic polymorphisms and laboratory variables as predictors of blood pressure response to antihypertensive drugs

Hypertension is one of the major risk factors for cardiovascular morbidity. The advantages of antihypertensive therapy have been clearly demonstrated, but only about 30% of hypertensive patients have their blood pressure (BP) controlled by such treatment. One of the reasons for this poor BP control may lie in the difficulty in predicting BP response to antihypertensive treatment. The average BP reduction achieved is similar for each drug in the main classes of antihypertensive agents, but there is a marked individual variation in BP responses to any given drug. The purpose of the present study was to examine BP response to four different antihypertensive monotherapies with regard to demographic characteristics, laboratory test results and common genetic polymorphisms. The subjects of the present study are participants in the pharmacogenetic GENRES Study. A total of 208 subjects completed the whole study protocol including four drug treatment periods of four weeks, separated by four-week placebo periods. The study drugs were amlodipine, bisoprolol, hydrochlorothiazide and losartan. Both office (OBP) and 24-hour ambulatory blood pressure (ABP) measurements were carried out. BP response to study drugs were related to basic clinical characteristics, pretreatment laboratory test results and common polymorphisms in genes coding for components of the renin-angiotensin system, alpha-adducin (ADD1), beta1-adrenergic receptor (ADRB1) and beta2-adrenergic receptor (ADRB2). Age was positively correlated with BP responses to amlodipine and with OBP and systolic ABP responses to hydrochlorothiazide, while body mass index was negatively correlated with ABP responses to amlodipine. Of the laboratory test results, plasma renin activity (PRA) correlated positively with BP responses to losartan, with ABP responses to bisoprolol, and negatively with ABP responses to hydrochlorothiazide. Uniquely to this study, it was found that serum total calcium level was negatively correlated with BP responses to amlodipine, whilst serum total cholesterol level was negatively correlated with ABP responses to amlodipine. There were no significant associations of angiotensin II type I receptor 1166A/C, angiotensin converting enzyme I/D, angiotensinogen Met235Thr, ADD1 Gly460Trp, ADRB1 Ser49Gly and Gly389Arg and ADRB2 Arg16Gly and Gln27Glu polymorphisms with BP responses to the study drugs. In conclusion, this study confirmed the relationship between pretreatment PRA levels and response to three classes of antihypertensive drugs. This study is the first to note a significant inverse relation between serum calcium level and responsiveness to a calcium channel blocker. However, this study could not replicate the observations that common polymorphisms in angiotensin II type I receptor, angiotensin converting enzyme, angiotensinogen, ADD1, ADRB1, or ADRB2 genes can predict BP response to antihypertensive drugs.

Ambulatory blood pressure measurement and antihypertensive therapy.

The traditional basis for assessing the effect of antihypertensive therapy is the blood pressure reading taken by a physician. However, several recent trials have been designed to evaluate the blood pressure lowering effect of various therapeutic agents during the patients' normal daytime activities, using a portable, semi-automatic blood pressure recorder. The results have shown that in a given patient, blood pressure measured at the physician's office often differs greatly from that prevailing during the rest of the day. This is true both in treated and untreated hypertensive patients. The difference between office and ambulatory recorded pressures cannot be predicted from blood pressure levels measured by the physician. Therefore, a prospective study was carried out in patients with diastolic blood pressures that were uncontrolled at the physician's office despite antihypertensive therapy. The purpose was to evaluate the response of recorded ambulatory blood pressure to treatment adjustments aimed at reducing office blood pressure below a pre-set target level. Only patients with high ambulatory blood pressures at the outset appeared to benefit from further changes in therapy. Thus, ambulatory blood pressure monitoring can be used to identify those patients who remain hypertensive only when facing the physician, despite antihypertensive therapy. Ambulatory monitoring could thus help to evaluate the efficacy of antihypertensive therapy and allow individual treatment.

Impact de l'adhésion aux agents antihypertenseurs sur l'incidence des maladies vasculaires cérébrales en prévention primaire

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Antihypertensive treatments obscure familial contributions to blood pressure variation

The linkage and association between inherent blood pressure and underlying genotype is potentially confounded by antihypertensive treatment. We estimated blood pressure variance components (genetic, shared environmental, individual-specific) in 767 adult volunteer families by using a variety of approaches to adjusting blood pressure of the 244 subjects (8.2%) receiving antihypertensive medications. The additive genetic component of variance for systolic pressure was 73.9 mm Hg(2) (SE, 8.8) when measured pressures (adjusted for age by gender within each generation) were used but fell to 61.4 mm Hg(2) (SE, 8.0) when treated subjects were excluded. When the relevant 95th percentile values were substituted for treated systolic pressures, the additive genetic component was 81.9 mm Hg(2) (SE, 9.5), but individual adjustments in systolic pressure ranged from -53.5 mm Hg to +64.5 mm Hg (mean, +17.2 mm Hg). Instead, when 10 mm Hg was added to treated systolic pressure, the additive genetic component rose to 86.6 mm Hg(2) (SE, 10.1). Similar changes were seen in the shared environment component of variance for systolic pressure and for the combined genetic and shared environmental (ie, familial) components of diastolic pressure. There was little change in the individual-specific variance component across any of the methods. Therefore, treated subjects contribute important information to the familial components of blood pressure variance. This information is lost if treated subjects are excluded and obscured by treatment effects if unadjusted measured pressures are used. Adding back an appropriate increment of pressure restores familial components, more closely reflects the pretreatment values, and should increase the power of genomic linkage and linkage disequilibrium analyses.

A comparison between diuretics and angiotensin-receptor blocker agents in patients with stage I hypertension (PREVER-treatment trial): Study protocol for a randomized double-blind controlled trial

Background: Cardiovascular disease is the leading cause of death in Brazil, and hypertension is its major risk factor. The benefit of its drug treatment to prevent major cardiovascular events was consistently demonstrated. Angiotensin-receptor blockers (ARB) have been the preferential drugs in the management of hypertension worldwide, despite the absence of any consistent evidence of advantage over older agents, and the concern that they may be associated with lower renal protection and risk for cancer. Diuretics are as efficacious as other agents, are well tolerated, have longer duration of action and low cost, but have been scarcely compared with ARBs. A study comparing diuretic and ARB is therefore warranted.Methods/design: This is a randomized, double-blind, clinical trial, comparing the association of chlorthalidone and amiloride with losartan as first drug option in patients aged 30 to 70 years, with stage I hypertension. The primary outcomes will be variation of blood pressure by time, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new subclinical atherosclerosis and sudden death. The study will last 18 months. The sample size will be of 1200 participants for group in order to confer enough power to test for all primary outcomes. The project was approved by the Ethics committee of each participating institution.Discussion: The putative pleiotropic effects of ARB agents, particularly renal protection, have been disputed, and they have been scarcely compared with diuretics in large clinical trials, despite that they have been at least as efficacious as newer agents in managing hypertension. Even if the null hypothesis is not rejected, the information will be useful for health care policy to treat hypertension in Brazil. Clinical trials registration number: ClinicalTrials.gov: NCT00971165. © 2011 Fuchs et al; licensee BioMed Central Ltd.

Effects of antihypertensive drugs on blood pressure and proteinuria in childhood

BACKGROUND: Historically, there have been few drug trials for antihypertensive treatment in childhood and recommendations have been extrapolated from data obtained in adulthood. During the last decade an increased awareness of the risks of childhood hypertension stimulated clinical trials of antihypertensive agents in children. OBJECTIVE: The aim of this article is to systematically review the studies published between 1995 and 2006 that deal with the effect of antihypertensive drugs on childhood hypertension or proteinuria. METHODS: Medline, Current Contents, personal files and reference lists were used as data sources. RESULTS: Fifty-two out of 79 initially found reports were excluded. Consequently 27 articles were retained for the final analysis. The blood pressure reduction was similar with angiotensin-converting enzyme inhibitors (10.7/8.1 mmHg), angiotensin II receptor antagonists (10.5/6.9 mmHg) and calcium-channel blockers (9.3/7.2 mmHg). In addition angiotensin-converting enzyme inhibitors (by 49%) and angiotensin II receptor antagonists (by 59%) significantly reduced pathological proteinuria. CONCLUSIONS: The blood pressure reduction of angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists and calcium-channel blockers is almost identical. In children with pathological proteinuria angiotensin-converting enzyme inhibitors or angiotensin II antagonists are superior to calcium-channel blockers.

Hypertension, antihypertensive treatment and cancer incidence and mortality : a pooled collaborative analysis of 12 Australian and New Zealand cohorts

BACKGROUND: Observational studies examining associations between hypertension and cancer are inconsistent. We explored the association of hypertension, graded hypertension and antihypertensive treatment with cancer incidence and mortality. METHOD: Eighty-six thousand five hundred and ninety-three participants from the Australian and New Zealand Diabetes and Cancer Collaboration were linked to the National Death Index and Australian Cancer Database. Cox proportional hazards models estimated hazard ratios and 95% confidence intervals (95% CI) for the association of treated and untreated hypertension with cancer incidence and mortality. RESULTS: Over a median follow-up of 15.1 years, 12 070 incident and 4350 fatal cancers were identified. Untreated and treated hypertension, compared with normotension, were associated with an increased risk for cancer incidence [hazard ratio 1.06, 95% CI (1.00-1.11) and 1.09 (1.02-1.16) respectively], and cancer mortality (1.07, 0.98-1.18) and (1.15, 1.03-1.28), respectively. When compared with untreated hypertension, treated hypertension did not have a significantly greater risk for cancer incidence (1.03, 0.97-1.10) or mortality (1.07, 0.97-1.19). A significant dose-response relationship was observed between graded hypertension and cancer incidence and mortality; Ptrend = 0.053 and Ptrend = 0.001, respectively. When stratified by treatment status, these relationships remained significant in untreated, but not in treated, hypertension. CONCLUSION: Hypertension, both treated and untreated, is associated with a modest increased risk for cancer incidence and mortality. Similar risks in treated and untreated hypertension suggest that the increased cancer risk is not explained by the use of antihypertensive treatment.

Cost-effectiveness analysis of a kidney and cardiovascular disease treatment program in an Australian Aboriginal population

The objective of the study was to assess, from a health service perspective, whether a systematic program to modify kidney and cardiovascular disease reduced the costs of treating end-stage kidney failure. The participants in the study were 1,800 aboriginal adults with hypertension, diabetes with microalbuminuria or overt albuminuria, and overt albuminuria, living on two islands in the Northern Territory of Australia during 1995 to 2000. Perindopril was the primary treatment agent, and other medications were also used to control blood pressure. Control of glucose and lipid levels were attempted, and health education was offered. Evaluation of program resource use and costs for follow-up periods was done at 3 and 4.7 years. On an intention-to-treat basis, the number of dialysis starts and dialysis-years avoided were estimated by comparing the fate of the treatment group with that of historical control subjects, matched for disease severity, who were followed in the before the treatment program began. For the first three years, an estimated 11.6 person-years of dialysis were avoided, and over 4.7 years, 27.7 person-years of dialysis were avoided. The net cost of the program was 1,210 dollars more per person per year than status quo care, and dialyses avoided gave net savings of 1.0 million dollars at 3 years and 3.4 million dollars at 4.6 years. The treatment program provided significant health benefit and impressive cost savings in dialysis avoided.

Study protocol: the Adherence and Intensification of Medications (AIM) study--a cluster randomized controlled effectiveness study.

BACKGROUND: Many patients with diabetes have poor blood pressure (BP) control. Pharmacological therapy is the cornerstone of effective BP treatment, yet there are high rates both of poor medication adherence and failure to intensify medications. Successful medication management requires an effective partnership between providers who initiate and increase doses of effective medications and patients who adhere to the regimen. METHODS: In this cluster-randomized controlled effectiveness study, primary care teams within sites were randomized to a program led by a clinical pharmacist trained in motivational interviewing-based behavioral counseling approaches and authorized to make BP medication changes or to usual care. This study involved the collection of data during a 14-month intervention period in three Department of Veterans Affairs facilities and two Kaiser Permanente Northern California facilities. The clinical pharmacist was supported by clinical information systems that enabled proactive identification of, and outreach to, eligible patients identified on the basis of poor BP control and either medication refill gaps or lack of recent medication intensification. The primary outcome is the relative change in systolic blood pressure (SBP) measurements over time. Secondary outcomes are changes in Hemoglobin A1c, low-density lipoprotein cholesterol (LDL), medication adherence determined from pharmacy refill data, and medication intensification rates. DISCUSSION: Integration of the three intervention elements--proactive identification, adherence counseling and medication intensification--is essential to achieve optimal levels of control for high-risk patients. Testing the effectiveness of this intervention at the team level allows us to study the program as it would typically be implemented within a clinic setting, including how it integrates with other elements of care. TRIAL REGISTRATION: The ClinicalTrials.gov registration number is NCT00495794.

Patterns in blood pressure medication use in US incident dialysis patients over the first 6 months.

BACKGROUND: Several observational studies have evaluated the effect of a single exposure window with blood pressure (BP) medications on outcomes in incident dialysis patients, but whether BP medication prescription patterns remain stable or a single exposure window design is adequate to evaluate effect on outcomes is unclear. METHODS: We described patterns of BP medication prescription over 6 months after dialysis initiation in hemodialysis and peritoneal dialysis patients, stratified by cardiovascular comorbidity, diabetes, and other patient characteristics. The cohort included 13,072 adult patients (12,159 hemodialysis, 913 peritoneal dialysis) who initiated dialysis in Dialysis Clinic, Inc., facilities January 1, 2003-June 30, 2008, and remained on the original modality for at least 6 months. We evaluated monthly patterns in BP medication prescription over 6 months and at 12 and 24 months after initiation. RESULTS: Prescription patterns varied by dialysis modality over the first 6 months; substantial proportions of patients with prescriptions for beta-blockers, renin angiotensin system agents, and dihydropyridine calcium channel blockers in month 6 no longer had prescriptions for these medications by month 24. Prescription of specific medication classes varied by comorbidity, race/ethnicity, and age, but little by sex. The mean number of medications was 2.5 at month 6 in hemodialysis and peritoneal dialysis cohorts. CONCLUSIONS: This study evaluates BP medication patterns in both hemodialysis and peritoneal dialysis patients over the first 6 months of dialysis. Our findings highlight the challenges of assessing comparative effectiveness of a single BP medication class in dialysis patients. Longitudinal designs should be used to account for changes in BP medication management over time, and designs that incorporate common combinations should be considered.