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Context: Although the long-term goal of antihypertensive therapy is to reduce adverse clinical outcomes, the only way to evaluate the efficacy of treatment in an individual is the magnitude of blood pressure (BP) reduction. ACE inhibitors and angiotensin receptor blockers (ARBs) are two drug classes that, by different mechanisms, inhibit the renin-angiotensin- aldosterone system that regulates BP. As these drugs are widely prescribed for hypertension, it is essential to determine and compare their effects on BP, heart rate and tolerability. Objectives: 1) To determine the dose-related effect of ACE inhibitors and ARBs on BP, heart rate and withdrawals due to adverse effects (WDAE), compared with placebo in the treatment of primary hypertension (SBP ≥ 140 mm Hg and/or ≥ DPB 90 mm Hg); and 2) To compare the relative effect on BP, heart rate and WDAE of a) each ACE inhibitor with other ACE inhibitors, b) each ARB with other ARBs, and c) all ACE inhibitors with all ARBs. Methods: Two systematic reviews of published, double-blind, randomized, controlled trials (RCTs) evaluating the BP lowering efficacy of fixed dose monotherapy with an ACE inhibitor or ARB compared with placebo for a duration of 3 to 12 weeks in patients with primary hypertension were conducted. Electronic databases were searched for RCTs and similar trial inclusion criteria and methods of analysis were used in both reviews. Results: Ninety two RCTs evaluated the dose-related BP lowering efficacy of 14 ACE inhibitors in 12 954 participants with a baseline BP of 157.1/101.2 mm Hg. Forty six RCTs evaluated the dose-related BP lowering efficacy of 9 ARBs in 13 451 participants with a baseline BP of 155.6/101.0 mm Hg. The best estimate of the near maximal trough BP reduction for ACE inhibitors and ARBs was -8/-5 mm Hg and -8/-5 mm Hg, respectively. ACE inhibitors and ARBs do not affect heart rate. The evidence for short-term WDAE (tolerability) was incomplete and weak and did not demonstrate a difference between the two classes of drugs. Conclusion: ACE inhibitors and ARBs are not different individually or as drug classes in BP lowering efficacy.

Context: Although the long-term goal of antihypertensive therapy is to reduce adverse clinical outcomes, the only way to evaluate the efficacy of treatment in an individual is the magnitude of blood pressure (BP) reduction. ACE inhibitors and angiotensin receptor blockers (ARBs) are two drug classes that, by different mechanisms, inhibit the renin-angiotensin- aldosterone system that regulates BP. As these drugs are widely prescribed for hypertension, it is essential to determine and compare their effects on BP, heart rate and tolerability. Objectives: 1) To determine the dose-related effect of ACE inhibitors and ARBs on BP, heart rate and withdrawals due to adverse effects (WDAE), compared with placebo in the treatment of primary hypertension (SBP ≥ 140 mm Hg and/or ≥ DPB 90 mm Hg); and 2) To compare the relative effect on BP, heart rate and WDAE of a) each ACE inhibitor with other ACE inhibitors, b) each ARB with other ARBs, and c) all ACE inhibitors with all ARBs. Methods: Two systematic reviews of published, double-blind, randomized, controlled trials (RCTs) evaluating the BP lowering efficacy of fixed dose monotherapy with an ACE inhibitor or ARB compared with placebo for a duration of 3 to 12 weeks in patients with primary hypertension were conducted. Electronic databases were searched for RCTs and similar trial inclusion criteria and methods of analysis were used in both reviews. Results: Ninety two RCTs evaluated the dose-related BP lowering efficacy of 14 ACE inhibitors in 12 954 participants with a baseline BP of 157.1/101.2 mm Hg. Forty six RCTs evaluated the dose-related BP lowering efficacy of 9 ARBs in 13 451 participants with a baseline BP of 155.6/101.0 mm Hg. The best estimate of the near maximal trough BP reduction for ACE inhibitors and ARBs was -8/-5 mm Hg and -8/-5 mm Hg, respectively. ACE inhibitors and ARBs do not affect heart rate. The evidence for short-term WDAE (tolerability) was incomplete and weak and did not demonstrate a difference between the two classes of drugs. Conclusion: ACE inhibitors and ARBs are not different individually or as drug classes in BP lowering efficacy.

Boston University. University Professors Program Senior theses. / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2031-01-02

Context: Although the long-term goal of antihypertensive therapy is to reduce adverse clinical outcomes, the only way to evaluate the efficacy of treatment in an individual is the magnitude of blood pressure (BP) reduction. ACE inhibitors and angiotensin receptor blockers (ARBs) are two drug classes that, by different mechanisms, inhibit the renin-angiotensin- aldosterone system that regulates BP. As these drugs are widely prescribed for hypertension, it is essential to determine and compare their effects on BP, heart rate and tolerability. Objectives: 1) To determine the dose-related effect of ACE inhibitors and ARBs on BP, heart rate and withdrawals due to adverse effects (WDAE), compared with placebo in the treatment of primary hypertension (SBP ≥ 140 mm Hg and/or ≥ DPB 90 mm Hg); and 2) To compare the relative effect on BP, heart rate and WDAE of a) each ACE inhibitor with other ACE inhibitors, b) each ARB with other ARBs, and c) all ACE inhibitors with all ARBs. Methods: Two systematic reviews of published, double-blind, randomized, controlled trials (RCTs) evaluating the BP lowering efficacy of fixed dose monotherapy with an ACE inhibitor or ARB compared with placebo for a duration of 3 to 12 weeks in patients with primary hypertension were conducted. Electronic databases were searched for RCTs and similar trial inclusion criteria and methods of analysis were used in both reviews. Results: Ninety two RCTs evaluated the dose-related BP lowering efficacy of 14 ACE inhibitors in 12 954 participants with a baseline BP of 157.1/101.2 mm Hg. Forty six RCTs evaluated the dose-related BP lowering efficacy of 9 ARBs in 13 451 participants with a baseline BP of 155.6/101.0 mm Hg. The best estimate of the near maximal trough BP reduction for ACE inhibitors and ARBs was -8/-5 mm Hg and -8/-5 mm Hg, respectively. ACE inhibitors and ARBs do not affect heart rate. The evidence for short-term WDAE (tolerability) was incomplete and weak and did not demonstrate a difference between the two classes of drugs. Conclusion: ACE inhibitors and ARBs are not different individually or as drug classes in BP lowering efficacy. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Introduction: Angiotensin 2 is a biologically active octapeptide known to bind with high affinity to two separate receptors, angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R). The two receptors can be seen having opposite effects when activated. The effects of AT2R activation oppose the pathophysiological effects of AT1R and causes vasodilation, anti-inflammatory and anti-fibrotic effects. The first non-peptide selective AT2R agonist compound 21(C21) has as of recent entered phase two clinical trials for the indication idiopathic pulmonary fibrosis. Two novel newly synthesized non-peptide compounds MH280 and MH727 which exert AT2R selectivity have been evaluated. The data regarding these compounds is limited and the compounds are still being investigated. MH280 was tested as an antagonist to complement previous work, while MH727 was tested as an agonist and an antagonist on AT2R in mouse thoracic aortic vessels. Method: Isolated mouse thoracic aortic vessels was used to assess the functional cardiovascular effects of compounds MH280 and MH727 in vitro. The thoracic aortic vessel was used to determine whether the compound could contract the vessel indicating agonistic effect or blocking a vasorelaxant effect indicating antagonistic effect. Result: MH280 could not be seen abolishing the effects of C21-mediated vasorelaxation in mouse thoracic aortic vessels. MH727 evoked a concentration-dependent relaxation in mouse thoracic aortic vessels. MH727 caused a relaxation of 89.9% which was very similar to the relaxations by C21 which was 86.2 ± 8.6%. The compound could not be seen abolishing the effects of C21 when tested for antagonistic effects. Additionally, the concentration-dependent vasorelaxant effect of MH727 was abolished in the presence of the AT2R antagonist PD123319. Conclusion: Both MH280 and MH727 compounds seem to exert agonistic behavior which is believed to be caused by the stimulation of AT2R in isolated thoracic aortic vessels

Research Objectives Heart failure (HF) is a common condition in persons older than 65 years. Existing literature indicated that hospital readmission rates after discharge for heart failure patients are immensely high. However, previous studies showed that almost half of the early hospital readmissions could be prevented. Moreover, Angiotensin-converting enzyme (ACE) inhibitor and Angiotensin receptor blocker (ARB) are the commonly used medications for heart failure patients to control blood pressure. Nevertheless, studies indicated that these two medications could also cause the risk of hospital readmission. Little studies examined the associations of medication use and hospital readmission of heart failure patients in Taiwan. This study aims to investigate the influence factors of hospital readmissions among heart failure patients in Taiwan. Study Design We collected the data from National Health Insurance (NHI) database during the period from year 2000 to 2006. Based on the rule of Bureau of National Health Insurance in Taiwan, the 14-day readmission is considered as a poor quality indicator. We categorized readmissions into 4 groups (14-day, 30-day, 180-day and over 180-day) and evaluated each group¡¦s demographic, hospital characteristics, medical resource utilization, Charlson Comorbidity Index and medication utilizations of ACE inhibitor and ARB. We conducted descriptive analyses by using chi-square and t tests and applied multivariate logistic regression analyses to estimate the probabilities of hospital readmissions of heart failure patients. Population Studied Patients aged 50 or older with heart failure were identified based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Principle Findings Among 1920 heart failure patients, 19.9% of them were readmitted within 14 days, 7.6% were readmitted within 30 days and 26% were readmitted within 180 days. The medical resource utilizations such as average inpatients cost per patient, average outpatients cost per patient, total medical cost, average of inpatients times per patient and average of outpatients times per patient were significantly higher in patients with readmissions than those without readmission. Age, Charlson Comorbidity Index, patients who had been treated with ACE inhibitors and patients who had been treated with ARB were significantly affected the probabilities of readmissions. Conclusion The heart failure patients with readmissions had significantly higher medical resource utilizations than those without readmission. The medication uses of ACE inhibitors or ARB were significantly affected the probabilities of hospital readmissions. By understanding more about the influence factors of readmissions among heart failure patients, we may provide continue improvements of quality of care and reduce unnecessary medical costs. This study results provide useful reference for policy-makers to establish effective disease management program and appropriate health care financing arrangement in the future.

The purpose of this study was to determine whether androgen promotes AT1aR expression on smooth muscle to confer high prevalence of AngII-induced AAAs in hyperlipidemic mice. In addition, we also investigate the role of androgen in the progression of established AngII-induced AAAs. First, we sought to examine the role of endogenous androgen in the growth of established AngII-induced AAAs. By castrating male mice, we demonstrated that removal of endogenous androgen significantly decreased the progressive lumen dilation of established AngII-induced AAAs in male ApoE-/- mice, but had no effect on external AAA diameters. These results suggest that androgen contributes to the progression of established AAAs through distinct mechanisms that differentially influence aortic lumen and wall diameters. We also investigate whether androgen regulates aortic AT1aR expression to promote AngII-induced AAA formation. Our data demonstrated that in male and female mice, both endogenous and exogenous androgen stimulate AT1aR level particularly in abdominal aortas. This androgen-dependent enhanced expression of abdominal aortic AT1aR was correlated with increased AngIIinduced AAA formation in male and female mice. Smooth muscle AT1aR deficiency significantly reduced luminal and external diameters of abdominal aortas as well as the incidence of AngII-induced AAAs in adult female mice administered exogenous androgen. Collectively, these results indicate that in adult mice androgen stimulate smooth muscle AT1aR expression to promote AngII-induced AAA formation. To determine the role of androgen during development on AT1aR expression on SMC and AngII-induced vascular pathologies, we exposed neonatal female mice to one single dose of testosterone. Our data demonstrated that neonatal testosterone administration dramatically increased AngII-induced AAA, atherosclerosis and ascending aortic aneurysms in adult female mice. In addition, smooth muscle AT1aR deficiency reduced effects of neonatal testosterone to promote AAAs, but had no effect on the other two AngII-induced vascular pathologies. In summary, our findings demonstrated that androgen, both in adult life and during development, stimulate smooth muscle AT1aR expression and promote AngII-induced AAA in female hyperlipidemic mice.

Background: Amiodarone (AM) is a widely used anti-arrhythmic medication. Its utility is, however, limited by adverse side effects. The mechanism of amiodarone-induced toxicity (APT) in the lungs is attributed primarily to stimulation of the angiotensin enzyme system leading to lung cell apoptosis and cell death. This mechanism has been demonstrated by in vitro and in vivo experimental animal studies. To date, however, no in vivo human studies have confirmed this mechanism for APT. Purpose: This study was undertaken to determine whether angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) offer a protective effect against APT in humans. Demonstration of a protective effect of an ACE-I or ARB would suggest that stimulation of the angiotensin enzyme system may be a key process in APT. Design: An 8-year retrospective analysis of all patients on AM therapy at the James H. Quillen Veterans Affairs Medical Center was undertaken. Results: A total of 1000 patients on AM were identified. One-hundred-and-seventeen were excluded from the study. Five-hundred-and-twenty-four patients were simultaneously on an ACE-I or ARB. The remaining 359 patients were not. Pulmonary toxicity attributed to AM was identified in five and 14 patients with and without concomitant ACE-I or ARB therapy, respectively. The APT rate for the entire patient sample was 2.2%. APT occurred in 1% of patients on an ACE-I or ARB and in 3.9% of patients not taking an ACE-I or ARB. This observed difference in percentage of APT was statistically significant. Conclusion: The concomitant use of ACE-I or ARB in patients taking AM appears to offer a protective effect against APT. This observation suggests that the stimulation of the angiotensin enzyme system may play an important role in APT in humans.

Orientadores: José Antonio Rocha Gontijo, Konradin Metze / Tese (doutorado) - Universidade Estadual de Campinas. Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-16T09:14:09Z (GMT). No. of bitstreams: 1 Borges_RafaeldeCamargoPenteado_D.pdf: 2255338 bytes, checksum: 0a8e55e3d0ad46a2d03da9d085f9fc64 (MD5) Previous issue date: 2010 / Resumo: A hipertensão arterial (HA) é um dos principais fatores de risco para a elevada morbidade e mortalidade cardiovascular. O exercício físico aeróbico promove alterações fisiológicas e morfológicas importantes para o controle da HA mediados pelo sistema renina angiotensina (SRA), porém muitos destes mecanismos continuam obscuros. Foram utilizados 80 animais, SHR (n=40) e WKy (n=40), controle (c) (n=20) e exercício (e) (n=20), com acesso livre a ração padrão e água, em um ciclo dia/noite 12h cada. Os animais SHRe e WKye realizaram treinamento de natação com sobrecarga durante 8 semanas consecutivas. Ao término do período experimental, foram aferidas a freqüência cardíaca (FC), pressão arterial sistólica (PAS) e manipulação tubular de sódio. Após o período experimental os animais (n=12 por grupo) foram perfundidos para análise morfológica da aorta (Ao), artéria mesentérica (AMes) e massa cardíaca (MCard), e para análise de western blotting (WB) (n=8 por grupo) para Ao, ventrículo esquerdo (VE) e rim. Os animais WKye e SHRe responderam com uma redução significativa (p<0,05) da FC, sendo que, o SHRe reduziu (p<0,05) a PAS quando comparado ao SHRc. A fração de excreção de sódio e fração de excreção pós proximal de sódio apresentaram-se aumentadas (p<0,05) para SHRe e reduzidas (p<0,05) para WKye. As análises morfológicas indicaram que os animais Wkye aumentaram (p<0,05) o número de camadas da Ao e MCard, e reduziram (p<0,05) a distância média entre camadas da AMes; enquanto os SHRe aumentaram a MCard (p<0,05), porém reduziram (p<0,05) o número de camadas da Ao e a espessura total da AMes. As análises de WB demonstraram que os WKye tiveram um aumento (p<0,05) da razão AT1R/AT2R no VE e Ao, e redução (p<0,05) no rim, enquanto os SHRe tiveram um aumento (p<0,05) da razão AT1R/AT2R somente no VE, e redução (p<0,05) na Ao e rim. As alterações morfológicas da Ao no Wkye foram promovidas pelo aumento (p<0,05) das vias ERK1, ERK2 e AKT, no VE pela ERK2, e no rim mediado pela via JAK2/STAT3. Já nos animais SHRe as alterações na Ao foram mediadas pela redução (p<0,05) da via ERK1 e ERK2, no VE pelo aumento (p<0,05) da via ERK2 e no rim pelo aumento (p<0,05) das vias ERK1, ERK2 e STAT3. Este estudo evidenciou que o exercício promoveu mecanismos distintos para manipulação tubular de sódio, adaptações morfológicas da Ao, AMes e MCard mediados pela razão AT1R/AT2R e hemodinâmicas em normotensos e hipertensos, este com redução de PAS, através do SRA atuante de forma sistêmica e localizada através de sinalização intracelular mediada por AKT, ERK1 e ERK2, JAK2 e STAT3 / Abstract: Systemic hypertension is one of the main risk factors for the high morbidity and mortality. Aerobic exercise promotes important morphological and physiological changes for the hypertension control mediated by renin angiotensin system (RAS), however many of these mechanisms are still obscure. 80 animals were used, SHR (n = 40) and WKy (n = 40), (c) (n = 20) and (e) (n = 20), with free access to standard rat chow and tap water in a day/night cycle 12 each. Animals SHRe and WKye practiced swimming with overload for 8 consecutive weeks. At the end of the experimental period, was measured the heart rate (HR), systolic blood pressure (SBP) and tubular sodium handling. After the experimental period animals (n = 12 per group) have been perfused for segmentation of the aorta (Ao), mesenteric artery (MesA) and cardiac mass (CardM), and for analysis of western blotting (WB) (n = 8 per group) to the Ao, left ventricle, (LV) and kidney. Animals WKye and SHRe replied with a significant reduction (p<0,05) to HR, were, SHRe reduced (p<0,05) the SBP when compare with SHRc. The fraction of sodium excretion and fraction of post proximal sodium excretion showed a increase (p<0,05) for SHRe and reduction (p<0,05) for WKye. The morphological analysis indicated that Wkye animals increased (p<0,05) the Ao layers number and CardM, and reduced (p<0,05) the distance between layers of MesA; while the SHRe increased the CardM (p<0,05), but reduced (p<0,05) the layers number of Ao and the total thickness of MesA. The WB analysis, showed that Wkye answered with the increase (p<0,05) in AT1/AT2 ratio in LV and Ao, and a decrease (p<0,05) in kidney, during SHRe answer only with an increase (p<0,05) of AT1/AT2 ratio in LV, and reduction (p<0,05) in Ao and kidney. The morphologic alterations of Ao in WKye was promoted by increase (p<0,05) of ERK1, ERK2 and AKT stream, in the LV by ERK2, and in the kidney the increase (p<0,05) by ERK1, ERK2 and STAT3. This study showed that the exercise promoted different mechanisms for tubular sodium handling, morphological adaptations to MesA and CardM mediated by AT1R/AT2R ratio and hemodynamic in normotensive and hypertensive rats, which answer with SBP reduction by RAS acts of systemic form and located by intracellular signaling mediated AKT, ERK1 and ERK2, JAK2 and STAT3 / Doutorado / Medicina Experimental / Doutor em Fisiopatologia Medica