O tratamento da hipertensão arterial sistêmica (HAS) mais usual envolve uma abordagem farmacológica baseada, principalmente, na inibição do sistema renina-angiotensinaaldosterona (SRAA). Contudo, outras abordagens têm sido utilizadas com excelentes resultados, como a prescrição de exercícios físicos regulares, principalmente o aeróbio, muitas vezes como terapia coadjuvante ao tratamento farmacológico. No entanto, embora a literatura mostre que a associação dos tratamentos promova maiores reduções da pressão arterial (PA), pouco sabemos sobre os efeitos teciduais e funcionais cardíacos. Portanto, o principal objetivo do estudo foi investigar os efeitos dos tratamentos isolados e associados da inibição do SRAA e do treinamento físico aeróbio sobre a hemodinâmica, morfologia e funcionalidade cardíaca em ratos espontaneamente hipertensos (SHR), bem como sobre a reatividade do leito coronariano e contratilidade do ventrículo esquerdo. Para tanto, a tese foi dividida em dois estudos; o primeiro abordou os efeitos da hipertensão sobre os parâmetros supracitados, e as adaptações promovidas pelo treinamento físico aeróbio; enquanto que no segundo estudo comparamos os efeitos do treinamento físico aeróbio e da inibição do SRAA prescritos de forma isolada ou associada. Foram utilizados ratos Wistar (N=12) e SHR, machos, com 18 semanas de vida (N=24). Os animais foram distribuídos em três grupos: grupo de ratos Wistar normotensos (N=12), grupo de SHR (N=12) tratados com veículo (água) e grupo de SHR (N=12) tratados com maleato de Enalapril (10mg/kg/dia-1) por 10 semanas. A metade de cada grupo foi submetida ao treinamento físico aeróbio por meio da natação durante 10 semanas. Todos os grupos foram submetidos a dois protocolos experimentais; a avaliação morfofuncional do ventrículo esquerdo por meio da ecocardiografia bidimensional convencional, realizada nos animais vivos; e o estudo da reatividade do leito coronariano e da contratilidade do ventrículo esquerdo em corações isolados por meio da técnica de Langendorff. Nossos resultados mostraram que a associação do treinamento físico com o maleato de Enalapril promoveu as reduções mais expressivas da PA. Os resultados da avaliação ecocardiográfica nos animais vivos evidenciaram que os SHR apresentavam importantes alterações morfológicas quando comparados com os normotensos. O treinamento físico teve pouco efeito sobre essas alterações, ao contrário do maleato de Enalapril que modificou diversos parâmetros avaliados. Por sua vez, os resultados da técnica de Langendorff em corações isolados mostraram que os SHR apresentavam maior reatividade ao fluxo coronariano e menor pressão sistólica intraventricular. O treinamento físico e o maleato de Enalapril aumentaram a pressão sistólica intraventricular, e quando comparados, o treinamento físico apresentou maiores valores. A associação dos tratamentos não potencializou os resultados. Em conclusão, no exame ecocardiográfico o tratamento com maleato de Enalapril apresentou resultados mais proeminentes, enquanto que os efeitos do treinamento físico sobre o coração foram melhores evidenciados pela técnica de Langendorff. A associação dos dois tratamentos não apresentou efeitos adicionais sobre os parâmetros avaliados. / The most common systemic arterial hypertension (HBP) treatment involves a pharmacological approach based mainly on the inhibition of the renin-angiotensin-aldosterone system (RAAS). However, other approaches have been used with excellent results, such as the prescription of regular physical exercises, mainly aerobic, often as adjunctive therapy to pharmacological treatment. However, although the literature shows that the combination of treatments promotes greater blood pressure reductions (PA), we know little about the tissue and functional effects of the heart. Therefore, the main objective of the study was to investigate the effects of isolated and associated treatments of RAAS inhibition and aerobic physical training on hemodynamics, morphology and cardiac function in spontaneously hypertensive rats (SHR), as well as on the reactivity of the coronary bed and contractility of the left ventricle. For that, the thesis was divided in two studies; The first addressed the effects of hypertension on the aforementioned parameters, and the adaptations promoted by aerobic physical training; While in the second study we compared the effects of aerobic physical training and inhibition of prescribed RAAS alone or in combination. Male Wistar rats (N = 12) and SHR, 18 weeks of age (N = 24) were used. The animals were divided into three groups: group of normotensive Wistar rats (N = 12), SHR (N = 12) group treated with vehicle (water) and SHR group (N = 12) treated with Enalapril maleate (10 mg / Kg / day-1) for 10 weeks. Half of each group underwent aerobic physical training by swimming for 10 weeks. All groups were submitted to two experimental protocols; The morphofunctional evaluation of the left ventricle using conventional two-dimensional echocardiography performed on live animals; And the study of coronary bed reactivity and left ventricular contractility in isolated hearts by the Langendorff technique. Our results showed that the association of physical training with Enalapril maleate promoted the most significant reductions in BP. The results of the echocardiographic evaluation in the live animals showed that the SHR had important morphological alterations when compared with the normotensive ones. Physical training had little effect on these alterations, unlike Enalapril maleate that modified several parameters evaluated. In turn, results from the Langendorff technique in isolated hearts showed that SHR presented higher reactivity to coronary flow and lower intraventricular systolic pressure. Physical training and Enalapril maleate increased intraventricular systolic pressure, and when compared, physical training presented higher values. The combination of the treatments did not potentiate the results. In conclusion, in the echocardiographic examination the treatment with Enalapril maleate presented more prominent results, whereas the effects of the physical training on the heart were better evidenced by the technique of Langendorff. The combination of the two treatments had no additional effects on the parameters evaluated.

Introduction The consequences of falling can be fatal to elderly. The mortality, morbidity and the risk ofanxiety and depression increases following a fall. Drug prescription is a preventable fall risk,making the association between antihypertensive medications and risk of falling an importantarea of investigation. Aim Compile the results from studies which have examined the effect of initiating or changing theantihypertensive medication on fall risk in people aged 60 years or older. Methods Data sources: MEDLINE and Cochrane databases. Study selection: Original articles ofcohort-, case control-, case crossover-, cross-sectional- and randomized controlled trial type,published between January 2000 and May 2019 and written in English were included. Dataassessment: 6 studies met the criteria and were included. Study quality was assessed for eachstudy. Results Three studies found significant short-term increase in fall risk, regardless of drug type. Onestudy discovered an 18% increase in fall risk for every 5-day gap in treatment. Two studiesevaluated antihypertensive drug types separately and found contradictive results of thiazidediuretics on short-term fall risk. Calcium channel blockers showed a protective effect andbeta blockers an increased risk during the first 3 weeks after initiating treatment. Conclusions No consistent consensus was seen regarding the short-term fall risk in separateantihypertensive drug types, though most studies agree in a short-term risk increase aftergeneral antihypertensive treatment initiation or change.

Background: In the treatment of hypertension, physicians’ attitudes and practice patterns are receiving increased attention as contributors to poor blood pressure (BP) control. Thus, current use of antihypertensive drugs in primary care was analyzed and the association with selected physician and patient characteristics was assessed. Methods: The Hypertension and Diabetes Risk Screening and Awareness (HYDRA) study is a cross-sectional point prevalence study of 45,125 primary care attendees recruited from a representative nationwide sample of 1912 primary care practices in Germany. Prescription frequencies of the various antihypertensive drugs in the individual patients were recorded by the physicians using standardized questionnaires. We assessed the association of patient variables [age, gender; co-morbidities such as diabetes, nephropathy or coronary heart disease (CHD)] and physician variables (general practitioner vs internist, guideline adherence, etc.) with drug treatment intensity and prescription patterns. Results: Of all 43,549 patients for whom a physician diagnosis on hypertension or diabetes was available, 17,485 (40.1%) had hypertension. Of these hypertensive patients, 1647 (9.4%) received no treatment at all, 1191 (6.8%) received non-pharmacological measures only, and 14,647 (83.8%) were given one or more antihypertensive drugs. Drug treatment rates were lower in young patients (16–40 years: 57.4%). BP control was poor: 70.6% of all patients were not normalized, i.e., had BP ≥140/90 mmHg. Antihypertensive treatment was generally intensified with increasing age, or if complications or comorbidities were present. The use of the different drug classes was rather uniform across the various patient subgroups (e.g., by age and gender). Individualized treatment with regard to co-morbidities as recommended in guidelines was not the rule. Adherence to guidelines as self-reported by physicians as well as other physician characteristics (region, training etc.) did not result in more differentiated prescription pattern. Conclusions: Despite the broad armamentarium of drug treatment options, physicians in primary care did not treat hypertension aggressively enough. Treatment was only intensified at a late stage, after complications had occurred. Treatment should be more differentiated in terms of coexisting morbidities such as diabetes, nephropathy, or CHD.

According to the change of Taiwan economic structure, Taiwan is gradually moving into an aging society and more and more population in Taiwan will suffer from chronic disease in the near future. Hypertension is not only the first cause of death among the top ten COD in Taiwan, but is also the major source of other four types of disease in the top ten COD list. Market size for hypertension treatment has enormous potential thus all multi-national pharmaceutical companies seize for opportunities in it. Hypertension treatment research and development are always a priority for pharmaceutical companies and medical research centers, however, new compound takes a long time to develop and patent protection period is getting shorter, therefore, how to increase physician acceptance of a new compound becomes the critical success factor of the new launch product for pharmaceutical companies. This research is an attempt to study the relationship between ¡§Current Prescription¡¨, ¡§New Drug Usage¡¨ and ¡§Environmental Factors-Medical Provider¡¨ and ultimately to find the vital factors which would influence the ¡§Willingness¡¨ of the physicians to prescribe product X. One aim of this research is also to understand the potential factors which would affect the physician acceptance of a new mechanism drug. Based on the Multiple Regression Analysis, Analysis of Variance and Factor Analysis, the research results are as follows: 1. The effect of ¡§Current Prescription¡¨ on ¡§Willingness to Prescribe New Product X¡¨ is limited, and factors such as ¡§Satisfaction on Current Prescription¡¨ and ¡§Current Prescription¡¨ do not influence the ¡§Willingness to Prescribe New Product X¡¨. Only the satisfaction of BLOPRESS and PLENDIL and current prescription percentage on ADALOT OROS and CO-DIOVAN show a significant affect. So the research hypothesis H-1 and H1-3 are partially supported. AS far as ¡§Level of Fame¡¨ of the product shows a significant influence on the ¡§Willingness to Prescribe New Product X¡¨, so the research hypothesis H1-2 is fully supported. 2. Relationship between ¡§New Drug Usage¡¨ and ¡§Willingness to Prescribe New Product X¡¨ is not all significant. ¡§External Information¡¨, ¡§Physician Specialty¡¨ and factors a physician will consider when prescribing did not have a large impact on whether the physician will prescribe the new drug or not. Only the familiarity on ¡§Renin system is an import treatment indicator on blood pressure control and organ protection¡¨, ¡§External Information Orientated¡¨, and ¡§Market Follower¡¨ type of physicians and ¡§Will still use broadly to treat, even despite the high cost of new drugs¡¨ and ¡§New product X will always be part of the prescription in combination therapy¡¨ show significant impact. Thus hypothesis H2-1, H2-3 & H2-4 are partial supported. ¡¨Type of Patient¡¨ shows no difference in effect physician¡¦s willingness to prescribe new product X, so the hypothesis H2-2 are not supported. 3. ¡§Level of Fame¡¨ just has partial significance effect to physician¡¦s ¡§Current Prescription¡¨. ¡§Level of fame¡¨ for CCB, ARB and ACEI have significant effect to the physician¡¦s ¡§Current Prescription¡¨, but other drugs like ALPHA BLOCKER, BETA BLOCKER & OTHERS have no effect to the physician¡¦s ¡§Current Prescription¡¨, so the research hypothesis is partially supported. 4. ¡§Environment Factors¡ÐMedical Provider¡¨ has limited effect to physician¡¦s ¡§Current Prescription¡¨. Among all the physician specialties, only Cardiovascular, Nephrology and Meta/Endo physicians show a difference in ¡§Current Prescription¡¨ among all specialties. ¡§Type of Hospital¡¨ shows no effect on ¡§Current Prescription¡¨, thus the research hypothesis is not supported. According to the findings above, pharmaceutical companies should increase call frequency from sales representatives to the physicians; increased call frequency will effectively increase the brand awareness of the new launch products and also to increase the new product prescription rate. Improvement of Sales Training and after sales service can also be a key area for improved for the pharmaceutical companies to improve the effectiveness and efficiency for product promotion. In addition, product efficacy and treatment differentiation messages should also be customized for physicians in different specialties and in different types of hospitals; increased frequency and customized messages will ensure the success of the new product launch.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 53-59).

Background: According to the World Health Organization (WHO), hypertension is a major risk factor for cardiovascular disease (CVD), renal impairment, peripheral vascular disease, and blindness. In Panama, a recent study estimated the prevalence of hypertension at 38.5% in the two main provinces of the country, with a rate of uncontrolled hypertension of 47.2%. Objectives: The aims of this study were to assess the feasibility of the study design and to describe the characteristics of the hypertensive population and the physician's adherence to Panamanian antihypertensive protocols and their relationship with uncontrolled hypertension. Methods: This is a cross-sectional study of adult hypertensive patients attending a primary healthcare facility in Panama City. Clinical charts from eligible participants were examined to describe the demographic and clinical characteristics related to uncontrolled hypertension and the use of antihypertensive protocols by medical doctors. Descriptive and central tendency statistics were used to characterize the study population. Bivariate relationships between demographic and clinical characteristics, and uncontrolled hypertension were explored using specific test for no association. Logistic regression modeling was used to examine the association between physician's adherence to antihypertensive protocols and the presence of uncontrolled hypertension. Results: In this study the mean age was 56.7 years (±13.6); 58.1% of participants were females; 71.3% of participants had body mass index >25.0kg/m2; and 53.0% of participants had stage 2 hypertension. Uncontrolled hypertension was present in 66.7% of the study sample. 82.9% of participants had one or more comorbidities. The medical doctors were compliant with antihypertensive protocols in 43.6% of participants, primarily due to lower compliance with lifestyle modification recommendations. In the multivariate analysis, a significant interaction was found with age, suggesting that age is a potential effect modifier. Conclusions: The rate of uncontrolled hypertension was high among this study population. Nearly half of the attending physicians did not follow the recommendations given by current antihypertensive protocols. Further research is necessary to explore the relationships between subject characteristics, such as age, number of comorbidities, and the presence of diabetes mellitus with uncontrolled hypertension

Erectile dysfunction and cardiovascular disease share etiologies, and commonly coexist. One unifying concept is that the arterial insufficiency in hypertension is also the primary basis for blunted sexual responses. The objective of these studies was to characterize the age-related changes in the structure and function of the pudendal artery (the main resistance vessel) in young and old normotensive and hypertensive animals in relation to erectile function. In addition, we assessed the impact of antihypertensive treatments and lifestyle modifications, such as exercise and/or caloric restriction, on erectile responses and the structure and function of the pudendal artery. In 30 week old hypertensive rats or following re-challenges at 50 and 70 weeks, antihypertensive treatment (enalapril or hydralazine) did not prevent the age-related decline in erectile function. Experiments involving cross-over kidney transplantations between treated and untreated young hypertensive rats revealed that changes in penile vasculature and not the level of arterial pressure were important for normalizing erectile responses. In addition, intervention with exercise and caloric restriction showed that these treatments substantially improved erectile responses in normotensive and hypertensive rats. The pudendal artery in young normotensive rats was found to have a thick medial layer but a relatively small lumen. With age, the pudendal lumen didn’t change, but all components of the medial layer were markedly increased. Of interest, the smooth muscle cells within the pudendal medial layer became more disorganized with aging, although iii contractions were similar. In contrast, endothelium-dependent relaxation decreased with age. Young hypertensive rats also had an increased wall thickness, but not lumen diameter or extracellular matrix. Antihypertensive therapy significantly decreased the pudendal wall thickness. In aging hypertensive rats, the pudendal artery walls were even thicker, lumen decreased and extracellular matrix greatly enhanced compared to younger rats. In addition, there were numerous regions of intimal thickening associated with marked disruptions of the internal elastic lamina. Moreover, pudendal smooth muscle cells bordering the intima and in the neointima were round in shape, and electron microscopy confirmed their synthetic state. Taken together, these findings provide key evidence of the importance of the structure and function of the pudendal artery in facilitating erectile responses. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2009-05-19 12:55:30.469

Food protein-derived peptides have increasingly become important sources of ingredients for the formulation of therapeutic products. The main aim of this work was to study the in vitro and in vivo bioactive properties of structurally diverse group of peptides produced through enzymatic hydrolysis of flaxseed proteins (FP). Hydrolysis of FP with seven proteases followed by fractionation into low-molecular-weight (LMW) cationic fractions yielded multifunctional peptides that inhibited angiotensin converting enzyme (ACE) and renin activities, which are molecular targets for antihypertensive agents. The LMW peptides also exhibited antioxidant properties by scavenging free radicals and inhibiting amine oxidase activity. The peptide fractions showed inhibition of calmodulin-dependent phosphodiesterase, an enzyme that has been implicated in the pathogenesis of several chronic diseases. Moreover, FP hydrolysis with thermolysin and pronase followed by mixing with activated carbon yielded branched-chain amino acids (BCAA)-enriched multifunctional peptide mixture (Fischer ratio of 23.65) with antioxidant properties and in vitro ACE inhibition; Fischer ratio of 20.0 is considered minimum for therapeutic purposes. The BCAA-enriched peptide product can be used in clinical nutrition to treat muscle wasting symptoms associated with hepatic diseases. Furthermore, an arginine-rich peptide mixture (31% arginine versus 11% in the original flaxseed protein) was produced by hydrolysis of FP with trypsin and pronase followed by separation using electrodialysis-ultrafiltration. Arginine plays important physiological roles especially as precursor to vasodilator, nitric oxide. The arginine-rich peptide mixture exhibited in vitro ACE and renin inhibition and led to decreased systolic blood pressure (–17.9 and –11.7 mmHg, respectively at 2 and 4 h) after oral administration to spontaneously hypertensive rats. For the first time in the literature, we showed that arginine peptides have superior physiological effects when compared to the amino acid form of arginine. Lastly, quantitative structure-activity relationship studies using partial least squares (PLS) regression yielded two predictive models for renin-inhibiting dipeptides with z-scales amino acid descriptors. The PLS models indicated that hydrophobic and bulky side chain-containing amino acids contribute to renin inhibition if present at the amino- and carboxyl-terminal of dipeptides, respectively. Based on this study, Ile-Trp was discovered as potent renin-inhibiting dipeptide, and may serve as a useful template for the development of potent antihypertensive peptidomimetics.

Food protein-derived peptides have increasingly become important sources of ingredients for the formulation of therapeutic products. The main aim of this work was to study the in vitro and in vivo bioactive properties of structurally diverse group of peptides produced through enzymatic hydrolysis of flaxseed proteins (FP). Hydrolysis of FP with seven proteases followed by fractionation into low-molecular-weight (LMW) cationic fractions yielded multifunctional peptides that inhibited angiotensin converting enzyme (ACE) and renin activities, which are molecular targets for antihypertensive agents. The LMW peptides also exhibited antioxidant properties by scavenging free radicals and inhibiting amine oxidase activity. The peptide fractions showed inhibition of calmodulin-dependent phosphodiesterase, an enzyme that has been implicated in the pathogenesis of several chronic diseases. Moreover, FP hydrolysis with thermolysin and pronase followed by mixing with activated carbon yielded branched-chain amino acids (BCAA)-enriched multifunctional peptide mixture (Fischer ratio of 23.65) with antioxidant properties and in vitro ACE inhibition; Fischer ratio of 20.0 is considered minimum for therapeutic purposes. The BCAA-enriched peptide product can be used in clinical nutrition to treat muscle wasting symptoms associated with hepatic diseases. Furthermore, an arginine-rich peptide mixture (31% arginine versus 11% in the original flaxseed protein) was produced by hydrolysis of FP with trypsin and pronase followed by separation using electrodialysis-ultrafiltration. Arginine plays important physiological roles especially as precursor to vasodilator, nitric oxide. The arginine-rich peptide mixture exhibited in vitro ACE and renin inhibition and led to decreased systolic blood pressure (–17.9 and –11.7 mmHg, respectively at 2 and 4 h) after oral administration to spontaneously hypertensive rats. For the first time in the literature, we showed that arginine peptides have superior physiological effects when compared to the amino acid form of arginine. Lastly, quantitative structure-activity relationship studies using partial least squares (PLS) regression yielded two predictive models for renin-inhibiting dipeptides with z-scales amino acid descriptors. The PLS models indicated that hydrophobic and bulky side chain-containing amino acids contribute to renin inhibition if present at the amino- and carboxyl-terminal of dipeptides, respectively. Based on this study, Ile-Trp was discovered as potent renin-inhibiting dipeptide, and may serve as a useful template for the development of potent antihypertensive peptidomimetics.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 4 uppsatser.