angiotensin II AT1 receptor antagonists

In the last three decades, ischemic heart disease, stroke, and diabetes became leading causes of mortality and years of life lost (YLL), although with some divergences among countries in the ratio of observed and expected YLLs which is based on sociodemographic indexes. 1 Worldwide, the morbidity and mortality burden associated to cardio-metabolic risk appears to be largely influenced by a rise in blood pressure (BP) levels, body mass index, glucose, and cholesterol. These risk factors are responsible of more than 60% of global death from cardiovascular disease (CVD), chronic kidney disease (CKD), and diabetes, with the high BP having the largest effect. 2 In 2013, high systolic blood pressure (SBP) accounted for 10.4 million deaths and 208.1 million Disability-Adjusted Life Years. 3 People with hypertension (BP ≥140/90 mm Hg or those receiving BP-lowering drugs) have a higher lifetime risk of overall CVD at 30 years of age (63.3% vs 46.1% of those with normal BP) and tend to develop CVD 5.0 years earlier. 4 Even among individuals without known vascular Summary Elevated blood pressure (BP) is a major determinant of morbidity and mortality burden related to cardio-metabolic risk. Current guidelines indicate that controlling and lowering BP promotes cardiovascular (CV) risk reduction. Among antihypertensive agents, angiotensin receptor blockers (ARBs) are characterized by an efficacy profile equivalent to other antihypertensive agents and are provided with excellent tolera-bility and low discontinuation rates during chronic treatments. Moreover, CV outcomes are reduced by ARBs. Olmesartan is a long-lasting ARB which proved to achieve a comparable or more effective action in lowering BP when compared to other ARBs. Olmesartan, in fact, displayed a larger and more sustained antihyperten-sive effect over the 24 hours, with a buffering effect on short-term BP variability. These are important features which differentiate olmesartan from the other principles of the same class and that may help to control the increased CV risk in the presence of high BP variability. Olmesartan shows similar benefits as other ARBs in terms of all-cause and CV mortality, and a favorable tolerability profile. Combination of ol-mesartan with long-lasting calcium-channel blockers and thiazide diuretics represents a rational and effective therapy. Thus, ARBs, including olmesartan, represent one of the most effective and safe treatments for patients with arterial hypertension. K E Y W O R D S ambulatory blood pressure, angiotensin receptor blockers, arterial hypertension, blood pressure, blood pressure variability, olmesartan

A series of 6-substituted carbamoyl benzimidazoles were designed and synthesised as new nonpeptidic angiotensin II AT 1 receptor antagonists. The preliminary pharmacological evaluation revealed a nanomolar AT 1 receptor binding affinity for all compounds in the series, and a potent antagonistic activity in an isolated rabbit aortic strip functional assay for compounds 6f, 6g, 6h and 6k was also demonstrated. Furthermore, evaluation in spontaneous hypertensive rats and a preliminary toxicity evaluation showed that compound 6g is an orally active AT 1 receptor antagonist with low toxicity.

Thoracic aortic aneurysms can be triggered by genetic disorders such as Marfan syndrome (MFS) and related aortic diseases as well as by inflammatory disorders such as giant cell arteritis or atherosclerosis. In all these conditions, cardiovascular risk factors, such as systemic arterial hypertension, may contribute to faster rate of aneurysm progression. Optimal medical management to prevent progressive aortic dilatation and aortic dissection is unknown. β-blockers have been the mainstay of medical treatment for many years despite limited evidence of beneficial effects. Recently, losartan, an angiotensin II type I receptor antagonist (ARB), has shown promising results in a mouse model of MFS and subsequently in humans with MFS and hence is increasingly used. Several ongoing trials comparing losartan to β -blockers and/or placebo will better define the role of ARBs in the near future. In addition, other medications, such as statins and tetracyclines have demonstrated potential benefit in experimental aortic aneurysm studies. Given the advances in our understanding of molecular mechanisms triggering aortic dilatation and dissection, individualized management tailored to the underlying genetic defect may be on the horizon of individualized medicine. We anticipate that ongoing research will address the question whether such genotype/pathogenesis-driven treatments can replace current phenotype/syndromedriven strategies and whether other forms of aortopathies should be treated similarly. In this work, we review currently used and promising medical treatment options for patients with heritable aortic aneurysmal disorders.

Integrando los inhibidores de neprilisina y receptores de angiotensina a los distintos escenarios de la insuficiencia cardíaca.
Los progresos en el tratamiento de la insuficiencia cardíaca (IC) son continuos, pese a lo cual la enfermedad permanece como uno de los principales desafíos de la cardiología debido tanto a su prevalencia como a su decepcionante pronóstico. Se trata de un síndrome con formas clínicas heterogéneas y mecanismos fisiopatológicos
diferentes que condicionan una estrategia de abordaje compleja.
La Federación Argentina de Cardiología y la Sociedad Argentina de Cardiología han considerado necesario establecer en conjunto, lineamientos de cómo abordar el uso de ARNI en los diferentes escenarios del continuo de la IC. Estas recomendaciones no pretenden reemplazar a las actuales guías disponibles del tema, sino a partir
de la evidencia disponible aportar una toma de posición basada en el juicio crítico para colaborar en las decisiones frente al paciente.
Tras varios años de estancamiento en los progresos terapéuticos, a partir del estudio PARADIGM-HF en el año 2014 con sacubitrilo/valsartán (S/V), nuevas alternativas superadoras generaron gran expectativa pero también la necesidad de definir cómo implementarlas ante las múltiples situaciones clínicas que la enfermedad plantea.1
El presente documento está básicamente dividido en dos secciones. En la primera se plantean los diferentes escenarios clínicos que propone la IC, con el objeto de definir cuál es la mejor estrategia terapéutica en cada uno de ellos. (Figura 1) Se toman en cuenta la presentación clínica de acuerdo con el estadio y la clase funcional, la fracción de eyección y la consecuente estratificación de la IC, y la comprensión dinámica de fases recurrentes: ambulatorio-hospitalizado, que implican diferencias en los tratamientos, pero siempre orientados a la etapa posterior
(prevenir la descompensación y la re-hospitalización). Una parte de esta sección está dedicada a analizar diferentes aspectos que condicionan el tratamiento y no deben soslayarse en el paciente individual: comorbilidades, estado de fragilidad, vinculación con otras enfermedades coexistentes, circunstancias que demandan plasticidad para adaptar los recursos terapéuticos a las posibilidades concretas a fin de individualizar el mejor tratamiento posible.

Accumulating data suggest the involvement of renin angiotensin system (RAS) in the pathogenesis of inflammatory bowel disease. The aim of the present study was to evaluate the potential protective and therapeutic effects of captopril and valsartan on acetic acid induced-ulcerative colitis in rats. The results were assessed by macroscopic and microscopic examinations of colonic tissues as ell as by biochemical measurement of malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), transforming growth factor-beta1 (TGF-β β β β 1 ), angiotensin converting enzyme (ACE), reduced glutathione (GSH) and platelet activating factor (PAF) levels in colonic tissues. Oral treatment with captopril or valsartan in a dose of 30 mg kg -1 body weight, starting one day before induction of colitis and continuing for 1 week (prophylactic groups) or starting one week after induction of colitis and continuing for another one week (therapeutic groups), significantly reduced MDA, TNF-α, PAF, TGF-β β β β1 and significantly increased colonic GSH in colonic tissues as compared to acetic acid control groups. Captopril and valsartan attenuated the macroscopic and microscopic colonic damage induced by acetic acid. No significant difference between the effect of either drug could be detected other than the significant decrease in ACE activity in colonic tissue exerted by captopril and not by valsartan, These results suggest that either captopril or valsartan may be effective in prophylaxis as well as in treatment of ulcerative colitis through targeting RAS.

A series of 6-substituted aminocarbonyl benzimidazole derivatives were designed and synthesized as nonpeptidic angiotensin II AT 1 receptor antagonists. The preliminary pharmacological evaluation revealed nanomolar AT 1 receptor binding affinity and good AT 1 receptor selectivity over AT 2 receptor for all compounds of the series, a potent antagonistic activity in isolated rabbit aortic strip functional assay for compounds 6b, 6d and 6i was also demonstrated. Furthermore, evaluation in spontaneous hypertensive rats and a preliminary toxicity evaluation showed that compound 6i is an orally active AT 1 receptor antagonist with low toxicity.

Hypertension is a major public health problem of modern era. Fimasartan is a new Angiotensin Receptor Blocker approved for
treatment of hypertension. It is more potent and longer acting angiotensin receptor blocker with effects lasting over 24 hours. Many
clinical studies have affirmed its role in pharmacotherapy of hypertension. Further, it is renoprotective and has proven beneficial
in diabetes also. This article briefly discusses the pharmacology and clinical evidence with fimasartan with a short summary of
previous angiotensin receptor blockers.