New and developing pharmacotherapies for hypertension.

INTRODUCTION: Despite the significant contribution of hypertension to the global burden of disease, disease control remains poor worldwide. Considering this unmet clinical need, several new antihypertensive drugs with novel mechanisms of action are under development. AREAS COVERED: The present review summarizes the recent advances in the development of emerging pharmacological agents for the management of hypertension. The latest technological innovations in the design of optimized formulations of available antihypertensive drugs and the potential role of the modification of intestinal microbiota to improve blood pressure (BP) control are also covered. EXPERT OPINION: Significant efforts have been made to develop new antihypertensive agents with novel actions that target the main mechanisms involved in resistant hypertension. Sacubitril/valsartan may emerge as a potential first-line drug due to its superiority over renin angiotensin system inhibitors, and SGLT2 inhibitors can reduce BP in difficult-to-control hypertensive patients with type 2 diabetes. In addition, firibastat and aprocitentan may expand the therapeutic options for resistant hypertension by novel mechanism of actions. Since gut dysbiosis not only leads to hypertension but also causes direct target organ damage, prebiotics and probiotics could represent a potential strategy to prevent or reduce the development of hypertension and to contribute to BP control.

Nebivolol is more effective than atenolol for blood pressure variability attenuation and target organ damage prevention in L-NAME hypertensive rats.

ß-Adrenergic blockers are no longer recommended as first-line therapy due to the reduced cardioprotection of traditional ß-blockers compared with other antihypertensive drugs. It is unknown whether third-generation ß-blockers share the limitations of traditional ß-blockers. The aim of the present study was to compare the effects of nebivolol or atenolol on central and peripheral systolic blood pressure (SBP) and its variability and target organ damage (TOD) in N-nitro-L-arginine methyl ester (L-NAME) hypertensive rats. Male Wistar rats were treated with L-NAME for 8 weeks together with oral administration of nebivolol 30 mg/kg (n = 8), atenolol 90 mg/kg (n = 8), or vehicle (n = 8). The control group was composed of vehicle-treated Wistar rats. SBP and its variability, as well as echocardiographic parameters, were assessed during the last 2 weeks of treatment. Tissue levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor ß (TGF-ß), and histopathological parameters were evaluated in the left ventricle and aorta. Nebivolol had a greater ability than atenolol to decrease central SBP and mid-term and short-term blood pressure variability (BPV) in L-NAME rats. Echocardiographic analysis showed that nebivolol was more effective than atenolol on E/A wave ratio normalization. Compared with atenolol treatment, nebivolol had a greater protective effect on different TOD markers, inducing a decrease in collagen deposition and a reduction in the proinflammatory cytokines IL-6 and TNF-α in the left ventricle and aorta. Our findings suggest that the adverse hemodynamic profile and the reduced cardiovascular protection reported with traditional ß-blockers must not be carried forward to third-generation ß-blockers.

Effects of third-generation ß-blockers, atenolol or amlodipine on blood pressure variability and target organ damage in spontaneously hypertensive rats.

BACKGROUND: ß-blockers are no longer considered as first-line antihypertensive drugs due to their lower cardioprotection. METHOD: Considering the differences in the pharmacological properties of ß-blockers, the present work compared the effects of third-generation ß-blockers - carvedilol and nebivolol - with a first-line agent - amlodipine - on hemodynamic parameters, including short-term blood pressure variability (BPV), and their ability to prevent target organ damage in spontaneously hypertensive rats (SHR). SHR rats were orally treated with carvedilol, nebivolol, atenolol, amlodipine or vehicle for 8 weeks. Wistar Kyoto rats treated with vehicle were used as normotensive group. Echocardiographic evaluation, BP, and short-term BPV measurements were performed. Left ventricle and thoracic aorta were removed for histological evaluations and to assess the expression of transforming growth factor ß (TGF-ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). RESULTS: Carvedilol, nebivolol or amlodipine induced a greater reduction of carotid BP, short-term BPV and echocardiography parameters than atenolol in SHR rats. Carvedilol, nebivolol and amlodipine were more effective than atenolol in the prevention of cardiac hypertrophy, and cardiac and aortic collagen deposit. Carvedilol and nebivolol, but not atenolol, reduced the expressions of fibrotic and inflammatory biomarkers - TGF-ß, TNF-α and IL-6 - in SHR rats to a similar extent to that of amlodipine. CONCLUSION: Chronic treatment with carvedilol or nebivolol attenuates carotid BP and short-term BPV, and reduces target organ damage in SHR to a greater extent than atenolol. Our findings suggest that the lower cardiovascular protection of nonvasodilating ß-blockers, as atenolol, in hypertension must not be translated to third-generation ß-blockers.

Losartán y metformina previenen alteraciones en el tejido adiposo perivascular y en la liberación de prostanoides del lecho vascular mesentérico producidas por una dieta alta en grasa y sobrecarga de fructosa en ratas / Losartan and Metformin Prevent Abnormalities in Perivascular Adipose Tissue and in Mesenteric Vascular Bed Prostanoid Release Induced by High-fat High-fructose Diet in Rats

RESUMEN Objetivo: El objetivo de este trabajo fue analizar los efectos del losartán (30 mg/kg/día) y de la metformina (500 mg/kg/día) sobre el índice de adiposidad y la liberación de prostanoides del lecho vascular mesentérico, así como su relación con la presión arterial sistólica en un modelo de síndrome metabólico inducido por una dieta alta en grasa y sobrecarga de fructosa en ratas Sprague-Dawley macho durante 9 semanas. Material y métodos: Los lechos vasculares mesentéricos extraídos se incubaron y los prostanoides liberados se midieron por cromatografía líquida de alta eficiencia. La presión arterial sistólica fue medida por método indirecto. Resultados: La dieta alta en grasa y la sobrecarga de fructosa produjo aumentos significativos en la presión arterial sistólica y del índice de adiposidad del lecho vascular mesentérico. Por su parte, la dieta alta en grasa y sobrecarga de fructosa incrementó la liberación de prostanoides vasoconstrictores tanto del tromboxano B2 como de la prostaglandina F2alfa; y del marcador de inflamación, la prostaglandina E2. La relación PGI2/TXA2 se redujo significativamente. La administración de losartán como de metformina previnieron todas estas alteraciones. Conclusión: Ambos fármacos ejercen efectos beneficiosos sobre el tejido adiposo perivascular del lecho mesentérico, lo que mejora la disfunción endotelial inducida por un desbalance de sustancias vasoactivas.

ABSTRACT Objective: The aim of this study was to analyze the effects of losartan (30 mg/kg/day) and metformin (500 mg/kg/day) on the adiposity index and on mesenteric vascular bed prostanoid release, and their relationship with systolic blood pressure in a metabolic syndrome model induced by high-fat high fructose-diet in male Sprague-Dawley rats for 9 weeks. Methods: Mesenteric vascular beds were extracted and incubated and prostanoids were measured by high-performance liquid chromatography. Systolic blood pressure was measured by an indirect method. Results: High-fat high-fructose diet produced significant increase in systolic blood pressure and mesenteric vascular bed adiposity index and in the release of vasoconstricting prostanoids as thromboxane B2 and prostaglandin F2α and of prosta-glandin E2, a marker of inflammation. The PGI2/TXA2 ratio was significantly reduced. The administration of losartan and metformin prevented all these changes. Conclusion: Both drugs have beneficial effects on mesenteric perivascular adipose tissue by improving endothelial dysfunction induced by an imbalance of vasoactive substances.