Effects of nebivolol on Obesity-induced increase in blood pressure and alteration of the anti-contractile phenotype of perivascular adipose tissue

• Grant number: 22/11304-0
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2023
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Carlos Renato Tirapelli
• Grantee: Carlos Renato Tirapelli
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The prevalence of obesity has increased worldwide reaching pandemic levels. Obesity is defined as a chronic disease that induces damage in different organs and systems and is an important risk factor for the development of cardiovascular complications. Obesity is pointed out as one of the main causes of secondary arterial hypertension. It affects the deposition of fat in perivascular adipose tissue (PVAT), which is a tissue formed by different cell types, with a predominance of adipocytes. PVAT produces several relaxing factors that are responsible for its anti-contractile action in distinctive vascular territories. The mechanism by which obesity induces loss of PVAT's anti-contractile function is complex and multi-mediate. Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-±, interleukin (IL)-6 and IL-1² are produced by macrophages infiltrated in PVAT or by adipocytes. These cytokines stimulate the generation of reactive oxygen species (ROS) leading to reduced bioavailability of nitric oxide (NO), an important mediator of the anti-contractile effect of PVAT. Thus, PVAT emerges as a potential therapeutic target for the treatment of obesity-induced vascular dysfunction. Hypertension associated with obesity must be controlled and the choice of antihypertensive drugs must prioritize classes that can improve or, at least, not worsen insulin resistance. ²-blockers are a therapeutic option in this scenario. Nebivolol is a third-generation ²-blocker that has metabolic/endocrine actions that favor its use in obesity. This drug has a beneficial action on glucose homeostasis, induces a reduction in insulin resistance, total cholesterol, LDL (low density lipoprotein) and triglycerides, in addition to increasing HDL (high density lipoprotein). Furthermore, nebivolol has vasculoprotective properties that result from its vasorelaxant, antioxidant and anti-inflammatory actions. However, there are no data on the action of nebivolol on PVAT during obesity. We hypostatized that, by reducing the production of ROS and pro-inflammatory proteins, nebivolol will restore the anti-contractile function of PVAT that is lost during obesity. The present study was designed to investigate whether nebivolol reverses obesity-induced loss of PVAT anti-contractile action and the mechanisms associated with this effect. We also propose to evaluate the effect of nebivolol on the increase in blood pressure induced by obesity and the possible mechanisms involved in the vasculoprotective action induced by the drug. With this purpose, male rats (Wistar Hannover) will be treated with a hypercaloric diet for 10 weeks to induce obesity. Then the animals will be treated with nebivolol (10 mg/kg/day) for 4 weeks. Parameters associated with redox imbalance and inflammation will be evaluated in resistance arteries of the mesenteric arterial bed and in the PVAT of the mesenteric arterial bed. (AU)