Metabolic actions of angiotensin receptor antagonists: PPAR-gamma agonist actions or a class effect?

Abstract

Accumulating basic and clinical data support the hypothesis that angiotensin receptor blockers have beneficial effects on glucose and lipid metabolism that are not shared by other classes of antihypertensive agents. These metabolic actions might only partially be shared by angiotensin-converting enzyme inhibitors. Specific benefits beyond those of other angiotensin receptor blockers have been claimed for telemesartan and, to a lesser extent, irbesartan based on a partial agonist action on PPAR-gamma receptors. Although the evidence is strong in vitro, specific actions not shared by other angiotensin receptor blockers have not yet been convincingly demonstrated in vivo or in clinical trials. In many cases, a full range of doses has not been compared, and the apparent superiority of telmesartan could be an artifact of its higher receptor binding affinity, greater tissue penetration owing to lipophilicity, and longer half life.

Figures

Figure 1

Metabolic effects of AT1 receptors. The schematic shows the influence of angiotensin II on the adipose tissue, liver, skeletal muscle, pancreatic β-cells, and the SNS. Adipocytes are a major source of circulating angiotensinogen, along with the liver. In adipose tissue, AT1 receptors inhibit differentiation of new adipocytes, thereby reducing the ability of adipose tissue to take up glucose and lipid. In the liver, AT1 receptors increase glycogenolysis, which favors hyperglycemia, but have an opposing action of gluconeogenesis. AT1 receptors also promote secretion of triglycerides into the circulation. Hemodynamic effects link AT1 receptor-mediated vasoconstriction to reduced delivery of glucose and insulin to skeletal muscle. In the pancreas, AT1 receptors promote insulin secretion in the short-term, but chronic stimulation leads to apoptosis and a loss of function. Activation of the RAS ties into SNS overactivity through actions in the central nervous system and presynaptic effects to promote norepinephrine release. Increased catecholamines promote impairments in glucose and lipid metabolism through multiple mechanisms. Modified with permission from [7]; figure created using Smart-Draw 6 (Smart-Draw, San Diego, CA).