Role of Renin-Angiotensin System Blockades in Reciprocal Relationship Between Insulin Resistance and Endothelial Dysfunction
To the Editor:
Azekoshi et al1 demonstrated that the enhanced production of angiotensin II by free fatty acid in mononuclear and polymorphonuclear cells caused activation of leukocytes that consequently impairs endothelial function. Obesity, metabolic syndrome, and type 2 diabetes mellitus are major risk factors for cardiovascular disease. This study strongly supports our hypothesis that reciprocal relationships between insulin resistance and endothelial dysfunction contribute to the development of cardiovascular events through inflammatory actions.2 Thus, therapies should target the vicious synergy between endothelial dysfunction and insulin resistance to prevent cardiovascular events.
In that point, inhibitors of the renin-angiotensin system are beneficial. Recently, several articles related to this topic have been published in Hypertension. Cole et al3 demonstrated that valsartan attenuated several deleterious effects of the Western diet at the systemic and local levels in pancreatic islets and adipose tissue, suggesting that valsartan provides additional therapeutic benefits in the metabolic syndrome and other obesity-related disorders beyond lowering blood pressure. In this study, valsartan blocked or attenuated Western diet-induced changes in the expression of several key inflammatory signals; furthermore, it tended to stimulate adiponectin expression. He et al4 demonstrated that telmisartan significantly upregulated peroxisome proliferator-activated receptor-δ expression in 3T3-L1 preadipocytes, whereas neither candesartan nor losartan affected peroxisome proliferator-activated receptor-δ expression, suggesting that telmisartan prevents adipogenesis and weight gain through activation of peroxisome proliferator-activated receptor-δ–dependent lipolytic pathways and energy uncoupling in several tissues.
We investigated the effects of either placebo or one class of antihypertensive drug on endothelial dysfunction and insulin resistance (atenolol: 100 mg, amlodipine: 10 mg, hydrochlorothiazide: 50 mg, ramipril: 10 mg, or candesartan: 16 mg) in 31 hypertensive patients during 8 weeks in each of 6 arms of a randomized, single-blind, placebo-controlled, parallel study.5 All of the antihypertensive drugs significantly reduced blood pressure when compared with placebo. However, atenolol and thiazide therapies significantly increased triglyceride levels from baseline, and the magnitude of increasing triglycerides levels after atenolol and thiazide therapies was significantly greater than that after ramipril or candesartan (P=0.005 by ANOVA). Ramipril and candesartan therapies significantly improved flow-mediated dilator response to hyperemia more than placebo, atenolol, or thiazide therapies (P<0.001 by ANOVA). By contrast, atenolol and thiazide therapies did not significantly improve compared with placebo. Ramipril and candesartan therapies significantly increased adiponectin levels to a greater extent than atenolol or thiazide therapies (P<0.001 by ANOVA). Ramipril and candesartan therapies significantly increased insulin sensitivity to a greater extent than atenolol or thiazide therapies (P=0.015 by ANOVA). Ramipril and candesartan significantly decreased leptin levels to a greater extent when compared with atenolol or thiazide therapies (P<0.001 by ANOVA). We observed differential effects of antihypertensive drugs on endothelial dysfunction, plasma adipocytokines, and insulin sensitivity.
Based on solid evidence from both translational basic science and clinical intervention trials, there is emerging support for the superiority of inhibitors of the renin-angiotensin system over β-blockers and diuretics in the optimal treatment of hypertension.
Azekoshi Y, Yasu T, Watanabe S, Tagawa T, Abe S, Yamakawa K, Uehara Y, Momomura S, Urata H, Ueda S. Free fatty acid causes leukocyte activation and resultant endothelial dysfunction through enhanced angiotensin II production in mononuclear and polymorphonuclear cells. Hypertension. 2010; 56: 136–142.
Kim J, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006; 113: 1888–1904.
Cole BK, Keller SR, Wu R, Carter JD, Nadler JL, Nunemaker CS. Valsartan protects pancreatic islets and adipose tissue from the inflammatory and metabolic consequences of a high-fat diet in mice. Hypertension. 2010; 55: 715–721.
He H, Yang D, Ma L, Luo Z, Ma S, Feng X, Cao T, Yan Z, Liu D, Tepel M, Zhu Z. Telmisartan prevents weight gain and obesity through activation of peroxisome proliferator-activated receptor-δ-dependent pathways. Hypertension. 2010; 55: 869–879.