Angiotensin antagonist drugs as �??source antioxidants�?� �?? Downregulation of nicotinamide adenine dinucleotide phosphate oxidase activation mediates many of their protective benefi ts, independent of hypertension control

Abstract

Mark F. McCarty, James J. DiNicolantonio, Charles F. Glassman

Angiotensin II (ATII), acting via Type I ATII receptors (AT1R), promotes vasoconstriction of vascular smooth muscle; hence, angiotensin antagonist drugs, i.e., angiotensin receptors blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors, are employed in the management of hypertension. However, AT1R stimulation also activates nicotinamide adenine dinucleotide phosphate oxidase complexes in a range of tissues, via joint stimulation of protein kinase C and Rac. Angiotensin antagonist drugs therefore function as “source antioxidants” preventing oxidative stress at its source by blocking superoxide production. This phenomenon may explain why these drugs have been found to convey a range of health benefits that are at least partially independent of their impact on blood pressure. These benefits appear to include: A reduction in risk for Type 2 diabetes; an improvement in endothelial function; reduced risk for vascular disorders including atrial fibrillation, left ventricular hypertrophy and aortic aneurysms; reduced mortality in, and a possible preventive impact on, chronic obstructive pulmonary disease; slowed progression of kidney disease; slowed progression of diabetic neuropathy and retinopathy; decreased risk for non-alcoholic fatty liver disease; neuroprotective effects which may aid prevention of Parkinson’s and Alzheimer’s diseases; and an inhibitory impact on induction and spread of prostate cancer. There is reason to suspect that each of these benefits is largely attributable to the source antioxidant activity of ARB and ACE inhibitors. In light of the versatility of the protection afforded by these drugs, and the low risk for side effects with ARB, consideration should be given to the possibility of using ARB as a preventive measure in the general population (excluding pregnant women), in non-hypertensives and hypertensives alike - perhaps as a component of a “polypill.” Moreover, the broadly favorable clinical experience with angiotensin antagonist drugs suggests that source antioxidants as a class may have far greater potential for preserving health than antioxidants which merely act as oxidant scavengers.