Manipulating the renin-angiotensin system: more than we bargained for?

Tigerstedt and Bergman are credited with the discovery of renin more than a century ago (1). Subsequent investigators pieced together the information that linked renin-dependent cleavage of the plasma protein angiotensinogen to the generation of angiotensin I and its conversion to angiotensin II by the angiotensinconverting enzyme (ACE). Angiotensin II is an octapeptide that promotes the constriction of resistance vessels and stimulates aldosterone secretion from adrenal glomerulosa, thereby increasing blood pressure level and extracellular fluid volume. Since renin is concentrated in the juxtaglomerular cells of the kidney, the plasma reninangiotensin system has been viewed largely as an endocrine servomechanism wherein changes in cardiovascular homeostasis are sensed in the kidney and translated into increased angiotensin II production in circulating plasma, resulting in increased blood pressure levels and urinary sodium retention. However, in reality the reninangiotensin system represents not a single system but a collection of systems, each with its own regulatory controls, selectivity in tissue expression, and physiological effects. Individual components of the classic renin-angiotensin system have been identified in the vasculature, heart, adrenal gland, ovary, and even the brain (2). These tissue renin-angiotensin systems have become the focus of intense study and have been identified as key participants in several physiological and pathophysiological processes, ranging from renal development to central regulation of blood pressure to control of cardiac hypertrophy. Two articles in this issue of The Green Journal highlight some of the more novel and, to some degree, unexpected features of the renin-angiotensin systems that have attracted attention in recent years. The review by Halkin and Keren (3) focuses on the potential role of the renin-angiotensin system in the development of atherosclerosis. Given the ability of the classic renin-angiotensin system to increase systemic blood pressure, one might anticipate observing some effects on the atherogenic process following activation of the reninangiotensin system; however, there appears to be more than simple blood pressure reduction involved. There is increasing evidence supporting the hypothesis that atherosclerosis represents an inflammatory disease of the vascular wall (4). Angiotensin II has various in vitro and in vivo properties that are regarded as proatherogenic, including the ability to promote endothelial dysfunction, low-density lipoprotein oxidation, local coagulation abnormalities, and growth and migration of smooth muscle cells in the vascular wall. In addition, some of its properties suggest a role in the initiation and maintenance of inflammatory activity in the vasculature. Angiotensin II has been shown to stimulate cytokine production (interleukin 6) in vascular smooth muscle cells in culture (5). Through a unique mechanism, it promotes the generation of reactive oxygen species in the same cell type (6) and signals transcriptional regulatory activity through the transcription factor NFB, which is associated with the activation of cytokine genes (7). Almost all of these activities are reversible with ACE inhibition or blockade with selective type I angiotensin receptor blockers. Thus, the data support a role for angiotensin II as an inflammatory mediator in the pathogenesis of atherosclerotic vascular disease. Results from the recent Heart Outcomes Prevention Evaluation (HOPE) study (8), which demonstrated improved cardiovascular outcomes (combined endpoint of cardiovascular mortality, myocardial infarction, and stroke) in patients with known atherosclerotic disease who had been treated with an ACE inhibitor, lends additional credence to the proposed role of the renin-angiotensin system in contributing to the atherosclerotic process. The second article, by Morimoto et al. (9), examines one of the so-called side effects of ACE inhibitor therapy. ACE inhibition, which blocks the conversion of angiotensin I to angiotensin II, is an accepted and effective therapy in the management of hypertension, congestive heart failure, and renal insufficiency in diabetic patients. However, the effects of ACE inhibitors are not confined to the renin-angiotensin cascade. In addition to suppressing the production of angiotensin II, they prevent degradation of bradykinin and substance P. In fact, elevated levels of bradykinin and substance P are thought to be the source of the cough that limits the utility of ACE inhibitor therAm J Med. 2002;112:152–153. From the Diabetes Center/Metabolic Research Unit and the Department of Medicine, University of California, San Francisco, San Francisco, California. Requests for reprints should be addressed to David G. Gardner, MD, Diabetes Center/Metabolic Research Unit and the Department of Medicine, University of California, San Francisco, 513 Parnassus HSW1119, Box 0540, San Francisco, California 94143-0540. Manuscript submitted September 27, 2001.