The circulating renin-angiotensin system (RAS) plays an important role in the maintenance of cardiovascular homeostasis. It has recently been demonstrated that endogenous RAS exist in target tissues that are important in cardiovascular regulation. This article reviews the multiple effects of angiotensin II in target tissues, the evidence for the presence of functional tissue RAS and the data that suggest a role for these tissue RAS in the pathophysiology of heart failure. Activation of circulating neurohormones is predictive of worsened survival in heart failure; however, cardiac and renal tissue RAS activities are also increased in the compensated stage of heart failure, when plasma renin-angiotensin activity is normal. It is hypothesized that the plasma RAS maintains circulatory homeostasis during acute cardiac decompensation, while changes in tissue RAS contribute to homeostatic responses during chronic sustained cardiac impairment. This concept of different functions of circulating and tissue RAS in the pathophysiology of heart failure may have important pharmacologic implications.
Bibliographical noteFunding Information:
From the Cardiovascular Physiology Laboratory, Cardiovascular Division, University of Minnesota Hospitals, Minneapolis, Minnesota, and Molecular and Cellular Vascular Rescarch Laboratory, Falk Carditr vascular Research Center, Stanford University, Stanford, California, Dr. Alan T. I lirsch is a rc%ipient of an individual NRSA award (F32 HL07702-02) from the National lleart, Lung, and Blood Institute, Bethesda, Maryland. Dr. Heribcrt Schunkert is a recipient of a grant of the Deutsche Forschungsgemeinschaft, Bonn, FRG. This study was also supported by NIH Grants lHL35610, 11L.35792, lIL35252, Hl.40210, HL42663, an NIH Specialized Center of Research in Hv-pertcnsion grant (HL36568), as well as a grant from the Squibb In&-tute for Medical Research, Princeton, New Jersey. Address for reprints: Alan T. Hirsch, MD, Cardiovascular Division, University of Minnesota Hospitals, Box 508-UMHC, 420 Delaware Street, Minneapolis, Minnesota 55455, and Victor J. Dzau, MD, Falk Cardiovascular Research Ccntcr, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305.
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