Maximizing hemodynamic-independent effects of angiotensin II antagonists in fibrotic diseases

Abstract

Better understanding of the hemodynamic-independent actions of the renin-angiotensin system (RAS) may lead to improved therapies for heart, kidney, and liver fibrosis. The conventional view of the RAS is that its role is solely hemodynamic. Pharmacologic blockade of the RAS is beneficial in treating hypertension, as well as primary renal and cardiac diseases. Recent findings from clinical trials and several laboratories that used different experimental approaches have revealed a whole new dimension to the RAS that is beyond the realm of hemodynamics. The RAS is best viewed as part of a system of interconnected molecules biologically designed to be activated after tissue injury to promote tissue repair and, when in excess, tissue fibrosis. This new understanding of the RAS has important clinical implications. It predicts and explains why blockade of the RAS with angiotensin-converting enzyme inhibitors (ACEI), the newer receptor antagonists, or both together, will significantly slow the progression of fibrotic disease. However, it further suggests that higher doses and/or a combination of angiotensin II blockade with another agent or agents might truly halt progressive fibrosis.