Adaptive changes in the periphery and their therapeutic consequences.

Systemic vasoconstriction in chronic heart failure is due to several compensatory mechanisms with different time courses. Peripheral vasoconstriction mediated by increased sympathetic tone and activation of the plasma renin-angiotensin system may act primarily for short-term control. The effects of the vascular renin-angiotensin system, impaired flow-dependent, endothelium-mediated dilation (resulting from chronically reduced flow) and structural alterations of the vessel wall slowly emerge with time. In addition, fluid retention may contribute to increased vascular stiffness in chronic heart failure. Improved cardiac output with acute administration of vasodilators and inotropes is not immediately translated into increased blood flow to skeletal muscle, because (1) the reversal of the peripheral alterations described develops slowly over time (in fact, vasodilators and inotropes given acutely may cause redistribution of blood flow in skeletal muscle without improving oxygen availability); and (2) intrinsic abnormalities of skeletal muscle exist in chronic heart failure (e.g., due to chronic deconditioning, resulting in reduced oxidative capacity of skeletal muscle, as suggested by ultrastructural analysis and nuclear magnetic resonance spectroscopy). Drugs that interfere with the underlying compensatory mechanisms (e.g., renin-angiotensin system) without development of tolerance during long-term therapy exert beneficial effects after long-term treatment (e.g., the beneficial effects of angiotensin-converting enzyme inhibitors are, in part, due to peripheral mechanisms--the inability of the peripheral vessels to dilate--and to improvement of peripheral oxygen extraction).