The endothelium is a major regulator of vascular tone because it releases vasoactive substances including: endothelium-derived relaxing factor (nitric oxide/EDRF), endothelium-derived hyperpolarizing factor (EDHF), prostacyclin, endothelin and endothelium-derived contracting factors (EDCFs). Three of these factors, nitric oxide, endothelin and a cyclooxygenase-dependent EDCF may play a role in congestive heart failure. A number of experimental and clinical studies describe impaired endothelium-dependent vasodilatations and increased plasma concentration of endothelin in congestive heart failure. The decrease of cardiac output, that results in a reduced shear stress on the endothelial cells and systemic endocrine compensatory mechanisms such as increased production of angiotensin-converting enzyme (leading to a greater breakdown of kinins) can modulate the release of nitric oxide and endothelin. It is unclear to which extent these modulations initiate, maintain, and/or compensate for the pathological process.