Recent Developments on Endothelin Antagonists as Immunomodulatory Drugs - from Infection to Transplantation Medicine

Abstract

Endothelin, a potent endogenous vasoconstrictor and mitogen that acts through the ET(A) and ET(B) receptors, has been not only implicated in the regulation of cardiovascular homeostasis but also in inflammatory responses, including that induced by infection and solid organ transplantation. Changes in capillary perfusion and leukocyte recruitment are important features of inflammation. The concentrations of ET are elevated in many forms of inflammation and are especially high in sepsis. The rise in plasma levels of ET during early stages of inflammation may initially have some positive homeostatic effects that might help to maintain vascular tone and blood pressure. However, high levels of ET compromise the appropriate matching of flow to tissue needs and contribute to the pathophysiology of microcirculatory derangements. Attempts at regulating the effects of ET by the use of pharmacological antagonists are complicated by important interactions between the ET(A) and ET(B) receptors. This review highlights findings of recent studies and patents in this area showing that the ET system, apart from being a marker of vascular and tissue injury, is directly involved in the pathophysiology of these disease processes as an immunomodulatory mediator.