The cardiovascular physiology and pharmacology of endothelin-1

Abstract

One year after the discovery in 1980 that the endothelium was obligatory for acetylcholine to relax isolated arteries, it was clearly shown that the endothelium could also promote contraction. In 1988, Dr Yanagisawa's group identified endothelin-1 (ET-1) as the first endothelium-derived contracting factor. The circulating levels of this short (21 amino acids) peptide were quickly determined in humans and it was reported that in most cardiovascular diseases, circulating levels of ET-1 were increased and ET-1 was then recognized as a likely mediator of pathological vasoconstriction in human. The discovery of two receptor subtypes in 1990, ET(A) and ET(B), permitted optimization of bosentan, which entered clinical development in 1993, and was offered to patients with pulmonary arterial hypertension in 2001. In this report, we discuss the physiological and pathophysiological role of endothelium-derived ET-1, the pharmacology of its two receptors, focusing on the regulation of the vascular tone and as much as possible in humans. The coronary bed will be used as a running example, but references to the pulmonary, cerebral, and renal circulation will also be made. Many of the cardiovascular complications associated with aging and cardiovascular risk factors are initially attributable, at least in part, to endothelial dysfunction, particularly dysregulation of the vascular function associated with an imbalance in the close interdependence of NO and ET-1, in which the implication of the ET(B) receptor may be central.

FIGURE 1. The pleiotropic nature of ET-1 receptor signaling

Schematic representation of the multiple pathways activated by 7-transmembrane ET_A and ET_B receptors either directly dependent on G protein activation or independent of G protein activation such as through direct interaction with β-arrestin or PDZ-domain-containing proteins that can act as scaffolds. In addition, ET-1 may act as a bivalent ligand leading to both ET_A and ET_B receptor activation and possibly dimerization, although this remains to be demonstrated. The signaling pathways activated by either a bivalent ET-1 or a dimerization remain unexplored. Gα_s/i/o/q/11, heterotrimeric G protein α subunits of different classes; β arr, β-arrestin; PKC, protein kinase C; Jak, Janus kinase; GIP, other GPCR interacting proteins; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase.

FIGURE 2. Multiple effects of ET-1 in the cardiovascular system

Physiological responses are presented in italic and black while the responses associated to pathological conditions are in light grey (and in red in the online version).