Thorin Eric, Clozel Martine
Department of Surgery, Montreal Heart Institute, Research Center, Université de Montréal, Montreal, Quebec, Canada.
Adv Pharmacol. 2010;60:1-26. doi: 10.1016/B978-0-12-385061-4.00001-5.
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.
1980年发现内皮细胞是乙酰胆碱使离体动脉舒张所必需的，一年后，有明确证据表明内皮细胞也可促进收缩。1988年，柳泽博士的研究小组鉴定出内皮素-1（ET-1）是首个内皮源性收缩因子。很快就测定了这种短肽（21个氨基酸）在人体中的循环水平，据报道，在大多数心血管疾病中，ET-1的循环水平升高，ET-1随后被认为是人类病理性血管收缩的可能介质。1990年发现了两种受体亚型，即ET(A)和ET(B)，这使得波生坦得以优化，波生坦于1993年进入临床研发，并于2001年应用于肺动脉高压患者。在本报告中，我们讨论内皮源性ET-1的生理和病理生理作用、其两种受体的药理学，重点关注血管张力的调节，并尽可能以人体研究为依据。冠状动脉床将作为一个贯穿始终的例子，但也会提及肺循环、脑循环和肾循环。许多与衰老和心血管危险因素相关的心血管并发症最初至少部分可归因于内皮功能障碍，特别是与一氧化氮和ET-1密切相互依存关系失衡相关的血管功能失调，其中ET(B)受体的作用可能至关重要。
