Parker J D, Thiessen J J, Reilly R, Tong J H, Stewart D J, Pandey A S
Division of Cardiology, Mount Sinai Hospital, Ontario, Canada.
J Pharmacol Exp Ther. 1999 Apr;289(1):261-5.
Levels of endothelin-1 (ET-1) are elevated in many disease states, although its total body kinetics of elimination are poorly understood. Therefore, it remains uncertain whether the presence of elevated levels of ET-1 in the setting of disease are secondary to changes in production or clearance or some combination thereof. Using a 125I-labeled ET-1 infusion technique, the volume of distribution and kinetics of clearance of endothelin were described in five normal volunteers. Heart rate, blood pressure, right atrial pressure, and arterial blood samples for the counting of 125I and the measurement of ET-1 were obtained at multiple time points before and up to 45 h after the start of the infusion. The radiotracer infusion had no effect on heart rate, blood pressure, right atrial pressure, or endogenous ET-1 levels. ET-1 clearance was best described by a three-compartment model, which revealed that ET-1 has a much longer terminal half-life and volume of distribution than was previously reported. This suggests extensive uptake of ET-1 in various organ systems and slow clearance. These new findings have important implications for the understanding of the pathophysiology of ET-1 in disease states as well as for the understanding and development of ET-1 receptor blockers and endothelin-converting enzyme inhibitors.
内皮素-1（ET-1）的水平在许多疾病状态下都会升高，尽管其在体内的整体消除动力学还知之甚少。因此，在疾病状态下ET-1水平升高是由于生成或清除的变化或两者的某种组合所致，这一点仍不确定。利用125I标记的ET-1输注技术，描述了5名正常志愿者体内内皮素的分布容积和清除动力学。在输注开始前及开始后长达45小时的多个时间点，获取心率、血压、右心房压力以及用于计数125I和测量ET-1的动脉血样本。放射性示踪剂输注对心率、血压、右心房压力或内源性ET-1水平没有影响。ET-1清除情况用三室模型能得到最佳描述，该模型显示ET-1的终末半衰期和分布容积比之前报道的要长得多。这表明ET-1在各种器官系统中被大量摄取且清除缓慢。这些新发现对于理解疾病状态下ET-1的病理生理学以及对于ET-1受体阻滞剂和内皮素转换酶抑制剂的理解与研发具有重要意义。
