Wilkinson I B, McEniery C M, Bongaerts K H, MacCallum H, Webb D J, Cockcroft J R
Clinical Pharmacology Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU.
Br J Clin Pharmacol. 2001 Aug;52(2):159-64. doi: 10.1046/j.0306-5251.2001.1420.x.
To compare the haemodynamic responses of proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (ADM) in the forearm vascular bed of healthy male volunteers, and to investigate the role of neutral endopeptidase (NEP) in the metabolism of ADM.
On two separate occasions, ADM (1-30 pmol x min(-1)) and PAMP (100-3000 pmol x min(-1)) were infused into the brachial artery of eight male subjects, and forearm blood flow (FBF) assessed using venous occlusion plethysmography. In a second study, eight male subjects received the same doses of ADM, co-infused with either the NEP inhibitor thiorphan (30 nmol x min(-1)) or the control vasoconstrictor noradrenaline (120 pmol x min(-1)), on separate occasions. Both studies were conducted in a double-blind, randomized manner.
ADM and PAMP produced a dose-dependent increase in FBF (P < or = 0.002). Based on the dose producing a 50% increase in FBF, ADM was approximately 60 times more potent than PAMP. Thiorphan and noradrenaline produced similar reductions in FBF of 14 +/- 4% (mean +/- s.e. mean) and 22 +/- 6%, respectively (P = 0.4). However, the area under the dose-response curve was significantly greater during co-infusion of ADM with thiorphan than with noradrenaline (P = 0.028), as was the maximum increase in FBF ratio (2.1 +/- 1.0 vs 1.2 +/- 0.2; P = 0.030).
ADM and PAMP both produce a local dose-related vasodilatation in the human forearm, but PAMP is approximately 60 times less potent than ADM. In addition, NEP inhibition potentiates the haemodynamic effects of ADM. These findings suggest that PAMP may not play a role in the physiological regulation of blood flow. However, in pathophysiological conditions such as hypertension and heart failure, NEP inhibition may exert a beneficial effect by increasing the biological activity of ADM.
比较健康男性志愿者前臂血管床中肾上腺髓质素前体N端20肽（PAMP）和肾上腺髓质素（ADM）的血流动力学反应，并研究中性内肽酶（NEP）在ADM代谢中的作用。
在两个不同的时间段，将ADM（1 - 30 pmol·min⁻¹）和PAMP（100 - 3000 pmol·min⁻¹）分别注入8名男性受试者的肱动脉，使用静脉阻断体积描记法评估前臂血流量（FBF）。在第二项研究中，8名男性受试者在不同时间段接受相同剂量的ADM，并分别与NEP抑制剂硫磷酰胺（30 nmol·min⁻¹）或对照血管收缩剂去甲肾上腺素（120 pmol·min⁻¹）联合输注。两项研究均采用双盲、随机方式进行。
ADM和PAMP使FBF呈剂量依赖性增加（P≤0.002）。基于使FBF增加50%的剂量，ADM的效力约为PAMP的60倍。硫磷酰胺和去甲肾上腺素分别使FBF降低了相似的幅度，即14±4%（平均值±标准误平均值）和22±6%（P = 0.4）。然而，ADM与硫磷酰胺联合输注期间的剂量 - 反应曲线下面积显著大于与去甲肾上腺素联合输注时（P = 0.028），FBF比值的最大增加幅度也是如此（2.1±1.0对1.2±0.2；P = 0.030）。
ADM和PAMP均可在人体前臂产生局部剂量相关的血管舒张作用，但PAMP的效力约比ADM低60倍。此外，NEP抑制可增强ADM的血流动力学效应。这些发现表明PAMP可能在血流量的生理调节中不起作用。然而，在高血压和心力衰竭等病理生理状态下，NEP抑制可能通过增加ADM的生物活性发挥有益作用。
