Rademaker M T, Charles C J, Lewis L K, Yandle T G, Cooper G J, Coy D H, Richards A M, Nicholls M G
Department of Medicine, The Christchurch School of Medicine, University of Auckland, New Zealand.
Circulation. 1997 Sep 16;96(6):1983-90. doi: 10.1161/01.cir.96.6.1983.
Adrenomedullin is a recently discovered endogenous peptide with hypotensive and natriuretic actions in normal animals. Circulating and ventricular adrenomedullin are elevated in congestive heart failure, suggesting a possible role in the pathophysiology of this disease. No studies have previously examined the effects of adrenomedullin in heart failure.
Eight sheep with pacing-induced heart failure received human adrenomedullin(1-52) at 10 and 100 ng x kg(-1) x min(-1) I.V. for 90 minutes each. Compared with vehicle control data, adrenomedullin increased plasma cAMP (high dose, P<.05) in association with dose-dependent falls in calculated peripheral resistance (13 mm Hg x L(-1) x min(-1), P<.001), mean arterial pressure (9 mm Hg, P<.001), and left atrial pressure (5 mm Hg, P<.001) and increases in cardiac output (0.5 L/min, P<.001). Adrenomedullin increased urine sodium (threefold, P<.05), creatinine (P<.05) and cAMP excretion (P<.01), creatinine clearance (P<.05), and renal production of cAMP (P<.05), whereas urine output was maintained during infusion and raised after infusion (P<.05). Adrenomedullin reduced plasma aldosterone levels (P<.05), whereas plasma atrial and brain natriuretic peptide concentrations were unchanged during infusion and rose after infusion (P<.01 and P<.05, respectively). Plasma catecholamine, cortisol, renin, calcium, and glucose concentrations were not significantly altered.
Adrenomedullin reduced ventricular preload and afterload and improved cardiac output in sheep with congestive heart failure. Despite the clear fall in arterial pressure, adrenomedullin increased creatinine clearance and sodium excretion and maintained urine output. These results imply an important pathophysiological role for adrenomedullin in the regulation of pressure and volume in heart failure and raise the possibility of a new therapeutic approach to this disease.
肾上腺髓质素是一种最近发现的内源性肽，在正常动物中具有降压和利钠作用。充血性心力衰竭时，循环和心室中的肾上腺髓质素水平升高，提示其在该疾病病理生理学中可能发挥作用。此前尚无研究探讨肾上腺髓质素在心力衰竭中的作用。
八只因起搏诱发心力衰竭的绵羊，分别接受静脉注射人肾上腺髓质素（1 - 52），剂量为10和100 ng·kg⁻¹·min⁻¹，各持续90分钟。与溶剂对照数据相比，肾上腺髓质素使血浆环磷酸腺苷（cAMP）升高（高剂量时，P <.05），同时外周阻力呈剂量依赖性下降（13 mmHg·L⁻¹·min⁻¹，P <.001）、平均动脉压下降（9 mmHg，P <.001）、左心房压下降（5 mmHg，P <.001），心输出量增加（0.5 L/min，P <.001）。肾上腺髓质素使尿钠排泄增加（增至三倍，P <.05）、肌酐排泄增加（P <.05）、cAMP排泄增加（P <.01）、肌酐清除率增加（P <.05）以及肾脏cAMP生成增加（P <.05），而输液期间尿量维持不变，输液后尿量增加（P <.05）。肾上腺髓质素降低血浆醛固酮水平（P <.05），而血浆心房利钠肽和脑钠肽浓度在输液期间未改变，输液后升高（分别为P <.01和P <.05）。血浆儿茶酚胺、皮质醇、肾素、钙和葡萄糖浓度无显著变化。
肾上腺髓质素可降低充血性心力衰竭绵羊的心室前负荷和后负荷，改善心输出量。尽管动脉压明显下降，但肾上腺髓质素增加了肌酐清除率和钠排泄，并维持了尿量。这些结果表明肾上腺髓质素在心力衰竭压力和容量调节中具有重要的病理生理作用，并提出了针对该疾病新治疗方法的可能性。
