Rademaker Miriam T, Charles Christopher J, Nicholls M Gary, Richards A Mark
Christchurch Cardioendocrine Research Group, University of Otago, Christchurch, New Zealand.
Circ Heart Fail. 2008 Jul;1(2):134-42. doi: 10.1161/CIRCHEARTFAILURE.107.755504. Epub 2008 May 28.
Adrenomedullin 2 (AM2) is a novel member of the calcitonin gene-related peptide family that is thought to play a regulatory role in circulatory homeostasis under normal physiological conditions. The effects of AM2 in heart failure have not been investigated previously.
Two incremental doses of human AM2 (10 and 100 ng[kg.min] for 90 minutes each) were given by intravenous infusion to 8 sheep with pacing-induced heart failure. Compared with time-matched control infusions, AM2 produced dose-dependent increases in left ventricular dP/dt(max) (control 1168+/-138 mm Hg/s versus AM2 high-dose 1402+/-130 mm Hg/s; P<0.01) and cardiac output (2.09+/-0.66 L/min versus 3.81+/-0.30 L/min; P<0.001) and reductions in calculated total peripheral resistance (40+/-6 mm Hg(L.min) versus 21+/-4 mm Hg(L.min); P<0.001), mean arterial pressure (74.4+/-2.4 mm Hg versus 66.2+/-2.5 mm Hg; P<0.001), and left atrial pressure (23.3+/-1.0 mm Hg versus 18.8+/-1.3 mm Hg; P<0.001). AM2 administration also induced significant elevations in plasma cAMP (P<0.01) in association with rises in atrial (P<0.05) and brain (P<0.01) natriuretic peptides and plasma renin activity (P<0.01). Despite the increase in renin activity, plasma aldosterone levels were not significantly altered, whereas the aldosterone/plasma renin activity ratio was reduced (P=0.08). Plasma vasopressin, endothelin-1, and catecholamines levels were also unchanged by AM2. Renal effects of AM2 included increased excretion of sodium (P<0.05), cAMP (P<0.01), and creatinine (P<0.05), with augmented creatinine clearance (P<0.05), and a trend for urine output to rise (P=0.068).
These results indicate that AM2 administration has favorable effects on cardiovascular, endocrine, and renal indexes in heart failure and identify the peptide as a potential therapeutic target in this disease.
肾上腺髓质素2（AM2）是降钙素基因相关肽家族的一个新成员，被认为在正常生理条件下对循环稳态起调节作用。此前尚未研究过AM2在心力衰竭中的作用。
通过静脉输注，向8只起搏诱导型心力衰竭绵羊给予两剂递增剂量的人AM2（分别为10和100 ng/（kg·min），各持续90分钟）。与时间匹配的对照输注相比，AM2使左心室dp/dt（max）呈剂量依赖性增加（对照为1168±138 mmHg/s，AM2高剂量为1402±130 mmHg/s；P<0.01），心输出量增加（2.09±0.66 L/min对3.81±0.30 L/min；P<0.001），计算得出的总外周阻力降低（40±6 mmHg/（L·min）对21±4 mmHg/（L·min）；P<0.001），平均动脉压降低（74.4±2.4 mmHg对66.2±2.5 mmHg；P<0.001），左心房压降低（23.3±1.0 mmHg对18.8±1.3 mmHg；P<0.001）。给予AM2还使血浆cAMP显著升高（P<0.01），同时心房利钠肽（P<0.05）、脑利钠肽（P<0.01）和血浆肾素活性升高（P<0.01）。尽管肾素活性增加，但血浆醛固酮水平无明显变化，而醛固酮/血浆肾素活性比值降低（P=0.08）。AM2对血浆血管加压素、内皮素-1和儿茶酚胺水平也无影响。AM2对肾脏的作用包括钠排泄增加（P<0.05）、cAMP排泄增加（P<0.01）和肌酐排泄增加（P<0.05），肌酐清除率升高（P<0.05），尿量有增加趋势（P=0.068）。
这些结果表明，给予AM2对心力衰竭的心血管、内分泌和肾脏指标有有益影响，并确定该肽为这种疾病的潜在治疗靶点。
