Szokodi I, Kinnunen P, Tavi P, Weckström M, Tóth M, Ruskoaho H
Department of Cardiovascular Surgery, Semmelweis University Medical School, Budapest, Hungary.
Circulation. 1998 Mar 24;97(11):1062-70. doi: 10.1161/01.cir.97.11.1062.
Adrenomedullin (ADM), a new vasorelaxing and natriuretic peptide, may function as an endogenous regulator of cardiac function, because ADM and its binding sites have been found in the heart. We characterize herein the cardiac effects of ADM as well as the underlying signaling pathways in vitro.
In isolated perfused, paced rat heart preparation, infusion of ADM at concentrations of 0.1 to 1 nmol/L for 30 minutes induced a dose-dependent, gradual increase in developed tension, whereas proadrenomedullin N-20 (PAMP; 10 to 100 nmol/L), a peptide derived from the same gene as ADM, had no effect. The ADM-induced positive inotropic effect was not altered by a calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP8-37, or H-89, a cAMP-dependent protein kinase inhibitor. ADM also failed to stimulate ventricular cAMP content of the perfused hearts. Ryanodine (3 nmol/L), a sarcoplasmic reticulum Ca2+ release channel opener, suppressed the overall ADM-induced positive inotropic effect. Pretreatment with thapsigargin (30 nmol/L), which inhibits sarcoplasmic reticulum Ca2+ ATPase and depletes intracellular Ca2+ stores, attenuated the early increase in developed tension produced by ADM. In addition, inhibition of protein kinase C by staurosporine (10 nmol/L) and blockade of L-type Ca2+ channels by diltiazem (1 micromol/L) significantly decreased the sustained phase of ADM-induced increase in developed tension. Superfusion of atrial myocytes with ADM (1 nmol/L) in isolated left atrial preparations resulted in a marked prolongation of action potential duration between 10 and -50 mV transmembrane voltage, consistent with an increase in L-type Ca2+ channel current during the plateau.
Our results show that ADM enhances cardiac contractility via cAMP-independent mechanisms including Ca2+ release from intracellular ryanodine- and thapsigargin-sensitive Ca2+ stores, activation of protein kinase C, and Ca2+ influx through L-type Ca2+ channels.
肾上腺髓质素（ADM）是一种新的血管舒张和利钠肽，可能作为心脏功能的内源性调节因子发挥作用，因为在心脏中已发现ADM及其结合位点。我们在此描述ADM对心脏的影响以及体外潜在的信号通路。
在离体灌注、起搏的大鼠心脏标本中，以0.1至1 nmol/L的浓度输注ADM 30分钟可诱导心脏舒张末期压力呈剂量依赖性逐渐增加，而肾上腺髓质素原N-20（PAMP；10至100 nmol/L），一种与ADM源自同一基因的肽，无此作用。降钙素基因相关肽（CGRP）受体拮抗剂CGRP8-37或cAMP依赖性蛋白激酶抑制剂H-89并未改变ADM诱导的正性肌力作用。ADM也未能刺激灌注心脏的心室cAMP含量。兰尼碱（3 nmol/L），一种肌浆网Ca2+释放通道开放剂，可抑制ADM诱导的整体正性肌力作用。用毒胡萝卜素（30 nmol/L）预处理，其抑制肌浆网Ca2+ATP酶并耗尽细胞内Ca2+储备，可减弱ADM引起的心脏舒张末期压力早期增加。此外，星形孢菌素（10 nmol/L）抑制蛋白激酶C以及地尔硫䓬（1 μmol/L）阻断L型Ca2+通道可显著降低ADM诱导的心脏舒张末期压力增加的持续期。在离体左心房标本中，用ADM（1 nmol/L）对心房肌细胞进行灌流，导致在10至 -50 mV跨膜电压之间动作电位时程显著延长，这与平台期L型Ca2+通道电流增加一致。
我们的结果表明，ADM通过不依赖cAMP的机制增强心脏收缩力，这些机制包括从细胞内对兰尼碱和毒胡萝卜素敏感的Ca2+储备释放Ca2+、激活蛋白激酶C以及通过L型Ca2+通道内流Ca2+。
