Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende (CS), Italy.
J Exp Biol. 2010 Nov 1;213(Pt 21):3636-43. doi: 10.1242/jeb.045567.
Catestatin (CST), the 21-amino acid, cationic and hydrophobic peptide proteolytically derived from the ubiquitous chromogranin A (CgA), is an endogenous inhibitor of catecholamine release, a potent vasodilator in vivo and an anti-hypertensive agent in mammals, including humans. Recently, we discovered that CST also functions as an important negative modulator of heart performance in frog and rat. To gain an evolutionary perspective on CST cardiotropism in fish, we analysed the influence of bovine CST (CgA₃₄₄₋₃₆₄) on the eel heart, as well as the eventual species-specific mechanisms of its myocardial action. Experiments were carried out on fresh-water eels (Anguilla anguilla L.) using an electrically paced isolated working heart preparation. Stroke volume and stroke work were used as measures of ventricular performance. Under basal conditions, CST (from 11 nmol l⁻¹ to 165 nmol l⁻¹) caused a concentration-dependent negative inotropism, which was abolished by inhibitors of either β₁/β₂ (propranolol) or β₃ (SR₅₉₂₃₀) adrenergic receptors, or by G(i/o) protein (PTx) or nitric oxide synthase (L-NMMA), or guanylate cyclase (ODQ) blockers. This suggests a β-adrenergic receptor-G(i/o) protein-NO-cGMP-dependent mechanism. By contrast, the CST-induced cardio-suppression was not influenced by atropine, unspecific muscarinic antagonist, thus excluding cholinergic receptor involvement. CST also counteracted the adrenergic (isoproterenol)-mediated positive inotropism. Under increased preload (i.e. Frank-Starling response) conditions, CST induced a significant increase of the Frank-Starling response, which was blocked by L-NMMA and thapsigargin, but independent from guanylate cyclase. In conclusion, this is the first report in fish that CST modulates myocardial performance under basal, as well as under increased preload, conditions and counteracts the adrenergic-mediated positive inotropism, which strikingly supports the evolutionary significance and establishes the cardioactive role of this peptide.
蛙和鼠的研究发现，CST 也是一种重要的心脏功能负调控因子。为了从进化角度阐明鱼类 CST 的心脏活性，我们分析了牛 CST（CgA₃₄₋₃₆₄）对鳗鲡心脏的影响，以及其心肌作用的潜在种间机制。实验在用电刺激起搏的离体工作心脏模型上进行，新鲜鳗鲡（Anguilla anguilla L.）为实验动物。心搏量和每搏功用于衡量心室功能。在基础状态下，CST（浓度 11 nmol l⁻¹ 至 165 nmol l⁻¹）引起浓度依赖性的负性肌力作用，这种作用被β₁/β₂（普萘洛尔）或β₃（SR₅₉₂₃₀）肾上腺素能受体抑制剂、G(i/o)蛋白（PTx）或一氧化氮合酶（L-NMMA）、或鸟苷酸环化酶（ODQ）抑制剂所消除，这提示一种β肾上腺素能受体-G(i/o)蛋白-NO-cGMP 依赖的机制。相反，CST 诱导的心脏抑制不受阿托品、非特异性毒蕈碱拮抗剂影响，因此排除了胆碱能受体的参与。CST 还拮抗了肾上腺素（异丙肾上腺素）介导的正性肌力作用。在增加前负荷（即 Starling 效应）条件下，CST 引起显著的 Starling 效应增加，该效应被 L-NMMA 和 thapsigargin 阻断，但与鸟苷酸环化酶无关。总之，这是鱼类中 CST 调节基础和增加前负荷条件下心肌功能以及拮抗肾上腺素介导的正性肌力作用的首个报道，这强烈支持了 CST 的进化意义，并确立了该肽类的心脏活性作用。
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