Chromogranin A (CGA) is present in various endocrine glands and in the central nervous system (Helle, 2004). In human plasma CGA concentration is nanomolar and increases in the presence of neuroendocrine tumors and heart failure (Ceconi et al. 2002). The CGA N-terminal 1-76 peptide has been named vasostatin-1 (VS-1) because of the inhibition of vasomotor tone. In isolated eel, frog and rat hearts, physiological concentrations of VS-1 depress contractility and counteract the effect b-adrenergic stimulation (Tota et al. 2004). In rat heart Langendorff preparations perfused at constant flow, VS-1-depending negative inotropic effect is abolished by the blockade of b-adrenergic receptors, Gi/o protein and NO-cGMP-PKG pathway (Angelone et al. 2004). On the basis of the above findings, a possible role of VS-1 in limiting the extent of the necrosis induced by ischaemia and reperfusion (I/R) was studied in the present investigation. Hearts excised from humanely killed Wistar rats were attached to a perfusion apparatus, perfused at constant flow with oxygenated Krebs-Henseleit buffer, paced at 280 b.p.m. and kept at 37°C. Left ventricular pressure (LVP) and aortic pressure (AP) were measured. In the control AP was about 90 mmHg for a coronary flow of 20 ml/min. Developed LVP was taken as an index of contractility. Infarct size was determined with the nitro-blue tetrazolium technique. The release of lactic dehydrogenase (LDH) was determined on samples of effluent fluid taken at regular intervals during reperfusion. The hearts were divided into four groups. Group I (n=5) was used as control. Before ischaemia, ischaemic preconditioning was performed in Group II (n=10) and VS-1 at 80 nM concentration for 19 min was given to Group III (n=12). Finally a 10 μM solution of the NO-synthase inhibitor L-N-nitroarginine (L-NNA) was infused into the hearts of Group IV (n=4), 5 min before, during and 5 min after the end of the infusion of VS-1. In Group I, necrosis affected 66±16% of left ventricle and was reduced to 34±18% (p<0.002) in preconditioned Group II. In VS-1-pretreated Group III, infarction was limited to 32±10% of the ventricle (p<0.001 vs. Group I and n.s. vs. Group II). In Group IV the protection by VS-1 was completely suppressed by L-NNA. During reperfusion LVP recovery was proportional to the extent of protection. The release of LDH, measured to confirm the extent of the damage by I/R, was 1813±670 U.L. in Group I, 780±226 in Group III (p<0.01) and 1129±322 in Group IV (n.s.). The results show that VS-1 limits the damage caused by I/R and that the protective activity is mediated by NO signalling.