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The acidic protein chromogranin A (CgA) is the precursor of several regulatory peptides generated by specific proteolytic processes. Human recombinant CgA NH₂-terminal fragment STA-CgA_1-78 (hrSTA-CgA_1-78), containing vasostatin-1 (CgA_1-76) domain, exerts a negative inotropic effect and counteracts the β-adrenergic positive inotropic effect on the rat heart. We hypothesized an involvement of nitric oxide (NO)-dependent pathway in both cardiodepression and cardioprotection by hrSTA-CgA_1-78. We also hypothesized an involvement of adenosine A₁ receptor and protein kinase C (PKC) in cardioprotection by hrSTA-CgA_1-78. Therefore, we evaluated whether 1) the cardioinhibition mediated by hrSTA-CgA_1-78 involves the G_i/o proteins/NO-dependent signal transduction cascade, 2) hrSTA-CgA_1-78 induces ischemic preconditioning-like protective effects on the myocardium, and 3) inhibition of NO …