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Erythrocyte-derived depressing factor (EDDF), a novel hypotensive factor purified from human erythrocytes, elicits endothelium-dependent vasorelaxation by reducing intracellular Ca2+ in vascular smooth muscle cells. However, its cardiac response is unknown.This study was designed to examine the cardiac contractile response of EDDF under both normotensive and hypertensive conditions.Ventricular myocytes were isolated from adult male spontaneously hypertensive rats (SHR) and age-matched Wistar–Kyoto (WKY) normotensive rats. Mechanical properties were evaluated using an IonOptix MyoCam system and intracellular Ca2+ was measured with fura-2 fluorescence. Myocytes were electrically stimulated to contract at 0.5 Hz. The contractile properties analyzed included peak shortening (PS), time-to-PS (TPS), time-to-90% re-lengthening (TR90), maximal velocity of shortening/re-lengthening (± dl/dt), fura-fluorescence intensity change (ΔFFI), and fura-fluorescence decay rate (τ).SHR rats displayed significantly elevated blood pressure. EDDF (10−9−10−4 g/ml) did not affect PS, TPS, TR90, ΔFFI and τ but depressed ± dl/dt at higher doses in WKY myocytes. However, EDDF depressed PS, ± dl/dt and ΔFFI, shortened TPS without affecting TR90 and τ in SHR myocytes. Pretreatment of the myocytes with the nitric oxide synthase inhibitor Nϖ-nitro-l-arginine methyl ester (l-NAME) did not affect the EDDF-induced inhibition of PS and ± dl/dt in SHR myocytes but unmasked an EDDF-induced negative response in WKY myocytes.These data indicate that EDDF may participate in the modulation of cardiac contractile function under hypertensive, but not normotensive, conditions. The cardiac depressive effect of EDDF is unlikely due to release of nitric oxide, as suggested in vascular smooth muscles.