The effect of trimetazidine (TMZ), an anti-anginal drug, on the mechanical response of the guinea-pig ductus arteriosus placed under conditions of mild hypoxia (PO2 approximately equal to 75 mmHg) was investigated. When the PO2 of the bathing solution was 75 mmHg, TMZ caused a dose-dependent increase in tension. The median effective dose (ED50) for the drug was 8 X 10(-5)M. TMZ-induced increase in tension was not significantly affected by pretreatment of the preparation with adrenoceptor blocking agents, or indomethacin. The amplitude of the PO2-dependent tension was significantly augmented by exposure of the strip to TMZ 10(-4)M, whereas neither the resting tone (low PO2), nor the oxygen-induced contraction (high PO2) were altered. This ability of TMZ to increase the tension response during hypoxia was dependent on the external calcium concentration. Under low PO2 conditions, a contractile activity of 10(-4)M TMZ was unmasked in preparations perfused with 18 mM K+-PSS medium. This response to TMZ disappeared after the removal of calcium from the bath. At the maximally effective dose of 10(-3)M, and during low PO2, the TMZ-induced contractile response changed to a relaxation response when the external K+ concentration was raised more than five fold. The possibility that TMZ stimulates the mechanism by which oxygen normally controls the concentration of free intracellular calcium in the ductus arteriosus is proposed.