1. We examined the mechanisms underlying Ca2+-induced relaxation in the presence of clentiazem, a new Ca2+-antagonist, in depolarized coronary arteries of the dog. 2. Ca2+ (3 x 10(-5)-3 x 10(-3) M) caused an unexpected relaxation in the presence of a high concentration of clentiazem (10(-6) M) in coronary, but not in mesenteric or renal arteries. 3. The Ca2+-induced relaxation was also observed in the presence of established Ca2+-antagonists such as diltiazem (3 x 10(-6) M), nifedipine (3 x 10(-8) M) and verapamil (3 x 10(-6) M). 4. The Ca2+-induced relaxation was inhibited by removal of the endothelium, treatment with oxyhaemoglobin (1.5 x 10(-6) M) or methylene blue (10(-5) M), but not by treatment with indomethacin (5 x 10(-6) M). 5. The Ca2+-induced relaxation was observed in an endothelium-denuded coronary artery segment when closely apposed to an endothelium-containing segment of coronary or mesenteric artery. 6. These results suggest that Ca2+-induced relaxation in the presence of high concentrations of Ca2+-antagonists is mediated through endothelium-derived relaxing factor (EDRF). In addition, Ca2+-antagonists do not affect the Ca2+-influx necessary for the release and/or synthesis of EDRF.