Pirarubicin-induced endothelium-dependent relaxation in rat isolated aorta.

The mechanism of relaxation produced by pirarubicin [(2"R)-4'-O-tetrahydropyranyladriamycin, THP] has been studied in rat isolated aorta. THP (1.5 x 10(-6)-4.5 x 10(-5) M) markedly relaxed contractions induced by noradrenaline (10(-7) M) in the aorta with endothelium, but not in that without endothelium. The relaxation induced by 1.5 x 10(-5) M THP was inhibited by methylene blue (5 x 10(-6) M), hydroquinone (10(-4) M), phenidone (5 x 10(-5) M), haemoglobin (10(-6) M) and p-bromophenacyl bromide (5 x 10(-5) M), but not by indomethacin (2.5 x 10(-5) M). The relaxation induced by THP (1.5 x 10(-7) -4.5 x 10(-5) M) was inhibited by NG-nitro-L-arginine (10(-5) M), but enhanced by superoxide dismutase (10 units mL-1) or by L-arginine (10(-2) M). However, the THP-induced relaxation was not inhibited by various receptor antagonists such as atropine (10(-6) M), cimetidine (10(-5) M), diphenhydramine (3 x 10(-6) M) and [D-Pro4, D-Trp7,9,10]-substance P(4-11) (1.5 x 10(-6) M). In fifteen anthracycline analogues, THP and 13-dihydropirarubicin (both with a tetrahydropyranyl group) produced endothelium-dependent relaxations. These results suggest that the THP-induced relaxation which is probably mediated by endothelium-derived relaxing factor (EDRF) was not produced by an activation of muscarine, histamine H1 or H2, or substance P receptor, and further that the tetrahydropyranyl group must play an important role in the THP-induced relaxation.