Masataka Shirai

Pirarubicin-induced Endothelium-dependent Relaxation in Rat Isolated Aorta

Abstract— The mechanism of relaxation produced by pirarubicin [(2″R)‐4′‐O‐tetrahydropyranyladriamycin, THP] has been studied in rat isolated aorta. THP (1·5 × 10−6–4·5 × 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 × 10−5 m THP was inhibited by methylene blue (5 × 10−6 m), hydroquinone (10−4 m), phenidone (5 × 10−5 m), haemoglobin (10−6 m) and p‐bromophenacyl bromide (5×10−5 m), but not by indomethacin (2·5 ×10−5 m). The relaxation induced by THP (1·5 × 10−7 − 4·5 × 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 × 10−6 m) and [D‐Pro4, D‐Trp7,9,10]‐substance P(4–11) (1·5 × 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.

Effects of pirarubicin, an antitumor antibiotic, on the cardiovascular system

SummaryIn the present study we examined the effects of pirarubicin [(2″R)-4′-0-tetrahydropyranyladriamycin, THP] on a cardiovascular system. An injection of THP (0.39–3.13 mg/kg, i. v.) reduced the mean blood pressure and caused an increase in the respiratory air rate in anesthetized rats. At 1.5×10−6–1.5×10−5m, THP markedly relaxed a contraction induced by 10−7m norepinephrine in rat aorta with endothelium but not in that without endothelium. At a dose of 0.02–0.5 mg, THP produced an increase in the contractile force and the perfusion flow of isolated perfused guinea pig hearts. At a higher concentration (4.5×10−5–1.5×10−4m), it produced a slight increase in the contractile force of the left atria in guinea pigs. This positive inotropic action of THP was inhibited by diphenhydramine (10−6–5×10−5m), chlorpheniramine (3×10−7–3×10−5m), and tripelennamine (3×10−7–3×10−5m) but not by propranolol (10−6m), cimetidine (10−5m), diltiazem (10−6m), or ryanodine (10−8m). THP given i. v. at 2.5 mg/kg elevated the plasma histamine level in anesthetized dogs. From these data, we conclude that THP mainly relaxed the rat aorta in the presence of endothelium and that at higher concentrations, it increased the contractile force in the cardiac muscle, probably mediated through the release of histamine.

A possible mechanism of endothelium-dependent relaxation induced by pirarubicin and carbachol in rat isolated aorta

Abstract— The mechanism of endothelium‐dependent relaxation induced by pirarubicin, (2″R)‐4′‐O‐tetrahydropyranyladriamycin, THP, or carbachol was investigated in the rat isolated aorta. The relaxant effect of THP (1·5 × 10−6‐4·5 × 10−5 m) or carbachol (10−8‐10−4 m) on the aorta with endothelium was decreased by lowering Ca2+ in the medium. The relaxation induced by THP was not inhibited by pretreatment with verapamil (10−6–10−5 m), and that induced by carbachol was only partially inhibited. However, on replacement of all but 20 Mm Na+ with either Li+ or choline, the THP‐ or carbachol‐induced relaxation was inhibited. Furthermore, the relaxing effect of THP or carbachol was inhibited by pretreatment with amiloride (10−4‐3 × 10−4 m), with ouabain (10−4‐10−3 m), or with K+‐depletion. These results suggest that the THP‐ or carbachol‐induced relaxation depending on endothelium was affected by modifying the calcium ion concentration, and that a Na+–Ca2+ exchange process is involved.