Vasodilating effect of doxorubicin on isolated thoracic aorta and carotid artery of rats and its mechnisms / 中国药理学与毒理学杂志

ABSTRACT

OBJECTIVE To investigate the effect and mechanisms of doxorubicin (DOX) on isolated thoracic aorta and carotid artery of rats. METHODS The cumulative dosing method was used to add DOX every 10 min to reach the final concentrations of 1, 3, 10, 30 and 100 μmol·L-1, and the tension of isolated thoracic aorta and carotid artery in basal tension, precontracted by phenylephrine (PE) 1 μmol ·L-1 and KCI 60 mmol ·L-1, was respectively recorded in vitro vascular ring perfusion apparatus. Furthermore, No-nitro-L-arginine methyl ester (L-NAME), tetraethylammonium (TEA), 4-aminopyridine (4-AP), BaCI2, glibenclamide (Gli), indometacin (Indo) and proparanolol were used to explore the mechnisms of the vasodilating effect of DOX. RESULTS DOX had no effect on the thoracic aorta and carotid artery in basal tension and precontracted by KCI. However, DOX induced concentration-dependent relaxation in both the thoracic aorta and carotid artery precontracted by PE (P<0.05), and it had stronger vasodilating effect on the endothelium-intact thoracic aorta than on the endothelium-denuded thoracic aorta (P<0.05). After the treatment with nitric oxidase inhibitor, L-NAME 0.1 mmol·L-1, calcium activated potassium channel (KCa) inhibitor, TEA 1 mmol·L-1, voltage-dependent potassium channel (KV) inhibitor, 4-AP 1 mmol·L-1 and inward rectifier potassium channel (KIR) inhibitor, BaCI2 1 mmol·L-1, the vasodilating effect of DOX was obviously decreased (P<0.05), but the application of Indo 0.01 mmol ·L-1 Gli 0.01 mmol ·L-1 and β-adrenregic receptor blocker propranolol 0.01 mmol·L-1 had no effect on the vasodilating effect of DOX. Additionally, DOX 1, 10 and 100 μmol·L-1 significantly reduced PE-induced contraction of the thoracic aorta in Ca2+-free solution, and the concentration-effect curve of CaCI2 could be shifted to the right in the presence of DOX (P<0.05). CONCLUSION These results have demonstrated that DOX vasodilating effects on the thoracic aorta and carotid artery are concentration-dependent. The mechanisms are likely to be related to nitric oxide/cGMP pathway, KV, KCa, K1R, intracellular calcium release and extracellular calcium influx.