Chronic vascular toxicity of doxorubicin in an organ-cultured artery.
1. We investigated the chronic effects of doxorubicin (DXR) on morphological and functional changes in the rabbit mesenteric artery using an organ culture system. 2. In arteries cultured with 0.3 microM DXR for 7 days, the contractions induced by noradrenaline, but not those induced by endothelin-1 or high K(+), were strongly inhibited. This reaction was followed by a decrease in the induction of the alpha(1A)-adrenoceptor without any change in the mRNA level. Inhibition of noradrenaline-induced contractions by DXR was attenuated by superoxide dismutase, and alpha(1A)-adrenoceptor protein expression recovered. 3. In the arteries cultured with 1 microM DXR for 7 days, contractions induced by endothelin-1 or high K(+) and absolute force in the permeabilized muscles were also inhibited. Morphological examinations revealed the existence of concentrated nuclei and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL)-positive smooth muscle cells, and internucleosomal DNA fragmentation was also detected, indicating the induction of apoptosis. 4. In the arteries cultured with 10 microM DXR for 7 days, nuclear swelling, karyolysis and random DNA fragmentation indicative of necrosis were observed, and muscle contractility was abolished. 5. These results suggest that 0.3 microM DXR selectively down-regulates the alpha(1A)-adrenoceptor protein expression, resulting in a decrease in the noradrenaline-induced contraction. This down-regulation may be at least partly due to the production of a superoxide radical. DXR also caused a decrease in muscle contractility followed by apoptotic changes at 1 microM and necrotic changes at 10 microM. These changes might be responsible for the disturbance of the circulatory system that is often observed during the course of repetitive chemotherapy.
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.
T
T
Murata
H
H
Yamawaki
M
M
Hori
K
K
Sato
H
H
Ozaki
H
H
Karaki
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002463:Cell Membrane Permeability; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019332:Endothelin-1 / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D009924:Organ Culture Techniques / Q000379:methods; D011188:Potassium / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D044022:Receptor, Endothelin A; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D013997:Time Factors; D010738:Type C Phospholipases / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D000970:Antineoplastic Agents; D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D018340:Receptors, Adrenergic, alpha-1; D017466:Receptors, Endothelin; D004317:Doxorubicin; D013482:Superoxide Dismutase; D010738:Type C Phospholipases; D011188:Potassium; D009638:Norepinephrine