Chronic vascular toxicity of doxorubicin in an organ‐cultured artery

Abstract

1 We investigated the chronic eects 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 mM 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 a 1A -adrenoceptor without any change in the mRNA level. Inhibition of noradrenaline-induced contractions by DXR was attenuated by superoxide dismutase, and a 1A -adrenoceptor protein expression recovered. 3 In the arteries cultured with 1 mM 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 mM 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 mM DXR selectively down-regulates the a 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 mM and necrotic changes at 10 mM. These changes might be responsible for the disturbance of the circulatory system that is often observed during the course of repetitive chemotherapy.

Fluvastatin Prevents Vascular Hyperplasia by Inhibiting Phenotype Modulation and Proliferation Through Extracellular Signal-Regulated Kinase 1 and 2 and p38 Mitogen-Activated Protein Kinase Inactivation in Organ-Cultured Artery

“…23,25 In all experiments, the endothelium was removed from the isolated tail artery. In the preparation for Western blot studies, adventitia was carefully removed as far as possible to avoid the contamination of fibroblast-like cells in the adventitia.…”

“…21 In addition, this experimental system has enabled us to study the long-term pharmacological actions of external stimuli. [22][23][24] Moreover, the vascular organ-culture method makes it possible to dissociate the influence of systemic cellular and humoral immune responses so that the direct effects of drugs on proliferation and the phenotypic change of smooth muscle cells can be investigated in a constant lipid concentration.…”

Organ Culture as a Useful Method for Studying the Biology of Blood Vessels and Other Smooth Muscle Tissues

“…Murata et al (48) investigated the chronic effects of doxorubicin, a commonly used anticancer agent, on morphological and functional changes in the rabbit mesenteric artery using an organ culture system. In arteries cultured with a low concentration (0.3 mM) of doxorubicin, considered a therapeutic concentration, for 7 days, the contractions induced by norepinephrine, but not those induced by endothelin-1 or high K + , were strongly inhibited.…”

Vascular Endothelium Has a Local Anti-Adenovirus Vector System and Glucocorticoid Optimizes Its Gene Transduction

“…12 In brief, muscle tension was recorded isometrically with a force-displacement transducer under a resting tension of 10 mN. Data are shown as the percent relaxation of the steady-state preconstruction.…”

“…The organ culture procedure was performed as described previously. 12 In brief, the main branches of the intrapulmonary arteries were isolated. Each artery was cut into rings with Ϸ1.3 to 1.4 mm diameter and 1.3 to 1.4 mm width.…”