4th US/Japan Symposium on Molecular and Cellular Aspects of Vascular Smooth Muscle Functions

Webb, R. Clinton; Karaki, H

doi:10.1159/000025682

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“…In the preliminary experiments, we examined the acute effect of DXR on smooth muscle contractility in a freshly isolated artery and found that DXR induced neither contraction nor relaxation at a dosage of 0.3 – 10 μ M . We also examined the effects of serum‐free organ culture on smooth muscle morphology and contractility (Figures 1, 2, 4 and 6), and confirmed that smooth muscle morphology was well maintained and smooth muscle contractility was preserved in the rabbit mesenteric arteries cultured in the serum‐free DMEM for 7 days, as reported previously ( Webb & Karaki 1999 ; Yamawaki et al ., 2000 ).…”

Section: Discussionsupporting

confidence: 83%

Chronic vascular toxicity of doxorubicin in an organ‐cultured artery

Murata

Yamawaki

Hori

et al. 2001

British J Pharmacology

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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.

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Section: Discussionsupporting

confidence: 83%