The effects of tubulin-binding agents on stretch-induced ventricular arrhythmias

Parker, Kevin Kit; Taylor, Luke; Atkinson, B. W.; Hansen, David E.; Wikswo, John P.

doi:10.1016/s0014-2999(01)00856-1

Cited by 35 publications

(33 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These observations were confirmed with a range of colchicine concentrations (1-100 μM), but treatment with taxol (5 μM) increased the frequency of these type of arrhythmias [54]. It seems likely these effects were due to microtubule-related alterations in the mechanical properties of the myocardium because taxol is reported to reduce intracellular Ca 2+ transients [30], which in isolation, would be expected to be anti-arrhythmic.…”

Section: Responses Of Microtubules To Mechanical Stimulationmentioning

confidence: 70%

“…It seems likely these effects were due to microtubule-related alterations in the mechanical properties of the myocardium because taxol is reported to reduce intracellular Ca 2+ transients [30], which in isolation, would be expected to be anti-arrhythmic. The observations of Parker et al [54] are interesting because in addition to a role in the contractile dysfunction of the heart, microtubules may also play a role in the increased incidence of arrhythmias in pressure-overloaded hearts. This speculation assumes that taxol-stabilised microtubules are equivalent to the MAP4 and post-translationally modified, stabilised microtubules described in pressure-overloaded hearts.…”

Section: Responses Of Microtubules To Mechanical Stimulationmentioning

confidence: 99%

See 1 more Smart Citation

Mechanical modulation of cardiac microtubules

White

2011

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Microtubules are a major component of the cardiac myocyte cytoskeleton. Interventions that alter it may influence cardiac mechanical and electrical activity by disrupting the trafficking of proteins to and from the surface membrane by molecular motors such as dynein, which use microtubules as tracks to step along. Free tubulin dimers may transfer GTP to the α-subunits of G-proteins, thus an increase in free tubulin could increase the activity of G-proteins; evidence for and against such a role exists. There is more general agreement that microtubules act as compression-resisting structures within myocytes, influencing visco-elasticity of myocytes and increasing resistance to shortening when proliferated and resisting deformation from longitudinal shear stress. In response to pressure overload, there can be post-translational modifications resulting in more stable microtubules and an increase in microtubule density. This is accompanied by contractile dysfunction of myocytes which can be reversed by microtubule disruption. There are reports of mechanically induced changes in electrical activity that are dependent upon microtubules, but at present, a consensus is lacking on whether disruption or proliferation would be beneficial in the prevention of arrhythmias. Microtubules certainly play a role in the response of cardiac myocytes to mechanical stimulation, the exact nature and significance of this role is still to be fully determined.

show abstract

Section: Responses Of Microtubules To Mechanical Stimulationmentioning

confidence: 70%

Section: Responses Of Microtubules To Mechanical Stimulationmentioning

confidence: 99%

Mechanical modulation of cardiac microtubules

White

2011

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

show abstract

“…One such study demonstrated that microtubule depolymerizing agents increase the probability that L-type Ca 2+ channels are in a closed state, whereas microtubule-stabilizing agents increase the probability that they are in an open state [68]. Consequently, hearts treated with microtubule stabilizing agents are more susceptible to stretch-activated arrhythmias [138]. The actin cytoskeleton has also been linked to ion channel behavior, as actin filament disruptors affect the gating of K(ATP) channels [67,171].…”

Section: Excitabilitymentioning

confidence: 99%

Mechanotransduction: the role of mechanical stress, myocyte shape, and cytoskeletal architecture on cardiac function

McCain

Parker

2011

Pflugers Arch - Eur J Physiol

Self Cite

195

178

View full text Add to dashboard Cite

Mechanotransduction refers to the conversion of mechanical forces into biochemical or electrical signals that initiate structural and functional remodeling in cells and tissues. The heart is a kinetic organ whose form changes considerably during development and disease, requiring cardiac myocytes to be mechanically durable and capable of fusing a variety of environmental signals on different time scales. During physiological growth, myocytes adaptively remodel to mechanical loads. Pathological stimuli can induce maladaptive remodeling. In both of these conditions, the cytoskeleton plays a pivotal role in both sensing mechanical stress and mediating structural remodeling and functional responses within the myocyte.

show abstract

“…The probability of eliciting a stretch-induced arrythmia increased in hearts treated with PTX, indicating the possible mode of arrhythmogenesis in patients receiving chemotherapy [10].…”

Section: Introductionmentioning

confidence: 99%

Cardiotoxicity of doxorubicin/paclitaxel combination in rats: Effect of sequence and timing of administration

Saad

Najjar

Alashari

2004

J Biochem & Molecular Tox

View full text Add to dashboard Cite

The higher incidence of cardiotoxicity of doxorubicin (DOX)/paclitaxel (PTX) combination compared with DOX alone remains to be a major obstacle against effective chemotherapeutic treatment. We investigated the effect of sequence and time interval between administration of both drugs on the severity of cardiotoxicity of the combination. Male Wistar rats were divided into seven groups. DOX was administered intraperitoneally (i.p.) at a single dose of 5 mg x kg(-1) every other 2 days, 2 doses per week for a total cumulative dose of 20 mg x kg(-1). PTX was administered by an i.p. route at a dose of 20 mg x kg(-1) every other 2 days. Both drugs were injected either alone or sequentially in combination. In one case, DOX preceded PTX by 30 min and 24 h and in the other case, PTX preceded DOX by 30 min and 24 h. Cardiotoxicity was evaluated by both biochemical and histopathological examination, 48 h after the last DOX dose. DOX-induced cardiotoxicity was manifested by abnormal biochemical changes including marked increases in serum creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and aspartate aminotransferase (AST) activity levels. Myocardial tissue from DOX-treated rats showed significant increases in malondialdehyde (MDA) production and total nitrate/nitrite (NOx) levels, parallel with depletion of "endogenous antioxidant reserve," including GSH contents and GSH-Px activity level. PTX treatment produced significant changes in the biochemical parameters measured by a lower magnitude than those changes produced by DOX alone. Combination of both drugs resulted in aggravation of DOX-induced cardiotoxicity regardless the sequence and time interval between administration of either drug. Administration of PTX 30 min and 24 h after DOX treatment showed exaggeration of combination-induced cardiotoxicity compared with the reverse sequence. This exacerbation was manifested by much more pronounced changes in serum and cardiac tissue parameters measured. Histopathological examination of ventricles of rat's heart revealed that DOX treatment produced myo-cytolysis and myocardial necrosis. Administration of PTX following DOX treatment showed extensive myocardial necrosis compared with those rats treated with either DOX alone or the reverse sequence of administration. Moreover, rats treated with PTX 24 h after DOX treatment showed exaggeration of the combination-induced cardiotoxicity. In conclusion, PTX might synergistically aggravate DOX-induced cardiotoxicity. The effect might be much more pronounced with those rats treated with PTX 24 h after DOX treatment.

show abstract

The effects of tubulin-binding agents on stretch-induced ventricular arrhythmias

Cited by 35 publications

References 30 publications

Mechanical modulation of cardiac microtubules

Mechanical modulation of cardiac microtubules

Mechanotransduction: the role of mechanical stress, myocyte shape, and cytoskeletal architecture on cardiac function

Cardiotoxicity of doxorubicin/paclitaxel combination in rats: Effect of sequence and timing of administration

Contact Info

Product

Resources

About