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Effect of the microtubule polymerizing agent taxol on contraction, Ca2+ transient and L-type Ca2+ current in rat
F C Howarth1, S C Calaghan, M R Boyett
1School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK.
Abstract:
1. Microtubules form part of the cytoskeleton. Their role in adult ventricular myocytes is not well understood although microtubule proliferation has previously been linked with reduced contractile function. 2. We investigated the effect of the anti-tumour drug taxol, a known microtubule polymerizing agent, on Ca2+ handling in adult rat ventricular myocytes. 3. Treatment of cells with taxol caused proliferation of microtubules. 4. In taxol-treated cells there was a reduction in the amplitude of contraction, no significant effect on the amplitude of L-type Ca2+ current, but a significant reduction in the amplitude of the Ca2+ transient. 5. Caffeine was used to release Ca2+ from the sarcoplasmic reticulum (SR). There was a significant reduction in the ratio of electrically stimulated : caffeine-induced Ca2+ transients in taxol-treated cells. This observation is consistent with the hypothesis that taxol reduces fractional SR Ca2+ release. 6. We suggest that the negative inotropic effect of taxol may, at least in part, be the result of reduced release of Ca2+ from the SR. Microtubules may be important regulators of Ca2+ handling in the heart.
Insights
The anti-cancer drug taxol promotes microtubule growth in heart cells, reducing their contraction strength by impairing calcium release from the sarcoplasmic reticulum.
Area of Science:
- Cardiovascular Biology
- Cell Biology
- Pharmacology
Background:
- Microtubules are key cytoskeletal components, but their function in adult ventricular myocytes remains unclear.
- Microtubule proliferation has been associated with diminished cardiac contractile function.
Purpose of the Study:
- To investigate the impact of taxol, a microtubule-disrupting agent, on calcium handling in adult rat ventricular myocytes.
- To explore the relationship between taxol-induced microtubule changes and cardiac contractility.
Main Methods:
- Adult rat ventricular myocytes were treated with taxol.
- Microtubule proliferation was assessed.
- Calcium transients, L-type calcium current, and caffeine-induced calcium release were measured.
Main Results:
- Taxol treatment led to significant microtubule proliferation.
- A reduction in contraction amplitude and calcium transient amplitude was observed.
- Fractional sarcoplasmic reticulum calcium release was significantly reduced in taxol-treated cells.
Conclusions:
- Taxol exerts a negative inotropic effect, potentially due to reduced calcium release from the sarcoplasmic reticulum.
- Microtubules may play a crucial role in regulating calcium handling within the heart.