Microtubule stabilization with paclitaxel does not protect against infarction in isolated rat hearts

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Microtubules play a major role in the transmission of mechanical forces within the myocardium and in maintenance of organelle function. However, this intracellular network is disrupted during myocardial ischaemia–reperfusion. We assessed the effects of prevention of microtubule disruption with paclitaxel on ischaemia–reperfusion injury in isolated rat cardiomyocytes and hearts. Isolated rat cardiomyocytes were submitted to normoxia (1 h) or 45 min of simulated ischaemia (pH 6.4, 0% O2, 37°C) and reoxygenation, without or with treatment with the microtubule stabilizer, paclitaxel (10−5 m), or the inhibitor of microtubule polymerization, colchicine (5 × 10−6 m). Simulated ischaemia leads to microtubule disruption before the onset of ischaemic contracture. Paclitaxel attenuated both microtubule disruption and the incidence of hypercontracture, whereas treatment with colchicine mimicked the effects of simulated ischaemia and reoxygenation. In isolated normoxic rat hearts, treatment with paclitaxel induced concentration-dependent decreases in heart rate and left ventricular developed pressure and increases in perfusion pressure. Despite protection against hypercontracture, paclitaxel pretreatment did not modify infarct size (60.37 ± 2.27% in control hearts versus 58.75 ± 10.25, 55.44 ± 10.32 and 50.06 ± 10.14% after treatment with 10−6, 3 × 10−6 and 10−5 m of paclitaxel) after 60 min of global ischaemia and reperfusion in isolated rat hearts. Lack of protection was correlated with a higher increase in cytosolic calcium levels during simulated ischaemia in cardiomyocytes treated with paclitaxel (2.32 ± 0.15 versus 1.13 ± 0.16 a.u. in the presence or absence of 10−6 m paclitaxel, respectively, P < 0.05), but not with changes in aortic reactivity. In conclusion, microtubule stabilization with paclitaxel reduces hypercontracture in isolated rat cardiomyocytes but does not protect against infarction in isolated rat hearts.

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