What is the central question of this study? The microtubule network is disrupted during myocardial ischaemia-
reperfusion injury. It was suggested that prevention of microtubule disruption with
paclitaxel might reduce cardiac
infarct size; however, the effects on
infarction have not been studied. What is the main finding and its importance?
Paclitaxel caused a reduction in microtubule disruption and cardiomyocyte hypercontracture during ischaemia-reperfusion. However, it induced a greater increase in cytosolic
calcium, which may explain the lack of effect against
infarction that we have seen in isolated rat hearts. The large increase in perfusion pressure induced by
paclitaxel in this model may have clinical implications, because detrimental effects of the
drug were reported after its clinical application. 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.