title: Microtubule stabilization with paclitaxel does not protect against infarction in isolated rat hearts.
abstract: 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.
authors.affiliation: Laboratorio de Cardiología Experimental, Vall d'Hebron University Hospital and Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rodríguez-Sinovas
authors.forename: Elena
authors.initials: E
authors.lastname: Abad
authors.forename: Jose A
authors.initials: JA
authors.lastname: Sánchez
authors.forename: Celia
authors.initials: C
authors.lastname: Fernández-Sanz
authors.forename: Javier
authors.initials: J
authors.lastname: Inserte
authors.forename: Marisol
authors.initials: M
authors.lastname: Ruiz-Meana
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Alburquerque-Béjar
authors.forename: David
authors.initials: D
authors.lastname: García-Dorado
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D050257:Tubulin Modulators / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D050257:Tubulin Modulators; D017239:Paclitaxel; D003078:Colchicine