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In contrast, in the present study we have investigated the infarct size-limiting effect of ischaemic postconditioning in isolated rabbit hearts and measured changes in cardiac MMP�C2 activity. To examine the link between MMP inhibition and ischaemic postconditioning cardioprotection, we have also studied the possible infarct size-limiting effect of pharmacological inhibition of MMPs with doxycycline, administered during the first 2 min of reperfusion. Doxycycline is a member of the tetracycline family of GPX4 antibiotics that has been shown to inhibit MMP expression and activity (Golub et al. 1991). New Zealand white male rabbits (1.8�C2.0 kg) were used. Experiments were approved by the Animal Care and Research Committee of the University of Buenos Aires, and this investigation conforms to the guidelines from the American Physiological Society Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication no. 85�C23, revised 1996). Rabbits were anaesthetized with a mixture intramuscular of ketamine (75 mg kg?1) and xylazine (0.75 mg kg?1), and then killed with an intravenous thiopentone (35 mg kg?1). The heart was excised from the animal and placed in a perfusion system according to the Langendorff technique. The heart was perfused with a Krebs�CHenseleit buffer containing Selleckchem Osimertinib (mm): NaCl, 118.5; KCl, 4.7; NaHCO3, 24.8; KH2PO4, 1.2; MgSO4, 1.2; CaCl2, 2.5; and glucose, 10 and gassed with 95% O2?5% CO2 at 37��C in order to maintain a pH 7.2�C7.4. Two electrodes were sutured Alectinib ic50 in right atrium and connected to a pacemaker to produce a constant heart rate of 200 beats min?1. A latex balloon connected to a pressure transducer (Deltram II, Utah Medical System, Midvale, UT, USA) via a polyethylene cannula (internal diameter: 2 mm; outer diameter: 3.7 mm) was inserted into the left ventricle (LV) for measurement of LV pressure. The latex balloon was filled with water to achieve a LV end-diastolic pressure of 8�C10 mmHg. We also recorded the coronary perfusion pressure (CPP) through a pressure transducer connected to the perfusion line. All hearts were perfused with constant flow. Coronary flow was adjusted to obtain a CPP of 70.5 �� 4.2 mmHg during the initial stabilization periodand was then maintained constant throughout the experiment. In a heart perfused at a constant coronary flow, the coronary perfusion pressure indicates coronary vascular resistance. The left ventricular pressure and CPP were recorded in real time using a computer with data acquisition hardware (National Instruments, NI PCI-6013, Austin, TX, USA) and software developed by the Department of Electronic Engineering, University of Buenos Aires, Argentina. The left ventricular developed pressure (LVDP) was calculated as the difference between peak systolic pressure and left ventricular end-diastolic pressure (LVEDP).