Ischemic and pharmacological preconditioning (IP) can successfully limit ischemia/reperfusion (I/R) injury. Since they consist of interventions carried out before an experimental infarction, their clinical importance is limited. Unlike IP, ischemic postconditioning (PostC) consists of a series of brief coronary occlusions followed by reperfusion starting 10-15 s after the beginning of reperfusion (1). Thus PostC can be performed at a selected time after an ischemia. Both a release of reactive oxygen species (ROS) and a reduced production of nitric oxide (NO) during reperfusion contribute to I/R injury (2). This research aims at investigating whether it is possible to induce protection with administration of NO-donors or antioxidant compounds during the first minutes of reperfusion and whether protection is enhanced by the simultaneous administration of the two types of compounds or of hybrid molecules having both effects. Experiments were performed on 40 Langendorff-perfused rat hearts from animal decapitated after general anaesthesia with ketamine. The hearts underwent 30 minutes of ischemia and 2 hours of reperfusion (I/R). Control Group 1 (n=10) underwent I/R only. In Group 2 (n= 6) antioxidant (AOX) compound 2,2,5,7,8-penthamethylcroman-6-olo (1 μM) was added to the buffer solution for 20 min at the beginning of reperfusion. In Group 3 (n=7) AOX was replaced by NO-donor 4-[(dimethylamino)methyl]furoxan-3-carbossiamide (1 μM) and in Group 4 (n=8) AOX and NO-donor have been given together at the same concentrations. Finally in Group 5 (n=9) the hybrid compound 4-((N-((6-idrossi-2,5,7,8-tetrametilcroman-2-il)metil)-N-metilamino)metil)furossan-3-carbossamide (1 μM) was infused for 20 min. Data are mean±SEM. While in the Group 1, the infarct size was 53±3%, it was not significantly modified in the hearts of Group 2 (48±8%) and 3 (37±7). In Group 4 infarct size was significantly (p<0.01, unpaired “t” test) reduced to 26±6% Finally in Group 5 the hybrid (1 μM) significantly (p<0.01) reduced the infart size to 22±5%. After ischemia, diastolic contracture was greater than in the baseline conditions in the Group 1 and after AOX (Group 3), while it was unchanged in all other groups. The results suggest that if AOX and NO-donor properties are concentrated in a hybrid molecule, the protection obtained with 1 μM of this compound is the same as that obtained with 1 μM of AOX plus 1 μM of NO-donor given together.
Combined protective effect of nitric oxide donor and antioxidants in the rat heart
RASTALDO, Raffaella;CAPPELLO, SANDRA;PAGLIARO, Pasquale;MANCARDI, Daniele;DI STILO, Antonella;GASCO, Alberto;
2007-01-01
Abstract
Ischemic and pharmacological preconditioning (IP) can successfully limit ischemia/reperfusion (I/R) injury. Since they consist of interventions carried out before an experimental infarction, their clinical importance is limited. Unlike IP, ischemic postconditioning (PostC) consists of a series of brief coronary occlusions followed by reperfusion starting 10-15 s after the beginning of reperfusion (1). Thus PostC can be performed at a selected time after an ischemia. Both a release of reactive oxygen species (ROS) and a reduced production of nitric oxide (NO) during reperfusion contribute to I/R injury (2). This research aims at investigating whether it is possible to induce protection with administration of NO-donors or antioxidant compounds during the first minutes of reperfusion and whether protection is enhanced by the simultaneous administration of the two types of compounds or of hybrid molecules having both effects. Experiments were performed on 40 Langendorff-perfused rat hearts from animal decapitated after general anaesthesia with ketamine. The hearts underwent 30 minutes of ischemia and 2 hours of reperfusion (I/R). Control Group 1 (n=10) underwent I/R only. In Group 2 (n= 6) antioxidant (AOX) compound 2,2,5,7,8-penthamethylcroman-6-olo (1 μM) was added to the buffer solution for 20 min at the beginning of reperfusion. In Group 3 (n=7) AOX was replaced by NO-donor 4-[(dimethylamino)methyl]furoxan-3-carbossiamide (1 μM) and in Group 4 (n=8) AOX and NO-donor have been given together at the same concentrations. Finally in Group 5 (n=9) the hybrid compound 4-((N-((6-idrossi-2,5,7,8-tetrametilcroman-2-il)metil)-N-metilamino)metil)furossan-3-carbossamide (1 μM) was infused for 20 min. Data are mean±SEM. While in the Group 1, the infarct size was 53±3%, it was not significantly modified in the hearts of Group 2 (48±8%) and 3 (37±7). In Group 4 infarct size was significantly (p<0.01, unpaired “t” test) reduced to 26±6% Finally in Group 5 the hybrid (1 μM) significantly (p<0.01) reduced the infart size to 22±5%. After ischemia, diastolic contracture was greater than in the baseline conditions in the Group 1 and after AOX (Group 3), while it was unchanged in all other groups. The results suggest that if AOX and NO-donor properties are concentrated in a hybrid molecule, the protection obtained with 1 μM of this compound is the same as that obtained with 1 μM of AOX plus 1 μM of NO-donor given together.
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