title: Mitochondrial KATP channels participate in the limitation of infarct size by cariporide.
abstract: The objective of this study is to assess the participation of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels in the cardioprotective effects of the Na(+)/H(+) exchanger (NHE-1) blocker cariporide in isolated rat hearts. Regional ischemia was induced by occlusion of left anterior descending coronary artery during 40 min followed by 2-h reperfusion (IC). Cariporide (C, 10 μΜ), or C plus 5-hydroxydecanoate (5-HD, 100 μM, a selective mitoK(ATP) channel inhibitor), or C plus chelerythrine (Chele, 1 μM, a PKC inhibitor), or an opener of mitoK(ATP) channels, diazoxide (Dz, 100 μM) was applied at the onset of reperfusion. Infarct size (IS) and myocardial function were evaluated. The calcium-induced permeability transition pore (mPTP) opening was determined by measuring the light scattering decrease (LSD, a.u.) in isolated mitochondria in the absence and presence of C, C + 5-HD and Dz. IS was 33 ± 2% of the risk area in IC and was significantly diminished by C (15 ± 2%, p < 0.05), which also improved myocardial function [LVDP = 58 ± 5% (IC) vs 80 ± 5% (C)] and blunted LSD [0.80 ± 0.04 (IC) vs 0.51 ± 0.04 (C) a.u.]. 5-HD and Chele were both able to abolish the cardioprotective effects of C on IS. Dz treatment decreased IS and LSD to a similar extent to that produced by C (15 ± 4% and 0.52 ± 0.04 a.u., respectively). The present data suggest that attenuation of mPTP opening after PKC-mediated mitoK(ATP) channel activation is a crucial step for the cardioprotective effects of cariporide.
authors.affiliation: Fellowship of CONICET, Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina.
authors.forename: Ignacio Pérez
authors.initials: IP
authors.lastname: Nuñez
authors.forename: Juliana
authors.initials: J
authors.lastname: Fantinelli
authors.forename: Luisa F González
authors.initials: LF
authors.lastname: Arbeláez
authors.forename: Susana M
authors.initials: SM
authors.lastname: Mosca
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D006146:Guanidines / Q000494:pharmacology*; D006880:Hydroxy Acids / Q000494:pharmacology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D015221:Potassium Channels / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D003652:Decanoic Acids; D006146:Guanidines; D006880:Hydroxy Acids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015221:Potassium Channels; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C117780:mitochondrial K(ATP) channel; C052853:5-hydroxydecanoic acid; C093373:cariporide; D011493:Protein Kinase C; D003981:Diazoxide; D002118:Calcium