Effects of the Na+/H+ exchange inhibitor cariporide (HOE 642) on cardiac function and cardiomyocyte cell death in rat ischaemic-reperfused heart.
1. Na+/H+ exchange has been implicated in the mechanism of reperfusion injury. We examined the effects of the cardiac-specific Na+/H+ exchange inhibitor cariporide (HOE 642) on postischaemic recovery of cardiac function and cardiomyocyte cell death (i.e. necrosis and apoptosis). 2. Rat isolated and buffer-perfused hearts were subjected to 25 min normothermic global ischaemia followed by 120 min reperfusion. Cariporide (10 micromol/L) or its vehicle (0.01% dimethylsulphoxide) was administered for 15 min before ischaemia and for the first 30 min after reperfusion. 3. Cariporide significantly improved the recovery of isovolumic left ventricular function (heart rate, left ventricular developed pressure and left ventricular end-diastolic pressure) and coronary flow throughout reperfusion. Creatine kinase release during reperfusion was significantly less in the cariporide-treated heart. In situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL)-positive cardiomyocytes were also significantly less in the cariporide-treated heart after 120 min reperfusion. Electron microscopy showed necrotic changes without typical apoptotic features in cardiomyocytes after reperfusion. Such necrotic changes were mitigated by cariporide. Simultaneous detection of necrotic and apoptotic cardiomyocytes using propidium iodide (PI) and Annexin V revealed that cardiomyocytes in the infarct area were stained with only PI or both PI and Annexin V. Cariporide did not alter the pattern of cardiomyocyte staining with PI and Annexin V, although the number of cardiomyocytes stained with PI or PI plus Annexin V was less than that in vehicle-treated hearts. 4. These results suggest that apoptosis is not a major manifestation of cardiomyocyte cell death in the ischaemic-reperfused myocardium and a cariporide-sensitive mechanism of reperfusion injury promotes both necrotic and apoptotic processes of cell death.
Otani
H
H
Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Moriguchi, Osaka, Japan. otanih@kmu.takii.ac.jp
Uchiyama
T
T
Yamamura
T
T
Nakao
Y
Y
Hattori
R
R
Ninomiya
H
H
Kido
M
M
Kawaguchi
H
H
Osako
M
M
Imamura
H
H
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide