Reduction of myocardial infarct size by SM-198110, a novel Na+/H+ exchange inhibitor, in rabbits.
The effects of 3-[2-({[amino(imino)methyl]amino}carbonyl)-4-chloro-1H-indol-1-yl]-1-propanesulphonic acid monohydrate (SM-198110), a novel potent Na+/H+ exchange inhibitor, and cariporide (Hoe642), another Na+/H+ exchange inhibitor, were studied in a myocardial ischaemia and reperfusion injury model. Anaesthetized rabbits were subjected to occlusion of the coronary artery for 30 min followed by reperfusion for 5 h. SM-198110 or cariporide was administered before ischaemia and before reperfusion. We also assessed the anti-necrotic effect of SM-198110 when given before reperfusion, both alone and together with glibenclamide, a K(ATP) channel blocker, 5-hydroxydecanoate (5-HD), a mitochondrial K(ATP) channel-selective blocker and 8-(p-sulphophenyl)-theophylline (8-SPT), an adenosine receptor blocker. The infarct size was reduced dose-dependently by i.v. administration of SM-198110 before ischaemia, with a significant reduction in serum creatine phosphokinase activity. Infarct sizes, normalized to the size of the area-at-risk (means+/-SE) were: vehicle 56.6+/-3.7%; low-dose SM-198110 39.2+/-6.3%; mid-dose 32.8+/-7.4% (P < 0.05); high-dose 22.1+/-6.7% (P < 0.01). This anti-necrotic effect of SM-198110 was achieved without significant haemodynamic changes. Cariporide given before ischaemia also reduced infarct size significantly and dose-dependently. SM-198110 administered before reperfusion also resulted in a dose-dependent reduction in the infarct size. Infarct sizes were: vehicle 56.6+/-3.7%; low-dose SM-198110 44.5+/-5.7%; mid-dose 36.3+/-6.6% (P < 0.01); high-dose 34.7+/-3.8% (P < 0.01). In contrast, cariporide given before reperfusion did not reduce infarct sizes significantly. The anti-necrotic effect of SM-198110 was observed even when given 10 min after the beginning of reperfusion. Glibenclamide and 5-HD abolished the anti-necrotic effect of treatment before reperfusion with SM-198110. However, the co-administration of 8-SPT with SM-198110 did not affect infarct size. These results suggest that, in addition to Na+/H+ exchange inhibition, mitochondrial and/or sarcolemmal K(ATP) channels contribute to the anti-necrotic effect of SM-198110 when the latter is given before reperfusion.
Yamada
Kazuto
K
Research Division, Sumitomo Pharmaceuticals Co., Ltd., 1-98 Kasugadenaka 3-chome, Osaka 554-0022, Japan. yamadak@sumitomopharm.co.jp
Matsui
Kazuki
K
Ogawa
Shoji
S
Yamamoto
Setsuko
S
Mori
Masaya
M
Kitano
Masahumi
M
Ohashi
Naohito
N
D017738:Alkanesulfonic Acids / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D006146:Guanidines / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009336:Necrosis; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D011817:Rabbits; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones / Q000627:therapeutic use*
D017738:Alkanesulfonic Acids; D006146:Guanidines; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093376:sodium-hydrogen exchanger regulatory factor; C068559:propylsulfonic acid; C093373:cariporide; D003402:Creatine Kinase