Differences in the effects of Na+-H+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts.
The protective effects of the Na+-H+ exchange (NHE) inhibitors SM-198110 (2-[[(aminoiminomethyl) amino] carbonyl]-4-chloro-1H-indole-1-propanesulfonic acid monohydrate) and SM-197378 (N-(aminoiminomethyl)-1-methyl-7-(sulfooxy)-4-(trifluoromethyl)-1H-indole-2-carboxamide monohydrate) were investigated in perfused Langendorff guinea-pig hearts subjected to ischemia (40 min) and reperfusion (40 min). The recovery of left ventricular developed pressure (LVDP) from ischemia by reperfusion was 39.0% in the control, while in the hearts pretreated with SM-198110 or SM-197378 (10(-7) M), it was about 100%. The ATP level, monitored simultaneously by (31)P-nuclear magnetic resonance spectrometry, was already higher than the control value at the end of the ischemic period, and the elevation in Na+ or Ca2+ fluorometric signals induced during ischemia was suppressed. In post-treated hearts, the LVDP recovery rate was significantly higher with SM-198110 than with SM-197378. By in vitro electron paramagnetic resonance spectrometry, SM-197378 was found to directly quench the active oxygen radical, whereas SM-198110 had no effect. Numbers of apoptotic cardiomyocytes after ischemia (1 h) followed by reperfusion (5 h) were significantly lower in SM-197378-treated than in SM-198110-treated hearts, consistent with the level of activity of caspase-3. These results suggest that the antioxidant effects of NHE inhibitors have an important role in apoptosis during ischemia-reperfusion, but apoptosis is not a major manifestation of cardiac function during postischemic recovery, and that NHE-sensitive mechanisms of reperfusion injury promote both necrotic and apoptotic processes death.
Hotta
Yoshihiro
Y
Department of Pharmacology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
Nishimaki
Haruaki
H
Takeo
Tomohiro
T
Itoh
Gen
G
Yajima
Michio
M
Otsuka-Murakami
Hidetsugu
H
Ishikawa
Naohisa
N
Kawai
Norio
N
Huang
Lei
L
Yamada
Kazuto
K
Yamamoto
Setsuko
S
Matsui
Kazuki
K
Ohashi
Naohito
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D002469:Cell Separation; D003326:Coronary Circulation / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005470:Fluorometry; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D017665:Hydroxyl Radical / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019831:Sodium-Calcium Exchanger / Q000187:drug effects; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D013481:Superoxides / Q000378:metabolism
D027682:Cation Transport Proteins; D008565:Membrane Proteins; C490997:Slc9a1 protein, mouse; D019831:Sodium-Calcium Exchanger; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013481:Superoxides; D017665:Hydroxyl Radical; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases