Y. Hotta et al., Protective effect of SM-20550, a selective Na+-H+ exchange inhibitor, on ischemia-reperfusion-injured hearts, J CARDIO PH, 37(2), 2001, pp. 143-154
Citations number
54
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
The protective effects of Na+-H+ exchange inhibitors SM-20550 (SM) and 5-(N
-ethyl-N-isopropyl)-amiloride (EIPA) against ischemia-reperfusion injury we
re investigated in guinea pig Langendorff hearts. The changes in intracellu
lar pH (pH(i)), high-energy phosphates, and biologic intracellular active i
ons ([Na+](i) and [Ca2+](i)) were regarded using the P-31-NMR and specific
fluorescent signals from the heart tissues together with simultaneous recor
dings of the left ventricular developed pressure (LVDP). The recovery rate
of LVDP from ischemia (30 min) by reperfusion was 36.8% in the control expe
riments, whereas in the presence of SM 10(-7) M, a gradual increase to 75.9
% (55.5% with 10(-8) M), in contrast to EIPA (10(-7) M), 47.5% was observed
. SM 10(-7) M restored the ATP level by 70% in 40-min reperfusion, which wa
s already higher than the control in the latter half (20-40 min) of the isc
hemic period. The recovery rate of phosphocreatine by pretreatment of the h
eart with SM 10(-7) M was 75% in 30 min reperfusion. The pH(i) estimated fr
om Pi/phosphoureatine chemical shift became highly acidic in ischemic heart
so that SM 10(-7) M caused slight but significant pH(i) reduction from con
trol pill of 5.89 to 5.75. The level returned to pH(i) at around 7.38 durin
g 30-40 min reperfusion, and the recovery was significantly greater than th
e control pH(i) of 7.24. The fura-2 Ca2+ or SBFI-Na+ signals during Langend
orff ischemia heart increased, and rapidly returned to the control level af
ter the reperfusion, SM suppressed the [Na+](i) or [Ca2+](i) elevation indu
ced in the late stage during ischemia, resulting in LVDP restoration after
reperfusion; Diastolic Ca2+ in the end period of ischemia, SM 10(-7) M 194%
versus drug free 220.7%, Na+: SM 10(-7) M 121.6% versus drug-free 128.0%.
The present results suggest that the selective Na+-H+ exchange inhibitor SM
is promising as a potent and specific protective agent against ischemia-re
perfusion injuries with Ca2+ overload induced via Na+-H+, Na+-Ca2+ exchange
.