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Vol. 286, Issue 1, 175-183, July 1998
Department of Pharmacology and Toxicology, Medical College of
Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin (R.J.G.,
T.M., J.J.S., G.J.G.) and
Department of Cardiovascular Pharmacology,
Biomed FO/HK, Merck KGaA, Frankfurter Strabe 250, D-64271 Darmstadt,
Germany (N.B., P.S.)
Administration of inhibitors of the Na+/H+
exchanger (NHE) have been shown to produce cardioprotective effects in
a number of animal models of ischemia-reperfusion injury; however,
controversy still exists as to the efficacy of these agents when
administered just before reperfusion. To address this question, the
efficacy of several doses of a new selective NHE-1 isoform inhibitor
(IC50 for inhibition of 22Na uptake in NHE-1
expressing mouse fibroblast cells = 10.4 ± 1.0 nM), EMD
85131 (2-methyl-5-methylsulfonyl-1-(1-pyrrollyl)-benzoylguanidine), was
tested in a canine infarct model in which the left anterior descending
coronary artery was occluded for 60 min followed by 3 hr of
reperfusion. EMD 85131 (0.75 or 3.0 mg/kg) was infused for 15 min
before left anterior descending occlusion or 15 min before reperfusion.
Infarct size was determined by use of the triphenyltetrazolium chloride
histochemical stain and was expressed as a percent of the area at risk.
EMD 85131 (0.75 or 3.0 mg/kg) administered before left anterior
descending occlusion produced a marked (*P < .05) and
dose-related reduction in IS/AAR (24.3 ± 3.6%, control; 9.3 ± 3.4%, EMD 0.75; 6.4 ± 2.3%, EMD 3.0). These two doses of EMD
also produced significant (*P < .05) reductions in infarct
size/area at risk (12.2 ± 2.1%, EMD 0.75; 13.0 ± 2.9%, EMD 3.0) when administered 15 min before reperfusion. These results suggest that selective NHE-1 inhibitors are able to markedly reduce infarct size when given before or during ischemia and also suggest that
these compounds may have clinical utility when administered after the
initiation of an ischemic insult.
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