The preischemic combination of the sodium-hydrogen exchanger inhibitor cariporide and the adenosine agonist AMP579 acts additively to reduce porcine myocardial infarct size.

BACKGROUND

We tested whether the combination of two known cardioprotective agents, the type-1 sodium-hydrogen exchanger inhibitor cariporide plus the adenosine A(1)/A(2a) receptor agonist AMP579 ([1S-[1a,2b,3b, 4a(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-methylpropyl]amino]-[(3)H]-imidazo[4,5-b]pyridyl-3-yl]cyclopentane carboxamide), acted additively to reduce myocardial infarct size.

METHODS

Pigs underwent 1 hour of coronary artery occlusion and 3 hours reperfusion. Vehicle-treated controls were compared with animals treated before ischemia with low-dose and high-dose cariporide and AMP579, and low-dose cariporide plus AMP579. The effects of both agents, alone and in combination, were also tested in isolated porcine polymorphonuclear neutrophils (PMNs). The PMN respiratory burst was induced with phorbol 12-myristate 13-acetate and quantified by the increase in 2',7'-dichlorofluorescein fluorescence, measured by flow cytometry.

RESULTS

Infarct size in the control pigs was 65 +/- 1% of the area at risk. Cariporide dose-dependently reduced infarct size to 39 +/- 2% and 24 +/- 3% in the low- and high-dose groups, respectively. Infarct size was 54 +/- 3% in the low-dose AMP579 group and 47 +/- 3% with high dose. The combination of low doses of cariporide and AMP579 reduced infarction to 25 +/- 6% of the area at risk. In the PMN studies, cariporide and AMP579 alone had no effect on 2',7'-dichlorofluorescein fluorescence, but the combination of the two agents reduced the PMN 2',7'-dichlorofluorescein increase to 79 +/- 5% of the vehicle control response.

CONCLUSIONS

The preischemic combination of low doses of cariporide and AMP579 decreased myocardial infarct size more than either agent used alone in low concentration, indicating an additive effect of the two agents. Given the effects that cariporide plus AMP579 combination exerted on PMN activity, it appears that this combination has the potential to reduce PMN-mediated effects during myocardial reperfusion.