Effects of acute and chronic treatment with the sodium hydrogen exchanger 1 (NHE-1) inhibitor cariporide on myocardial infarct mass in rabbits with hypercholesterolaemia

Abstract

We investigated the cardioprotective effect of acute and chronic sodium hydrogen exchanger 1 (NHE-1) inhibition with cariporide under pathological conditions in rabbits fed an atherogenic diet (0.25% cholesterol, 3% coconut oil), an experimental model of atherosclerosis. New Zealand White rabbits were fed over 4 weeks with normal diet or with atherogenic diet and randomized in 3 subgroups (n=7 in each group); placebo, acute cariporide (0.3 mg/kg, 10 min. before occlusion of left anterior descending coronary artery and chronic cariporide (4 weeks 0.1% in chow). In the final infarction experiments the animals were subjected to 30 min. of myocardial ischaemia by occlusion of a branch of the left anterior descending coronary artery followed by 2 hr of reperfusion. Infarct mass was evaluated by triphenyl-tetrazolium chloride staining and the infarct size expressed as a percentage of area at risk. Besides the assessment of aortic endothelium-dependent function aortic and cardiac vessels were inspected for atherosclerotic lesions. In cholesterol-fed rabbits, the infarct size was significantly increased when compared with normal diet animals (63±3% versus 41±3%). Acute cariporide treatment reduced the infarct size in normal diet rabbits to 14%±3% (66% decrease, P<0.05) as well as in atherogenic diet rabbits to 22±3% (65% decrease, P<0.05). Chronic treatment with cariporide also reduced the infarct size significantly: normal diet 19±2% (53% decrease, P<0.05), atherogenic diet 32±3% (49% decrease, P<0.05). Total cholesterol serum levels in rabbits with atherogenic diet were significantly higher (15.3±2.7 mmol/1) than those on a standard diet (0.65±0.08 mmol/1). Chronic cariporide treatment significantly attenuated the increase of serum cholesterol (7.9±1.9 mmol/l) and improved the lipoprotein pattern. Although the aortas and heart vessels of hypercholesterolaemic animals were without any histological evidence of atherosclerosis they developed endothelial dysfunction (reduced endothelium-dependent relaxation by ACh), which was prevented by chronic cariporide treatment. Acute and chronic treatment with the NHE-1 inhibitor cariporide significantly reduced infarct mass. This effect was associated with improved endothelial function.