In vitro and in vivo pharmacology of a structurally novel Na+-H+ exchange inhibitor, T-162559

Abstract

1. We investigated the inhibitory effects of a non-acylguanidine Na+-H+ exchange (NHE) inhibitor, T-162559 ((5E,7S)-[7-(5-flouro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6H)- quinolinylideneamino] guanidine dimethanesulphonate), on NHE-1, and its cardioprotective effect against ischaemia and reperfusion injury in rats and rabbits. 2. T-162559 inhibited human platelet NHE-1 in a concentration-dependent manner, with an IC50 value of 13±3 nmol 1-1, making it 16 and three times more potent than cariporide IC50: 209±75 nmol 1-1, P<0.01) and eniporide (IC50: 40±11 nmol 1-1, P=0.066), respectively. T-162559 also inhibited rat NHE-1 with an IC50 value of 14±2 nmol 1-1, which was five and three times lower than that of cariporide (IC50: 75±7 nmol 1-1, P<0.01) and eniporide (IC50: 44±2 nmol 1-1, P<0.0 1), respectively. 3. T-162559 inhibited, in a concentration-dependent manner, the reduction in cardiac contractility, progression of cardiac contracture, and increase in lactate dehydrogenase release after global ischaemia and reperfusion in perfused rat hearts. The inhibitory effects of T-162559 were observed at a lower concentration range (10-100 nmol 1-1 than with cariporide and eniporide. T-162559 did not alter basal cardiac contractility or coronary flow after reperfusion, suggesting that it exerts direct cardioprotective effects on the heart. 4. Intravenous administration of T-162559 (0.03 and 0.1 mg kg-1) significantly inhibited the progression of myocardial infarction induced by left coronary artery occlusion and reperfusion in rabbits; the infarct size normalized by area at risk was 74±6% in the vehicle group, and 47±5% and 51±7% in the T-162559-0.03 mg kg-1 and T-162559-0.1 mg kg-1 groups (both P<0.05), respectively. 5. These results indicate that the new structural NHE-I inhibitor T-162559 is more potent than cariporide and eniporide and possesses a cardioprotective effect against ischaemia and reperfusion injury in rat and rabbit models.