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In vitro and in vivo pharmacology of a structurally novel Na + ‐H + exchange inhibitor, T‐162559
Author(s) -
Kusumoto Keiji,
Igata Hideki,
Abe Akemi,
Ikeda Shota,
Tsuboi Ayako,
Imamiya Eikoh,
Fukumoto Shoji,
Shiraishi Mitsuru,
Watanabe Toshifumi
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704647
Subject(s) - contractility , in vivo , chemistry , pharmacology , sodium–hydrogen antiporter , endocrinology , medicine , biology , sodium , microbiology and biotechnology , organic chemistry
We investigated the inhibitory effects of a non‐acylguanidine Na + ‐H + exchange (NHE) inhibitor, T‐162559 ((5 E ,7 S )‐[7‐(5‐fluoro‐2‐methylphenyl)‐4‐methyl‐7,8‐dihydro‐5(6 H )‐quinolinylideneamino] guanidine dimethanesulphonate), on NHE‐1, and its cardioprotective effect against ischaemia and reperfusion injury in rats and rabbits. T‐162559 inhibited human platelet NHE‐1 in a concentration‐dependent manner, with an IC 50 value of 13±3 nmol l −1 , making it 16 and three times more potent than cariporide IC 50 : 209±75 nmol l −1 , P <0.01) and eniporide (IC 50 : 40±11 nmol l −1 , P =0.066), respectively. T‐162559 also inhibited rat NHE‐1 with an IC 50 value of 14±2 nmol l −1 , which was five and three times lower than that of cariporide (IC 50 : 75±7 nmol l −1 , P <0.01) and eniporide (IC 50 : 44±2 nmol l −1 , P <0.01), respectively. 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 l −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. 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. These results indicate that the new structural NHE‐1 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.British Journal of Pharmacology (2002) 135 , 1995–2003; doi: 10.1038/sj.bjp.0704647