The Cardioprotective Effects of Novel Na+/H+ Exchanger Inhibitor TY-51924 on Ischemia/Reperfusion Injury

Abstract

The inhibitory effects of sodium 3-guanidinocarbonyl-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9-ylmethyl sulfate monoethanolate (TY-51924) are selective for Na(+)/H(+) exchanger (NHE)-1 in PS120 cells expressing human NHE isoforms assayed by NH(4)Cl prepulse technique. The median inhibitory concentrations (micromolar) of TY-51924 were 0.095 ± 0.008 (NHE-1), 0.621 ± 0.093 (NHE-2), and >100 (NHE-3). In anesthetized dogs subjected to 90 minutes ischemia/300 minutes reperfusion, intravenous bolus TY-51924 at 5 and 10 mg/kg administered 5 minutes before reperfusion reduced infarct size. The infarct size reduction ratios of TY-51924 at 5 and 10 mg/kg versus vehicle were 32.8% and 52.4%, respectively. But TY-51924 at 10 mg/kg administered 10 minutes after reperfusion did not reduce infarct size. In 2-step intravenous infusion initiated 15 minutes before reperfusion, TY-51924 at low dose (3.8 mg/kg per 5 minutes, then 6.2 mg/kg per 20 minutes) and at high dose (7.6 mg/kg per 5 minutes, then 12.4 mg/kg per 20 minutes) reduced infarct size. The infarct size reduction ratios of TY-51924 at 10 and 20 mg/kg versus vehicle were 39.2% and 51.7%, respectively; plasma drug concentrations at reperfusion were 16.8 and 38.8 μg/mL, respectively. This indicates that maintaining a plasma drug concentration of >20 μg/mL at reperfusion enables TY-51924 to reduce infarct size by inhibiting the NHE, which is activated during the early period of reperfusion.

Inhibition of Na+/H+ Exchanger With EMD 87580 does not Confer Greater Cardioprotection Beyond Preconditioning on Ischemia–Reperfusion Injury in Normal Dogs

“…A recent study by Sasamori et al reported marked dose-dependent reduction in myocardial infarct size in dogs (90-minute ischemia and 300-minute reperfusion) with TY-51924 (selective NHE1 blocker) administered before reperfusion. 69 Maximum protection was provided when TY-51924 was given continuously before reperfusion and maintained thereafter. While the reasons for these different results are not clear, it is possible that distinct enzyme or receptor affinities of NHE1 blockers are responsible for the diverse results.…”

“…Optimal timing, dosage, plasma concentration, and mode of drug delivery also contribute markedly to potential efficacy; this was clearly shown by Sasamori et al in their study. 69 Bioavailability within the first minutes of reperfusion is critical to affect the following factors: 1-change in cellular Ca 2þ homeostasis, 2-control of intracellular pH postreoxygenation of ischemic myocytes, and 3-signaling pathways that involve Ca 2þ equilibrium or myofibrillar Ca2þ sensitivity. 82 Lack of presence of the inhibitor in the early minutes of ischemia or reperfusion markedly reduces the likelihood of a beneficial effect.…”

Randomized controlled trial of TY-51924, a novel hydrophilic NHE inhibitor, in acute myocardial infarction

“…TY-51924 is a novel NHE inhibitor that was synthesized by introducing a water-soluble functional group to TY-12533, reported to have cardioprotective effects against ischemiareperfusion injury caused by NHE inhibition in rats [9]. After intravenous administration, TY-51924 showed low levels in central nervous tissue and was rapidly eliminated from blood and tissues in animal experiments [10]. In a canine ischemiareperfusion model, TY-51924 administered intravenously before reperfusion reduced infarct size [10].…”

“…After intravenous administration, TY-51924 showed low levels in central nervous tissue and was rapidly eliminated from blood and tissues in animal experiments [10]. In a canine ischemiareperfusion model, TY-51924 administered intravenously before reperfusion reduced infarct size [10]. TY-51924 was also well tolerated in Phase I trials and a small Phase IIa pilot trial [11].…”

Ischemia–reperfusion injury is still a big hurdle to overcome for treatment of acute myocardial infarction

“…After intravenous administration, TY-51924 penetrated to central nervous tissue at a low level in central nervous tissue and was rapidly eliminated from blood and tissues in animal experiments. In a canine ischemia-reperfusion model, TY-51924 administered intravenously before reperfusion reduced infarct size [13]. TY-51924 was also well tolerated in Phase I trials and a small phase IIa pilot trial [14].…”