Effect on ex vivo platelet aggregation and in vivo cyclic flow with Na+/H+ exchange inhibition

Abstract

BIIB 513 and EMD 85131 are selective inhibitors of the Na+/H+ exchanger-1 (NHE-1) that are benzoylguanidine derivatives of the clinically employed diuretic amiloride. Prior studies have suggested a role for NHE-1 activity in platelet activation and aggregation using amiloride or its non-benzoylguanidines derivatives. However, the concentrations employed in these prior studies were at levels known to exert effects on other ion transport systems besides the NHE-1. Therefore, the purpose of this study was to examine the effects of more selective NHE-1 inhibitors, BIIB 513 and EMD 85131, on platelet aggregation and in vivo cyclic flow following arterial injury. BIIB 513 and EMD 85131 effects on ex vivo canine and human platelet aggregation in response to various agents was monitored via platelet aggregation. For analysis of in vivo thrombus formation, a femoral artery crush injury model was employed and a flow meter was used to monitor the effect of BIIB 513 on cyclic blood flow. Treatment of either canine or human platelets with up to 1 mM of BIIB 513 had no effect on aggregation induced by platelet activating factor (PAF), thrombin receptor activator peptide (TRAP), or adenosine diphosphate (ADP). Additionally, the structurally related compound EMD 85131 at up to 1 mM failed to inhibit TRAP induced platelet aggregation. In vivo administration of up to 9 mg/kg of BIIB 513 intravenously failed to affect cyclic flow in a canine model of femoral artery injury. These data demonstrate that the specific and selective NHE-1 inhibitors BIIB 513 or EMD 85131 have no effect on ex vivo platelet aggregation or in vivo cyclic flow following arterial injury.

Synthesis and multifaceted pharmacological activity of novel quinazoline NHE-1 inhibitors

“…Activation of NHE-1 also potentiates the formation of platelet aggregates 8 . Antiplatelet activity of NHE-1 inhibitors is believed to be mediated by inhibition of cytoplasmic Ca 2+ mobilization and arachidonic acid formation 9 .…”

Study on the Mechanism of the Adrenaline-Evoked Procoagulant Response in Human Platelets

“…The engagement of extracellular calcium ions in adrenaline-evoked PS exposure was measured in relation to sodium ions since activation of platelets by principal agonists is associated with sodium ion influx into platelet cytosol [ 53 , 54 ]. According to Sweatt et al, exposure of platelets to adrenaline results in activation of type 1 Na+/H+ exchanger (NHE1), leading to sodium accumulation and alkalization of platelet cytosol due to concomitant H + removal [ 55 ].…”