TY - JOUR
T1 - Effect on ex vivo platelet aggregation and in vivo cyclic flow with Na +/H+ exchange inhibition
AU - Gumina, Richard J.
AU - Newman, Peter J.
AU - Gross, Garrett J.
N1 - Funding Information:
Acknowledgments The authors thank Ms. Jeannine Moore and Anna Hsu for their excellent technical assistance with the experiments reported. This study was supported by NIH grants HL-08311 and HL-074314 and grants from Boehringer Ingelheim Pharma KG and Merck KGaA. RJG currently supported by NIH grants HL-096038 and HL-094703.
PY - 2011/5
Y1 - 2011/5
N2 - 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 orin vivo cyclic flow following arterial injury.
AB - 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 orin vivo cyclic flow following arterial injury.
KW - Animal model
KW - Arterial thrombosis
KW - Blood flow
KW - Human
KW - Platelet aggregation
KW - Sodium-hydrogen exchanger
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U2 - 10.1007/s11239-010-0530-0
DO - 10.1007/s11239-010-0530-0
M3 - Article
C2 - 21082215
AN - SCOPUS:80052320133
SN - 0929-5305
VL - 31
SP - 431
EP - 435
JO - Journal of Thrombosis and Thrombolysis
JF - Journal of Thrombosis and Thrombolysis
IS - 4
ER -