title: Indapamide inhibits human platelet aggregation in vitro: comparison with hydrochlorothiazide.
abstract: Among antihypertensive drugs with diuretic properties, indapamide was shown to inhibit platelet growth factors production in diabetic hypertensive patients, suggesting an antiplatelet activity. The present study aimed to demonstrate the antiaggregating properties of indapamide. The effect of indapamide on platelet function was compared in vitro to that of hydrochlorothiazide. Indapamide (100 microM) inhibited the second wave of adenosine diphosphate-induced aggregation and inhibited collagen-induced aggregation of platelet rich plasma by 50%. Using isolated platelets, indapamide also inhibited aggregation induced by low doses of thrombin (70% inhibition with 0.035 U/ml). This inhibition was dose-dependent and was still observed in presence of high thrombin concentrations, although the inhibition was moderate. Inhibitory effect of indapamide was more pronounced on the release reaction. Indapamide inhibited the thrombin-induced release of serotonin from dense granules by up to 80%. Hydrochlorothiazide at the same concentrations had no effect on platelet aggregation, and the inhibitory effect on the secretion was inconsistent and never exceeded 30%. By contrast, when the aggregation inducer was arachidonic acid, indapamide had no effect either on aggregation or on thromboxane formation, indicating that it was not acting on arachidonic catabolism. Calcium mobilization evoked by thrombin stimulation and measured with the fluorescent dye Indo 1 was also reduced in presence of indapamide by 30%. Myosin light chain and pleckstrin phosphorylation induced by thrombin were also reduced. These results demonstrate that indapamide inhibits platelet responses by inhibiting calcium mobilization. The anti-aggregating properties of indapamide could contribute to normalize the hyperresponsiveness of platelets from hypertensive patients.
authors.affiliation: CJF 9101 INSERM, Courbevoie, France.
authors.forename: F
authors.initials: F
authors.lastname: Rendu
authors.forename: C
authors.initials: C
authors.lastname: Bachelot
authors.forename: D
authors.initials: D
authors.lastname: Molle
authors.forename: J
authors.initials: J
authors.lastname: Caen
authors.forename: D
authors.initials: D
authors.lastname: Guez
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D016718:Arachidonic Acid / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007190:Indapamide / Q000494:pharmacology*; D009218:Myosins / Q000378:metabolism; D010750:Phosphoproteins; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011863:Radioimmunoassay; D012701:Serotonin / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D013929:Thromboxane B2 / Q000378:metabolism
chemical_list: D001798:Blood Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; C039077:platelet protein P47; D006852:Hydrochlorothiazide; D016718:Arachidonic Acid; D012701:Serotonin; D013929:Thromboxane B2; D000244:Adenosine Diphosphate; D003094:Collagen; D013917:Thrombin; D009218:Myosins; D007190:Indapamide; D002118:Calcium