Effect of doxazosin gastrointestinal therapeutic system on platelet degranulation and platelet–leukocyte microaggregate formation induced by physiologic shear stress in hypertension

Abstract 

Introduction

In this prospective, ex vivo, single-blind study, the effect of doxazosin on platelet function was studied in patients with hypertension.

Materials and methods

Platelet activation by shear stress was measured in whole blood samples of 22 hypertensive patients and 22 normotensive controls, using flow cytometry. Sheared samples were evaluated for CD62 expression, microaggregate formation, and Ca²⁺ mobilization. Results were collected at baseline and after 1 and 2 months of single-dose (4 mg/d) extended-release doxazosin gastrointestinal therapeutic system therapy.

Results

Doxazosin normalized blood pressure in hypertensive patients after 1 and 2 months of treatment. Hypertensive patients had a higher baseline percentage (mean±SD) of degranulated platelets (CD62+) than the normotensive control group (4.14±1.05 vs. 2.47±0.68, P<0.01). After 2 months of doxazosin gastrointestinal therapeutic system treatment, the percentage of CD62+ in the experimental group significantly decreased (P<0.05). At baseline, the number of platelet–leukocyte aggregates in vivo was greater in hypertensive patients (P<0.01); doxazosin did not normalize this measurement. Following shearing, platelet expression of CD62 increased significantly in the hypertensive group (P<0.001 vs. control). Shear stress-induced platelet activation and microaggregate formation were also greater in hypertensive patients. Intraplatelet-free calcium concentration was higher in hypertensive patients at baseline than in the normotensive group (P<0.001). At 2 months, doxazosin significantly reduced thrombin-stimulated Ca²⁺ mobilization in hypertensive patients (P<0.01 vs. baseline).

Conclusions

Platelets from hypertensive patients are more readily activated by shear stress and demonstrate significant alterations in cytoplasmic-free calcium mobilization. Doxazosin treatment reduced blood pressure and normalized alterations in platelet function.

Abbreviations: ADP, adenosine diphosphate, BMI, body mass index, DBP, diastolic blood pressure, DOX, doxazosin, FITC, fluorescence isothiocyanate, Fluor, fluorescence, GITS, gastrointestinal therapeutic system, HT, hypertensive patients, 5-HT, serotonin, LDH, lactate dehydrogenase, mab, monoclonal antibody, MAP, platelet microaggregates, NT, normotensive control, PE, phycoerythrin, SBP, systolic blood pressure

Keywords: Doxazosin, Hypertension, Platelet activation, Microaggregate formation, Shear stress