Inhibition of platelet aggregability by losartan in essential hypertension.
Most clinical events associated with hypertension have a thrombotic component. Losartan is a selective, competitive antagonist of the thromboxane A2 receptor in experiments performed in isolated vascular strips and in human and rat platelet-enriched plasma. In this study, we investigated for the first time whether losartan at therapeutic doses has an effect on platelet aggregability and indexes of fibrinolysis in essential hypertensive subjects. Changes in the dose-response curve to platelet aggregation induced by the thrombin receptor-activating peptide SFLRRN-NH2 were determined in 9 patients (56% men, 72% white; mean age 52.8 years) with stage I or II essential hypertension and in 9 untreated healthy volunteers. After a 4-week washout period, hypertensive subjects received 2 weeks of placebo followed by 4 weeks of losartan 50 mg/day. Both subjects and end points were blinded for treatment assignment. In addition, plasminogen activator inhibitor type 1 antigen and von Willebrand antigen were studied in all patients and controls. Four weeks of losartan produced a statistically significant (p <0.05) increase in the concentration of SFLRRN-NH2 required to induce a half-maximal response in platelet aggregation extent and rate 4 weeks after initiation of treatment. The decrease in platelet aggregability was independent of blood pressure control and the effects of gender and age. Losartan had no effect on plasma concentrations of plasminogen activator inhibitor-1 and von Willebrand factor in hypertensive subjects. These data demonstrate for the first time a novel antiplatelet effect of losartan at therapeutic doses, which was independent of changes in blood pressure, plasma markers of fibrinolytic activity, and endothelial perturbation.
Levy
P J
PJ
The Hypertension & Vascular Disease Center, and the Department of Hematology/Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Yunis
C
C
Owen
J
J
Brosnihan
K B
KB
Smith
R
R
Ferrario
C M
CM
D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy*; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D011446:Prospective Studies; D018179:Receptors, Thrombin / Q000819:agonists; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D014841:von Willebrand Factor / Q000378:metabolism
D000959:Antihypertensive Agents; D015415:Biomarkers; D009842:Oligopeptides; D017395:Plasminogen Activator Inhibitor 1; D018179:Receptors, Thrombin; D017482:Receptors, Thromboxane; C096900:thrombin receptor-activating peptide SFLLRNPNDKY; D014841:von Willebrand Factor; D019808:Losartan