Fibrinolytic function in diuretic-induced volume depletion

Abstract

Accumulating evidence suggests that the renin-angiotensin system (RAS) may participate in the regulation of fibrinolytic function. In clinical studies, however, angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor antagonist losartan have failed to consistently affect endogenous fibrinolysis. Because such an effect may depend on the degree of prestimulation of the RAS, we have studied parameters of fibrinolytic function in 15 healthy volunteer subjects during baseline (day 1) and after 10 days of treatment with 25 mg of hydrochlorothiazide (HCT)/day (day 11). On the last day of the study (day 12), a single oral dose of 50 mg of losartan was given to the volunteers in addition to HCT and fibrinolytic function was assessed at the peak effect of losartan (5 h later). Plasma renin activity (PRA) was significantly stimulated during diuretic treatment (1.35 ± 0.21 v 0.34 ± 0.06 ng mL −1 · h −1 [ P < .001]) and further increased after losartan (6.39 ± 1.16 ng mL −1 · h −1 [ P < .001]). No effects of either the diuretic or losartan could be observed on tissue-type plasminogen activator (t-PA) antigen concentration and activity. However, 10 days of treatment with HCT significantly increased plasminogen activator inhibitor-1 (PAI-1) antigen (26.8 ± 5.8 v 21.1 ± 3.4 ng/mL [p = .037]). In addition, PAI-1 activity was also tentatively raised by HCT treatment (5.48 ± 1.82 v 3.88 ± 0.79 IU/mL [ P = .067]). In spite of the marked further rise in PRA after losartan, the stimulation of PAI-1 antigen and activity was blunted by losartan (24.4 ± 3.6 ng/mL and 4.55 ± 0.99 IU/mL, respectively). Our results demonstrate that volume depletion induced by HCT treatment is associated with a rise in PAI-1. Acute administration of losartan is capable of blunting this effect, suggesting that the angiotensin II type 1 receptor may participate in this effect of angiotensin II.