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Spironolactone Abolishes the Relationship between Aldosterone and Plasminogen Activator Inhibitor-1 in Humans

Divisions of Clinical Pharmacology (P.S., S.K., N.J.B.), Pediatric Endocrinology (P.S.), and Cardiovascular Medicine (D.E.V.), Vanderbilt University Medical Center, Nashville, Tennessee 37232

Address all correspondence and requests for reprints to: Nancy J. Brown, M.D., 560 RRB, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6602. E-mail: nancy.brown{at}mcmail.vanderbilt.edu

Abstract

Recent studies have defined a link between the renin-angiotensin-aldosterone system and fibrinolysis. The present study tests the hypothesis that endogenous aldosterone regulates plasminogen activator inhibitor-1 (PAI-1) production in humans. Hemodynamic parameters, PAI-1 and tissue-type plasminogen activator (t-PA) antigen, potassium, PRA, angiotensin II, and aldosterone were measured in nine male hypertensive subjects after a 3-wk washout, after 2 wk of hydrochlorothiazide (HCTZ; 25 mg plus 20 mmol KCl/d), and after 2 wk of spironolactone (100 mg/d plus KCl placebo). Spironolactone (P = 0.04), but not HCTZ (P = 0.57 vs. baseline; P = 0.1 vs. spironolactone), significantly lowered systolic blood pressure. Angiotensin II increased from baseline during both HCTZ (P = 0.02) and spironolactone (P = 0.02 vs. baseline; P = 0.19 vs. HCTZ) treatments. Although both HCTZ (P = 0.004) and spironolactone (P < 0.001 vs. baseline) increased aldosterone, the effect was greater with spironolactone (P < 0.001 vs. HCTZ). HCTZ increased PAI-1 antigen (P = 0.02), but did not alter t-PA antigen. In contrast, there was no effect of spironolactone on PAI-1 antigen (P = 0.28), whereas t-PA antigen was increased (P = 0.01). There was a significant correlation between PAI-1 antigen and serum aldosterone during both baseline and HCTZ study days (r² = 0.57; P = 0.0003); however, treatment with spironolactone abolished this correlation (r² = 0.13; P = 0.33). This study provides evidence that endogenous aldosterone influences PAI-1 production in humans.

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