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Spironolactone abolishes the relationship between aldosterone and plasminogen activator inhibitor-1 in humans
Pairunyar Sawathiparnich1, Sandeep Kumar, Douglas E Vaughan
1Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Insights
Endogenous aldosterone influences plasminogen activator inhibitor-1 (PAI-1) production in humans. This study found aldosterone correlates with PAI-1 levels, but spironolactone treatment disrupts this link.
Area of Science:
- Endocrinology
- Cardiovascular Physiology
- Hemostasis
Background:
- The renin-angiotensin-aldosterone system (RAAS) plays a key role in blood pressure regulation.
- Emerging evidence suggests a connection between RAAS and fibrinolysis, the process of breaking down blood clots.
- Plasminogen activator inhibitor-1 (PAI-1) is a critical regulator of fibrinolysis.
Purpose of the Study:
- To investigate the hypothesis that endogenous aldosterone directly regulates plasminogen activator inhibitor-1 (PAI-1) production in humans.
- To examine the effects of aldosterone modulation on hemodynamic parameters, PAI-1, and tissue-type plasminogen activator (t-PA).
Main Methods:
- Nine male hypertensive subjects participated in a 3-week washout period followed by 2 weeks of hydrochlorothiazide (HCTZ) or spironolactone treatment.
- Measurements included hemodynamic parameters, PAI-1 and t-PA antigen levels, potassium, plasma renin activity (PRA), angiotensin II, and aldosterone.
- Statistical analysis was used to compare treatment effects and correlations.
Main Results:
- Spironolactone significantly lowered systolic blood pressure, while HCTZ did not.
- Both HCTZ and spironolactone increased aldosterone levels, with a more pronounced effect from spironolactone.
- HCTZ increased PAI-1 antigen levels, whereas spironolactone increased t-PA antigen levels but not PAI-1.
- A significant correlation between PAI-1 and aldosterone was observed at baseline and during HCTZ treatment, but this was abolished by spironolactone.
Conclusions:
- Endogenous aldosterone appears to influence PAI-1 production in humans.
- The relationship between aldosterone and PAI-1 is complex and may be modulated by RAAS-acting drugs.
- Further research is needed to fully elucidate the role of aldosterone in regulating fibrinolysis.
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 (r(2) = 0.57; P = 0.0003); however, treatment with spironolactone abolished this correlation (r(2) = 0.13; P = 0.33). This study provides evidence that endogenous aldosterone influences PAI-1 production in humans.