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Copyright © 2003 by The Endocrine Society Effect of Combined AT1 Receptor and Aldosterone Receptor Antagonism on Plasminogen Activator Inhibitor-1Pairunyar Sawathiparnich, Laine J. Murphey, Sandeep Kumar, Douglas E. Vaughan and Nancy J. BrownDivisions of Clinical Pharmacology (P.S., L.J.M., S.K., N.J.B.), Pediatric Endocrinology (P.S.), and Cardiovascular Medicine (D.E.V.), Vanderbilt University Medical Center, Nashville, Tennessee 37232-6602 Address all correspondence and requests for reprints to: Nancy J. Brown, M.D., 560 Robinson Research Building, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6602. E-mail: nancy.j.brown{at}vanderbilt.edu. Aldosterone enhances angiotensin II (Ang II)-induced plasminogen activator inhibitor (PAI)-1 expression in vitro. This study tested the hypothesis that angiotensin II type 1 (AT1) and aldosterone receptor antagonism interact to decrease PAI-1 in humans. Effects of candesartan (16 mg/d), spironolactone (25 mg/d), or combined candesartan/spironolactone on mean arterial pressure (MAP), endocrine, and fibrinolytic variables were measured in 18 normotensive subjects [age 33.7 yr (95% confidence interval 29.3, 38.0), body mass index 26.6 (24.7, 28.4) kg/m2] in whom the renin-angiotensin-aldosterone system was activated by furosemide (20 mg/d). Candesartan [83.3 mm Hg (78.9, 87.7)], but not spironolactone [89.4 mm Hg (85.4, 93.5)], decreased MAP, compared with baseline [92.2 mm Hg (88.9, 95.5), P < 0.001] and furosemide alone [89.1 mm Hg (85.7, 92.4), P = 0.002]. Coadministration of spironolactone with candesartan did not further decrease MAP. Candesartan dramatically increased Ang II [177.9 pg/ml (113.3, 242.6)], compared with baseline [34.8 pg/ml (29.3, 40.4), P = 0.002] and furosemide alone [40.6 pg/ml (29.7, 51.5), P = 0.003]. Spironolactone increased Ang II [51.5 pg/ml (41.3, 61.7), P = 0.014 vs. baseline, P = 0.004 vs. candesartan]. There was no additive effect of candesartan and spironolactone on Ang II [197.6 pg/ml (134.2, 261.0)]. Aldosterone was lower during candesartan [8.9 ng/dl (7.3, 10.6), P = 0.007] than during furosemide alone [14.1 ng/dl (10.9, 17.3), P = 0.007], spironolactone [18.7 ng/dl (14.5, 22.9), P = 0.002], or combined candesartan/spironolactone [13.9 ng/dl (11.8, 15.9), P = 0.006]. Furosemide increased PAI-1 antigen [27.8 ng/ml (20.6, 35.0), P = 0.002 vs. 19.3 ng/ml (13.4, 25.2) baseline], even in the presence of candesartan [27.2 ng/ml (16.5, 37.8), P = 0.042 vs. baseline] or spironolactone [27.3 ng/ml (17.9, 36.8), P = 0.015 vs. baseline]. However, coadministration of AT1 and aldosterone receptor antagonists prevented the furosemide-induced increase in PAI-1 [19.2 ng/ml (9.8, 28.6), P = 0.974 vs. baseline, P < 0.05 vs. candesartan, spironolactone or furosemide alone]. This study evidences an interactive effect of endogenous Ang II and aldosterone on PAI-1 production in humans. This work was supported by an unrestricted grant from AstraZenica and NIH Grants RO1HL67308, RO1HL60906, RO1HL65193, K23HL04445, MO1RR00095, and GM07569. Abbreviations: ACE, Angiotensin-converting enzyme; Ang II, angiotensin II; AT1, angiotensin II type 1; BP, blood pressure; MAP, mean arterial pressure; MR, mineralocorticoid receptor; PAI-1, plasminogen activator inhibitor-1; PRA, plasma renin activity; RAAS, renin-angiotensin-aldosterone system; t-PA, tissue-type plasminogen activator. This article has been cited by other articles:
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