Aldosterone and Not Plasminogen Activator Inhibitor-1 Is a Critical Mediator of Early Angiotensin II/N-Nitro-L-Arginine Methyl Ester–Induced Myocardial Injury

Background—Angiotensin II (Ang II) increases levels of aldosterone and plasminogen activator inhibitor-1 (PAI-1). Both aldosterone and PAI-1 seem to promote cardiovascular (CV) injury. Our objective was to determine the roles of PAI-1 and aldosterone in the development of myocardial and renal damage in a model with high Ang II and low nitric oxide (NO) availability, a pattern seen in patients with heart failure, diabetes mellitus, and arteriosclerosis. Methods and Results—Mice on a moderately high sodium diet were treated with the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) for 14 days plus Ang II during days 8 through 14. The roles of aldosterone and PAI-1 in the development of CV injury were assessed using the mineralocorticoid receptor antagonist spironolactone (0, 1.5, 15, and 50 mg · 100 g 1 · day ) and PAI-1–deficient mice (PAI-1 / ). Ang II/L-NAME–treated mice showed glomerular ischemia, proteinuria, and necrosis of myocytes and vascular smooth muscle cells with an associated mixed inflammatory response, deposition of loose collagen, and neovascularization. Compared with saline-drinking mice, Ang II/L-NAME–treated mice had significantly increased heart to body weight (HW/BW) ratios, cardiac and renal damage assessed by histological examination, PAI-1 immunoreactivity, and proteinuria. Spironolactone treatment decreased PAI-1 immunoreactivity and reduced in a dose-dependent fashion cardiac and renal damage. PAI-1 / animals had a similar degree of CV injury as PAI-1 / animals. Conclusions—Mineralocorticoid receptor antagonism, but not PAI-1 deficiency, protected mice from developing Ang II/L-NAME–mediated myocardial and vascular injury and proteinuria, suggesting that aldosterone, but not PAI-1, plays a key role in the development of early Ang II/L-NAME–induced cardiovascular injury. (Circulation. 2003;108:25172523.)