Aldosterone and not plasminogen activator inhibitor-1 is a critical mediator of early angiotensin II/NG-nitro-L-arginine methyl ester-induced myocardial injury.
ABSTRACT 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.
Mice on a moderately high sodium diet were treated with the NO synthase inhibitor NG-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 x 100 g(-1) x day(-1)) 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.
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.
Article: Effects of aldosterone blockade on left ventricular function and clinical status during acute myocardial infarction.[show abstract] [hide abstract]
ABSTRACT: Heart failure is frequently a serious complication of acute myocardial infarction (AMI). ACE inhibitors, Angiotensin II receptor blockers, beta-blockers and aldosterone receptor blockers have been shown to improve outcomes in this setting. This study aimed to determine the effect of spironolactone on the frequency of clinical heart failure, mortality, rehospitalization and left ventricular functions determined by echocardiography. A total of 82 patients with STEMI hospitalized within 6-12 h of debut of symptoms were included in the study. The patients were randomly assigned into spironolactone (group A) or placebo (group B) groups after informed consent had been obtained. All patients were followed for 6 months. There were no statistically significant differences between the two groups when demographic criteria were compared. The incidence of post-MI angina pectoris, rhythm and conduction disturbance during hospitalization was significantly higher in Group B than in Group A. Although not statistically significant, the incidence of clinical heart failure was slightly lower in Group A than in Group B (5% versus 11%). Left ventricular end-diastolic volumes were slightly lower in Group A than in Group B, although statistically this was not significant. In concordance with these findings, the ejection fraction was slightly higher in Group A than in Group B, although this was not statistically significant (47% versus 44%). This trend continued during a 6-month follow-up after randomization. Our findings suggest that early administration of aldosterone blockers provides additional benefits after AMI, reducing the incidence of post-MI angina pectoris and rhythm and conduction disturbances.Scandinavian journal of clinical and laboratory investigation 05/2009; 69(5):545-9. · 1.38 Impact Factor