Aldosterone Antagonism Improves Endothelial-Dependent Vasorelaxation in Heart Failure via Upregulation of Endothelial Nitric Oxide Synthase Production

Background: Altering the renin-angiotensin aldosterone system improve mortality in heart failure (HF) in part through an improvement in nitric oxide (NO)-mediated endothelial function. This study examined if spironolactone affects endothelial nitric oxide synthase (eNOS) and NO-mediated vasorelaxation in HF. Methods and Results: Rats with HF after coronary artery ligation were treated with spironolactone for 4 weeks. Rats with HF had a decrease (P < .05) in left ventricular (LV) systolic pressure (130 ± 7 versus 118 ± 6 mm Hg) and LV pressure with respect to time (9122 ± 876 versus 4500 ± 1971 mm Hg/second) with an increase in LV end-diastolic pressure (4 ± 2 versus 23 ± 8 mm Hg). Spironolactone did not affect hemodynamics but it improved (P < .05) endothelial-dependent vasorelaxation at more than 10^-8 M acetylcholine that was abolished with N^G-monomethyl-L-arginine. The eNOS levels were decreased (P < .05) in the LV and the aorta; spironolactone restored LV and aortic eNOs levels to normal. Conclusion: Spironolactone prevents the decrease in eNOS in the LV and aorta and improves NO-dependent vasorelaxation, suggesting that one potential mechanism of spironolactone is an improvement in vasoreactivity mediated though an increase in NO.