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Addition of spironolactone to angiotensin-converting enzyme inhibition in heart failure improves endothelial vasomotor dysfunction

Role of vascular superoxide anion formation and endothelial nitric oxide synthase expression

Johann Bauersachs, MD^*,*, Marina Heck, Daniela Fraccarollo, PhD^*, Steven K. Hildemann, MD, Georg Ertl, MD^*, Martin Wehling, MD and Michael Christ, MD

^* Medizinische Klinik der Julius-Maximilians-Universität Würzburg, Germany
Institut für Klinische Pharmakologie, Fakultät für Klinische Medizin Mannheim, Universität Heidelberg, Germany
Pharmacia GmbH, Erlangen, Germany
Klinik für Innere Medizin, Kardiologie, Philipps-Universität Marburg, Germany

View larger version (18K): [in a new window]   Figure 1 Relaxations induced by acetylcholine (A) and sodium nitroprusside (B) in the aortic rings of rats with congestive heart failure (CHF) at 12 weeks after myocardial infarction (solid circles, diamonds, triangles and squares), as compared with sham-operated animals (open circles). The animals were treated with either placebo (Plac; solid and open circles), trandolapril (TR) (0.3 mg/kg body weight per day; solid diamonds), spironolactone (SP) (10 mg/kg per day; solid triangles) or a combination of TR and spironolactone (SP) (solid squares). Data are presented as the mean value ± SEM from 8 to 10 separate experiments. **p < 0.01 CHF/placebo group vs. sham/placebo group and CHF/TR-SP group.

View larger version (13K): [in a new window]   Figure 2 Production of superoxide anion (O2–) (lucigenin 5 µmol/l) in the aortic rings of rats with congestive heart failure (CHF) at 12 weeks after myocardial infarction, as compared with sham-operated animals (for experimental groups, see Fig. 1). Data are presented as the mean value ± SEM from 8 to 10 separate experiments. **p < 0.01 CHF/placebo group vs. sham/placebo group. p < 0.01 CHF/spironolactone (SP) group and CHF/trandolapril (TR)-SP group vs. CHF/placebo group.

View larger version (48K): [in a new window]   Figure 3 Aortic endothelial nitric oxide synthase (eNOS) expression in rats with congestive heart failure (CHF) at 12 weeks after myocardial infarction (relative to the signals obtained in the sham-operated rats), as compared with sham-operated animals (for experimental groups, see Fig. 1). Densitometric analysis (bottom; n = 5 to 6) and a representative blot (top). Data are presented as the mean value ± SEM. *p < 0.05 vs. sham/placebo, CHF/placebo and CHF/spironolactone (SP) groups. TR = trandolapril.

View larger version (12K): [in a new window]   Figure 4 Generation of superoxide anion (O2–) in porcine coronary arteries cultured for 48 h in the absence (open bars) or presence of spironolactone (10 nmol/l; closed bars). Generation of O2– was determined at baseline and after addition of 100 µmol/l nicotinamide adenine dinucleotide (NADH). *p < 0.05.