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EXPERIMENTAL STUDY

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

Manuscript received April 13, 2001; revised manuscript received September 10, 2001, accepted October 18, 2001.

^* Reprint requests and correspondence: Dr. Johann Bauersachs, Medizinische Universitätsklinik, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany.
j.bauersachs{at}medizin.uni-wuerzburg.de

OBJECTIVES: We sought to investigate the effects of adding spironolactone (SP) to angiotensin-converting enzyme (ACE) inhibition on endothelium-dependent vasodilation in rats with chronic heart failure (CHF).

BACKGROUND: Adding SP to ACE inhibitors reduces mortality and morbidity in CHF. Endothelial vasomotor dysfunction contributes to increased peripheral vascular resistance and reduced myocardial perfusion in CHF.

METHODS: Seven days after extensive myocardial infarction (CHF) or sham operation, Wistar rats were treated with placebo, the ACE inhibitor trandolapril (TR, 0.3 mg/kg body weight per day), SP (10 mg/kg per day) or a combination of both for 11 weeks.

RESULTS: Maximal acetylcholine-induced, nitric oxide (NO)-dependent relaxation was significantly attenuated in aortic rings from rats with CHF as compared with sham-operated animals (R_max 44 ± 3% vs. 63 ± 3%). Spironolactone alone had no influence (46 ± 5%) and TR improved NO-mediated relaxation (55 ± 4%), whereas treatment with both completely restored endothelium-dependent vasorelaxation (64 ± 4%). Aortic superoxide formation was significantly increased in rats with CHF as compared with sham-operated animals, but was normalized by treatment with SP or SP plus TR. In addition, aortic messenger ribonucleic acid expression of the oxidase subunit p22^phox in rats with CHF was significantly reduced by SP or TR plus SP. Endothelial NO synthase expression was increased in TR-treated animals. Incubation of isolated porcine coronary arteries with SP dose-dependently attenuated superoxide formation.

CONCLUSIONS: Spironolactone added to an ACE inhibitor normalizes NO-mediated relaxation in experimental CHF by beneficially modulating the balance of NO and superoxide anion formation.

Abbreviations and Acronyms   ACE   angiotensin-converting enzyme   CHF   chronic heart failure   eNOS   endothelial nitric oxide synthase   MI   myocardial infarction   NO   nitric oxide   O2–   superoxide anion   RT-PCR   reverse transcription polymerase chain reaction   SP   spironolactone   TR   trandolapril

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