Research Paper
Subject Category: Cardiovascular and pulmonary pharmacology
British Journal of Pharmacology (2008) 153, 488–496; doi:10.1038/sj.bjp.0707599; published online 26 November 2007
Cardiac capsaicin-sensitive sensory nerves regulate myocardial relaxation via S-nitrosylation of SERCA: role of peroxynitrite
P Bencsik1,2, K Kupai1, Z Giricz1, A Görbe1, I Huliák1, S Fürst3,4, L Dux1, T Csont1,2, G Jancsó5 and P Ferdinandy1,2
- 1Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary
- 2PharmaHungary Group, Szeged, Hungary
- 3Neuro-psychopharmacological Research Group, Hungarian Academy of Sciences, Budapest, Hungary
- 4Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- 5Department of Physiology, University of Szeged, Szeged, Hungary
Correspondence: Professor P Ferdinandy, Department of Biochemistry, Cardiovascular Research Group, University of Szeged, Dóm tér 9, Szeged H-6720, Hungary. E-mail: peter.ferdinandy@pharmahungary.com
Received 17 August 2007; Revised 9 October 2007; Accepted 30 October 2007; Published online 26 November 2007.
Abstract
Background and purpose:
Sensory neuropathy develops in the presence of cardiovascular risk factors (e.g. diabetes, dyslipidemia), but its pathological consequences in the heart are unclear. We have previously shown that systemic sensory chemodenervation by capsaicin leads to impaired myocardial relaxation and diminished cardiac nitric oxide (NO) content. Here we examined the mechanism of diminished NO formation and if it may lead to a reduction of peroxynitrite (ONOO-)-induced S-nitrosylation of sarcoendoplasmic reticulum Ca2+-ATPase (SERCA2a).
Experimental approach:
Male Wistar rats were treated with capsaicin for 3 days to induce sensory chemodenervation. Seven days later, myocardial function and biochemical parameters were measured.
Key results:
Capsaicin pretreatment significantly increased left ventricular end-diastolic pressure (LVEDP) decreased cardiac NO level, Ca2+-dependent NO synthase (NOS) activity, and NOS-3 mRNA. Myocardial superoxide content, xanthine oxidoreductase and NADPH oxidase activities did not change, although superoxide dismutase (SOD) activity increased. Myocardial and serum ONOO- concentration and S-nitrosylation of SERCA2a were significantly decreased.
Conclusions and implications:
Our results show that sensory chemodenervation decreases cardiac NO via decreased expression and activity of Ca2+-dependent NOS and increases SOD activity, thereby leading to decreased basal ONOO- formation and reduction of S-nitrosylation of SERCA2a, which causes impaired myocardial relaxation characterized by increased left ventricular end-diastolic pressure (LVEDP). This suggests that capsaicin sensitive sensory neurons regulate myocardial relaxation via maintaining basal ONOO- formation and SERCA S-nitrosylation.
Keywords:
capsaicin, sensory nerves, myocardial function, free radicals, nitric oxide, peroxynitrite, S-nitrosylation, SERCA
Abbreviations:
AF, aortic flow; CF, coronary flow; ESR, electron-spin resonance spectroscopy; LVEDP, left ventricular end-diastolic pressure; ONOO-, peroxynitrite; SERCA, sarcoendoplasmic reticulum Ca2+-ATPase; SNO-Cys, S-nitroso-cysteine; SOD, superoxide dismutase; XOR, xanthine oxidoreductase
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