Cardiac capsaicin-sensitive sensory nerves regulate myocardial relaxation via S-nitrosylation of SERCA: role of peroxynitrite.
OBJECTIVE
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 Ca(2+)-ATPase (SERCA2a).


METHODS
Male Wistar rats were treated with capsaicin for 3 days to induce sensory chemodenervation. Seven days later, myocardial function and biochemical parameters were measured.


RESULTS
Capsaicin pretreatment significantly increased left ventricular end-diastolic pressure (LVEDP) decreased cardiac NO level, Ca(2+)-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
Our results show that sensory chemodenervation decreases cardiac NO via decreased expression and activity of Ca(2+)-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.
Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary.
P
P
Bencsik
K
K
Kupai
Z
Z
Giricz
A
A
Görbe
I
I
Huliák
S
S
Fürst
L
L
Dux
T
T
Csont
G
G
Jancsó
P
P
Ferdinandy
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000187:drug effects* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects*
D012333:RNA, Messenger; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002211:Capsaicin; D002118:Calcium