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Mitochondrial depolarization of perivascular nerves induces cerebral vasodilation by neuronal nitric oxide synthase activation (1079.5)
Author(s) -
Katakam Prasad,
Dutta Somhrita,
Grovenburg Samuel,
Gordon Angellica,
Sure Venkata,
Rutkai Ibolya,
Busija David
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1079.5
Subject(s) - depolarization , vasodilation , nitric oxide , nitric oxide synthase , chemistry , mitochondrion , endocrinology , medicine , biology , biochemistry
Mitochondrial depolarization promotes vasodilation of cerebral arteries; however, the contribution of neuronal nitric oxide synthase (nNOS) localized to the perivascular nerves to vasodilation has not been examined. Diameter measurements of endothelium‐denuded isolated rat cerebral arteries showed that mitochondrial depolarization agents, BMS‐191095 (BMS) and diazoxide (DZ) induced vasodilation (40±3% and 28±3%, respectively) that was sensitive to nNOS inhibition with 7‐NI. Fluorescence studies on primary rat cortical neurons showed increased fluorescence to Fluo‐4 and DAR in response to DZ and BMS indicating increased [Ca 2+ ] i and NO generation, respectively. ESR studies using NO‐specific spin trap (DETC) showed increased NO generation in response to DZ. Western blot studies of endothelium‐denuded cerebral arteries as well as neurons treated with BMS and DZ displayed increased ratio of phosphorylated/total nNOS and Akt versus vehicle. Thus, mitochondrial depolarization of perivascular nerves and cortical neurons promotes NO generation by increasing [Ca 2+ ] i and Akt‐dependent phosphorylation of nNOS leading to cerebral vasodilation. This novel mechanism may link the neuronal metabolic activity to vasodilation.Grant Funding Source : Supported by NIH grant numbers HL‐077731, HL‐030260, HL093554, and HL‐065380 (Busija)