Premium
TRPV1‐mediated Ca 2+ Influx and Middle Meningeal Artery Constriction
Author(s) -
Manuelyan I.,
Syed A,
Koide M.,
Shui B,
Sonkusare S.,
Kotlikoff M.,
Nelson M.,
Wellman G.
Publication year - 2015
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.29.1_supplement.943.6
Subject(s) - trpv1 , capsaicin , chemistry , capsazepine , biophysics , agonist , transient receptor potential channel , medicine , pharmacology , endocrinology , biochemistry , receptor , biology
The causes of migraine and cluster headaches are not clear, but may involve dilation of the meningeal vasculature. Recent evidence indicates that transient receptor potential channel V1 (TRPV1) agonists may benefit patients with migraine or cluster headaches. Here, we test the hypothesis that capsaicin, a TRPV1 agonist, constricts middle meningeal artery (MMA) via activation of smooth muscle (SM) TRPV1 channels. Consistent with this hypothesis, capsaicin induced constriction of isolated pressurized rat MMA (EC 50 ∼ 100 nM) that was blocked by the TRPV1‐selective antagonist, capsazepine (1 µM). Interestingly, capsaicin (10 µM) did not constrict cerebral arteries. Capsaicin‐induced MMA constriction was reduced ∼ 34% by the voltage‐dependent calcium channel (VDCC) blocker diltiazem (100 µM) and abolished by removal of extracellular Ca 2+ . To assess the direct impact of capsaicin on Ca 2+ influx, MMA myocytes were freshly isolated from transgenic (acta2‐GCaMP5‐mCherry) mice with SM‐specific expression of Ca 2+ ‐sensitive GCaMP5 and Ca 2+ ‐independent mCherry proteins. In these cells, 1 µM capsaicin increased the fluorescence ratio of GCaMP5/mCherry by 4‐fold. Further, optical imaging of unitary Ca 2+ events (sparklets) in intact MMA using Fluo‐4 revealed elementary capsaicin‐induced signals with a quantal fractional fluorescence change consistent with TRPV1 channels. In sum, these findings suggest capsaicin‐induced MMA constriction results from activation of TRPV1 channels on vascular myocytes. Capsaicin‐induced Ca 2+ influx in MMA SM likely reflects both direct Ca 2+ entry via TRPV1 channels and VDCC activation via TRPV1‐mediated Na + influx. Supported by: Totman Trust, Peter Martin Fund, AHA and NIH.