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Shear stress increases vasodilator sensitivity to the TRPV4 agonist GSK10167904 in rat cremaster arterioles (LB566)
Author(s) -
Woodman Owen,
Darby William,
Potocnik Simon,
Hollenberg Morley,
McIntyre Peter
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.lb566
Subject(s) - chemistry , endocrinology , agonist , medicine , vasodilation , muscarinic acetylcholine receptor , acetylcholine , cremaster muscle , arteriole , receptor , microcirculation , biochemistry
Shear stress, induced by blood flow, is an important activator of TRPV4 and a stimulant of endothelium‐dependent relaxation. We investigated how an increase in shear stress affects vasodilatation in response to activation of TRPV4 and muscarinic receptors. Responses to the TRPV4 agonist GSK10167904 (GSK, 10 nM‐10 μM) and the muscarinic receptor agonist acetylcholine (ACh, 10 nM‐10 μM) were assessed in cannulated and pressurised rat cremaster arterioles (resting diameter 60‐100 μm). GSK and ACh caused concentration‐dependent dilatation (pEC 50 , GSK 7.60±0.23 ACh 6.42 ± 0.22) which in each case was abolished by removal of the endothelium. The GSK‐induced dilatation was unaffected by inhibition of nitric oxide synthase and cyclooxygenase with L‐NAME (100 μM) and indomethacin (10 μM) but was abolished by the additional inhibition of SK Ca and IK Ca with apamin (1 μM) and TRAM‐34 (1 μM). The GSK‐induced dilatation was significantly impaired by the TRPV4 antagonist HC067047 (300 nM; pEC 50 6.80±0.12, p<0.05) but responses to ACh were unaffected. When shear stress was generated by causing a flow of 20 μl per min through the lumen there was a significant enhancement of the sensitivity to GSK (pEC 50 8.52±0.23, p<0.05) but not to ACh (pEC 50 6.34±0.23). In the rat cremaster arteriole activation of TRPV4 causes endothelium‐dependent dilatation that involves opening of SK Ca and IK Ca but is independent of NO or cyclooxygenase products. Lumenal flow enhanced the dilatation in response to GSK but not ACh. We conclude that shear stress enhances TRPV4 mediated vasodilatation without generally enhancing endothelium‐dependent vasodilatation.