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Increased Role for Large Conductance, Calcium‐Activated K Channels (BK Ca ) in Endothelium‐Dependent Relaxation of Nitrate Tolerant Mesenteric Arteries
Author(s) -
Sane Mukta,
Mughal Amreen,
Sun Chengwen,
O'Rourke Stephen
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.627.8
Subject(s) - iberiotoxin , mesenteric arteries , vasodilation , chemistry , endocrinology , acetylcholine , medicine , endothelium , vasoconstriction , nitric oxide , blood vessel , artery
Prolonged exposure to nitroglycerin (NTG) leads to tolerance and impaired endothelium‐dependent vasodilation. Causes of endothelial dysfunction in nitrate tolerant arteries are well studied, but little is known about mechanisms that underlie the responses to endothelium‐derived mediators in nitrate tolerant blood vessels. Here we evaluated the role of BK Ca in acetylcholine (ACh)‐induced relaxation of isolated mesenteric arterial rings from rats treated with or without application of transdermal NTG patches (0.6 mg/hr) for 3 days. Nitrate tolerance was confirmed by the impaired relaxation response to NTG (1 nM – 100 μM) observed in rings from rats treated with NTG patches (pD 2 = 5.6 + 0.1 vs 4.9 + 0.1, E max = 86 + 7 vs 53 + 5% relaxation; control vs treated, respectively). ACh‐induced (1 nM – 3 μM) relaxation was also impaired in tolerant rings (pD 2 = 7.1 + 0.1 vs 6.5 + 0.1; control vs tolerant, respectively) Incubation with nitro‐l‐arginine (30 μM) or indomethacin (10 μM) had no effect on the response to ACh in control or tolerant arteries, consistent with the release of a non‐NO, non‐prostanoid endothelium‐derived mediator in both control and tolerant arteries. ACh‐induced relaxation was unaffected by the selective BK Ca ‐blocker, iberiotoxin (IBT), in control rings, but was nearly abolished in tolerant rings (E max = 78 ± 9 vs 8 + 8% relaxation; without vs with IBT, respectively). Protein expression of BK Ca β‐subunits was increased by 50% in nitrate tolerant arteries, while BK Ca α‐subunit expression was unchanged. The data provide evidence that nitrate tolerance unmasks a pivotal role for BK Ca in the smooth muscle relaxation evoked by a non‐NO, non‐prostanoid endothelium‐derived mediator in mesenteric arteries.