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Effects of L‐type Ca 2+ blockers and the novel BK Ca channel opener, GoSlo‐SR5‐130, on tension responses in rabbit bronchial rings.
Author(s) -
Thornbury Keith D,
Bihun Victoriia Volodymyrivna,
Bradley Eamonn,
Hollywood Mark A,
Sergeant Gerard P
Publication year - 2018
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.2018.32.1_supplement.lb436
Subject(s) - carbachol , chemistry , endocrinology , medicine , charybdotoxin , isometric exercise , l type calcium channel , smooth muscle , cholinergic , biophysics , calcium channel , calcium , receptor , biochemistry , biology , organic chemistry
Although airway smooth muscle cells express L‐type Ca 2+ channels and large conductance Ca 2+ ‐ activated K + (BK Ca ) channels, the role of these voltage‐dependent channels in mediating cholinergic contractions is disputed (Perez‐Zoghbi et al. 2009). The aims of this study were: 1) to compare the effect of the novel, potent BKCa channel opener, GoSlo‐SR5‐130, on phasic responses and cumulative concentration‐effect relationships induced by carbachol (CCh); 2) to compare the effects of blocking L‐type channels on these two types of CCh response. Rabbits of either sex were euthanized according to European Union legislation and rings from 2 nd and 3 rd order bronchi were isolated post mortem for in vitro isometric tension recording. CCh was applied in cumulative concentrations (0.1, 0.3, 1, 3, 10 mM) to construct a concentration‐effect relationship (EC 50 = 0.41 μM, max response 14.0 ± 3.0 mN, n = 6). After wash out of CCh, the tissue was exposed to GoSlo‐SR5‐130 (30 mM) and the cumulative concentrations of CCh were repeated. In the presence of GoSlo‐SR5‐130, the CCh responses were not significantly different (EC 50 = 0.34 μM, max response 13.2 ± 2.8 mN, n = 6, p > 0.05). However, when rings were continuously exposed to CCh (0.1 μM), after a lag of 30 – 60 min, they developed phasic contractions (amplitude 3.1 ± 0.9 mN, frequency 15.9 ± 4.4 per hour, n = 6). In stark contrast to its lack of effect on the contractions induced by cumulative concentrations of CCh, these phasic contractions were abolished by GoSlo‐SR5‐130 (30 mM; n = 6, p < 0.05) and were restored by addition of iberiotoxin (100 nM; amplitude 4.6 ± 1.0 mN, frequency 7.9 ± 1.6 per hour, n = 6, p < 0.05). Two L‐type Ca 2+ channel blockers, nifedipine (100 nM) and verapamil (3 μM), also abolished the phasic contractions induced by CCh (n = 6, p < 0.05, in each case). However, when the effects of these agents were examined on the responses to cumulative concentrations of CCh, they reduced the responses at all concentrations. In the case of nifedipine (100 nM), the maximal response was reduced from 7.0 ± 3.1 mN to 2.7 ± 1.0 mN (n = 6, p < 0.05), while in verapamil the maximal response was reduced from 13 ± 2.6 mN to 4.1 ± 0.8 mN (n = 6, p < 0.05). In conclusion, phasic, but not tonic, CCh responses were susceptible to inhibition with a BK Ca channel opener, implying that electrical coupling of cells is important for the former, but not the latter. The fact that phasic responses were abolished by L‐type Ca 2+ channel blockers is also consistent with this idea. The reason why concentration‐effect relationships to CCh were more susceptible to L‐type Ca 2+ blockers than CCh responses reported elsewhere (Perez‐Zoghbi, 2009) is unclear, but suggests that, at least in some species, membrane depolarisation and Ca 2+ influx plays a part in such responses. Support or Funding Information Part of the BREATH project, funded by the EU's Interreg VA Programme, managed by Special EU Programmes Body (SEUPB). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .