Functional role of CFTR in rat mesenteric artery

Physiology 2014 (London, UK) (2014) Proc Physiol Soc 31, PCB200

Poster Communications: Functional role of CFTR in rat mesenteric artery

H. T. Pritchard1, N. Lee1, G. Carr1, A. P. Albert1, I. A. Greenwood1

1. Institute of Cardiovascular & Cell Sciences, St Georges, University Of London, London, United Kingdom.

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Introduction: As vascular smooth muscle actively accumulates Cl- ions, opening of Cl- channels will cause Cl- ion efflux, sufficient to depolarise the cell membrane. This is the manner by which Ca2+-activated Cl- channels (TMEM16A) play a role in contraction of vascular smooth muscle (Davis et al. 2013). Amongst others, vascular smooth muscle, also contain the Cl- channel cystic fibrosis transmembrane conductance regulator (CFTR); however the function of this channel within vascular smooth muscle is not clear. The aim of this study was to see the effects of CFTR and TMEM16A modulators on vascular tone in mesenteric arteries, and the effect of hypertension on these Cl- channels.Methods & results: Isometric tension recordings were carried out using 3rd order mesenteric artery segments, from normotensive and spontaneously hypertensive rats (SHR), killed in accordance with Schedule 1 of the United Kingdom Animals Act (1986). Pre-constricted vessels showed a dose dependent relaxation to the CFTR inhibitors GlyH 101 and oxo-CFTR-172, as well as the TMEM16A inhibitor T16inh-A01, all of which had no effect on high KCl induced contractions (n = 3). In SHR mesenteric arteries, GlyH 101 potency showed a trend to being decreased within SHR mesenteric, from 0.77 ± 0.16 μM to 2.49 ± 0.74 μM (n = 6-7, p = 0.058). However hypertension had no effect on the potency of oxo-CFTR-172 (2.16 ± 1.32 μM vs. 2.36 ± 2.36 μM, n = 6-7). Interestingly, T16inh-A01 potency was significantly decreased from 0.78 ± 0.11 μM in normotensive to 2.55 ± 0.75 μM (n = 7-8, p < 0.05). Western blot analysis confirmed the presence of CFTR within whole mesenteric artery protein lysate. Furthermore through the use of proximity ligation assay technology, we showed the close proximity of CFTR and TMEM16A, within isolated mesenteric artery cells.Conclusions: Here we have shown that both CFTR and TMEM16A are involved in contraction of vascular smooth muscle. It is known that CFTR and TMEM16A can functionally interact and this will be the direction of future studies, as to whether the effects of CFTR inhibition on contraction are through TMEM16A activity.



Where applicable, experiments conform with Society ethical requirements.

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