Effective contractile response to voltage-gated Na+ channels revealed by a channel activator

Author:

Ho W.-S. Vanessa1,Davis Alison J.1,Chadha Preet S.1,Greenwood Iain A.1

Affiliation:

1. Division of Biomedical Sciences, St. George's University of London, London, United Kingdom

Abstract

This study investigated the molecular identity and impact of enhancing voltage-gated Na+ (NaV) channels in the control of vascular tone. In rat isolated mesenteric and femoral arteries mounted for isometric tension recording, the vascular actions of the NaV channel activator veratridine were examined. NaV channel expression was probed by molecular techniques and immunocytochemistry. In mesenteric arteries, veratridine induced potent contractions (pEC50 = 5.19 ± 0.20, Emax = 12.0 ± 2.7 mN), which were inhibited by 1 μM TTX (a blocker of all NaV channel isoforms, except NaV1.5, NaV1.8, and NaV1.9), but not by selective blockers of NaV1.7 (ProTx-II, 10 nM) or NaV1.8 (A-80347, 1 μM) channels. The responses were insensitive to endothelium removal but were partly (∼60%) reduced by chemical destruction of sympathetic nerves by 6-hydroxydopamine (2 mM) or antagonism at the α1-adrenoceptor by prazosin (1 μM). KB-R7943, a blocker of the reverse mode of the Na+/Ca2+ exchanger (3 μM), inhibited veratridine contractions in the absence or presence of prazosin. T16Ainh-A01, a Ca2+-activated Cl channel blocker (10 μM), also inhibited the prazosin-resistant contraction to veratridine. NaV channel immunoreactivity was detected in freshly isolated mesenteric myocytes, with apparent colocalization with the Na+/Ca2+ exchanger. Veratridine induced similar contractile effects in the femoral artery, and mRNA transcripts for NaV1.2 and NaV1.3 channels were evident in both vessel types. We conclude that, in addition to sympathetic nerves, NaV channels are expressed in vascular myocytes, where they are functionally coupled to the reverse mode of Na+/Ca2+ exchanger and subsequent activation of Ca2+-activated Cl channels, causing contraction. The TTX-sensitive NaV1.2 and NaV1.3 channels are likely involved in vascular control.

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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