Histone Deacetylase Inhibitors Relax Mouse Aorta Partly through Their Inhibitory Action on L-Type Ca(2+) Channels.

Histone deacetylase (HDAC) inhibitors modulate acetylation/deacetylation of histone and nonhistone proteins. They have been widely used for cancer treatment. However, there have been only a few studies investigating the effect of HDAC inhibitors on vascular tone regulation, most of which employed chronic treatment with HDAC inhibitors. In the present study, we found that two hydroxamate-based pan-HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), could partially but acutely relax high extracellular K(+)-contracted mouse aortas. SAHA and TSA also attenuated the high extracellular K(+)-induced cytosolic Ca(2+) rise and inhibited L-type Ca(2+) channel current in whole-cell patch-clamp. These data demonstrate that SAHA could inhibit L-type Ca(2+) channels to cause vascular relaxation. In addition, SAHA and TSA dose dependently relaxed the arteries precontracted with phenylephrine. The relaxant effect of SAHA and TSA was greater in phenylephrine-precontracted arteries than in high K(+)-contracted arteries. Although part of the relaxant effect of SAHA and TSA on phenylephrine-precontracted arteries was related to L-type Ca(2+) channels, both agents could also induce relaxation via a mechanism independent of L-type Ca(2+) channels. Taken together, HDAC inhibitors SAHA and TSA can acutely relax blood vessels via their inhibitory action on L-type Ca(2+) channels and via another L-type Ca(2+) channel-independent mechanism.