Effects of a selection of histone deacetylase inhibitors on mast cell activation and airway and colonic smooth muscle contraction.

Studies of histone deacetylase (HDAC) inhibitors, novel anticancer drugs, in models of autoimmune diseases, asthma, and inflammatory bowel disease suggest that HDAC inhibitors may also have useful anti-inflammatory effects. Accordingly, in vitro studies relevant to asthma and inflammatory bowel disease were conducted using a selection of HDAC inhibitors: suberoylanilide hydroxamic acid (SAHA, Vorinostat), and a related branched hydroxamic acid, diamide (1), MGCD0103 and two short chain fatty acid derivatives: sodium butyrate (of use in inflammatory bowel disease) and sodium valproate. The ability of those HDAC inhibitors to modulate antigen- or agonist-induced contraction of isolated guinea pig tracheal rings and colon, agonist-induced contraction of rat colon, and histamine release from rat peritoneal mast cells was examined.

Inhibition of the antigen-induced activation of RBL-2H3 cells by cetiedil and some of its analogues.

Our previous studies on rat basophilic leukaemia (RBL-2H3) cells suggested that IK(Ca) channels similar to those in red blood cells (RBC) may be involved in the antigen-induced beta-hexosaminidase release. Since cetiedil blocks these channels in both cell types, we studied the inhibition by a selection of the synthetic analogues of cetiedil (UCL compounds) of antigen-induced beta-hexosaminidase release and 86Rb(+)-efflux from RBL-2H3 cells. We tested the (+)- and (-)-enantiomers of cetiedil (UCL 1348 and UCL 1349), the more lipophilic triphenylacetic acid derivatives (UCL 1495 and UCL 1617) and (9-benzyl-fluoren)-9-yl derivatives (UCL 1608 and UCL 1710).

Inhibition of the antigen-induced activation of RBL-2H3 cells by charybdotoxin and cetiedil.

Quinidine and Ba(2+), non-selective K(+)-channel blockers, have previously been shown to inhibit antigen-induced mediator (beta-hexosaminidase) release from RBL-2H3 cells, a mucosal-type mast cell line. We therefore used selective blockers of Ca(2+)-activated and other K(+) channels to determine if there was a role for these channels in antigen-induced mediator release. Charybdotoxin and cetiedil dose-dependently inhibited beta-hexosaminidase release with IC(50) values of 133 nM and 84 microM, respectively.