Pharmacological modulation of myocardial tumor necrosis factor alpha production by phosphodiesterase inhibitors

Phosphodiesterase (PDE) inhibitors are used as therapeutic agents for management of congestive heart failure. PDE inhibitors are potent inotropic and vasodilator drugs, which have also been shown to inhibit tumor necrosis factor alpha (TNF-alpha) production. TNF-alpha is a pleiotropic cytokine that has the ability to produce cardiac depressant and other cardiovascular effects in many disease conditions. TNF-alpha levels are elevated in patients with chronic congestive heart failure, and it is possible that TNF-alpha may play a role in this condition. The effects of PDE inhibitors on TNF-alpha secretion from rat heart were evaluated in this study. Rat left ventricle was minced and incubated for 4 hr with various PDE inhibitors, and the amount of TNF-alpha secretion was evaluated by cytotoxicity assay. Ro-20,1724, etazolate, amrinone, milrinone and pentoxifylline inhibited unstimulated TNF-alpha production, with IC50 values of 1.87, 2.07, 13.9, 153 and 201 mu M, respectively. Lipopolysaccharide-induced TNF-alpha secretion from rat left ventricle was also evaluated in this study. Amrinone, milrinone and pentoxifylline inhibited lipopolysaccharide-induced TNF-alpha secretion, with IC50 values of 14.8, 81.6 and 748 mu M, respectively, whereas Ro-20,1724 and etazolate had no effect on lipopolysaccharide-induced TNF-alpha secretion. These results demonstrated that TNF-alpha was secreted from rat left ventricle after 4 hr and different pharmacological manipulations were able to inhibit the secretion of TNF-alpha from left ventricle. These initial pharmacological results may provide an important tool for further investigation into the beneficial effects of PDE inhibitors in congestive heart failure or other conditions where TNF-alpha levels are elevated.