DIFFERENTIAL MODULATION OF CYTOKINE PRODUCTION BY DRUGS - IMPLICATIONS FOR THERAPY IN HEART-FAILURE

We studied the effects of various phosphodiesterase (PDE) III inhibito rs: amrinone, pimobendan and vesnarinone: a PDE IV inhibitor (Ro 20-17 24) and a PDE V inhibitor (E-4021) on the production of cytokines whic h have been shown to depress myocardial function. Recently developed i notropic agents which inhibit PDE III activity have produced short-ter m hemodynamic benefits in patients with advanced heart failure, but lo ng-term treatment with these agents has an adverse effect on survival, However, vesnarinone, which has been shown to improve survival dramat ically, has an immunomodulating effect and inhibits the production of cytokines. Peripheral blood mononuclear cells obtained from healthy hu man subjects were stimulated with lipopolysaccharide and each PDE inhi bitor was added. After 24 h of incubation, tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) and IL-6 in the culture s upernatants were measured by an enzyme-linked immunosorbent assay, All three PDE III inhibitors, amrinone, pimobendan and vesnarinone, inhib ited TNF-alpha production, but vesnarinone's inhibitory effect was the most prominent. Amrinone and pimobendan enhanced IL-1 beta production , whereas vesnarinone had no effect. Vesnarinone inhibited IL-6 produc tion and pimobendan slightly decreased IL-6 production, whereas amrino ne had no significant effect on IL-6 production. The PDE IV inhibitor, Ro 20-1724, decreased the production of IL-1 beta and TNF-alpha and a lso tended to inhibit IL-6 production; its modulation of cytokine prod uction was similar to the effects of vesnarinone, Because 8Br-cAMP or 8Br-cGMP did not suppress cytokine production, the modulating effects were not considered to result from an increase in cAMP or cGMP. Differ ential modulation of cytokine production may play a role in the therap eutic effect in heart failure patients who are treated with drugs that have PDE-inhibitory actions. It may be important to study whether the use of dual inhibitors of PDE III and PDE IV is therapeutically more useful for the treatment of heart failure due to their immunomodulatin g properties.