cyclic-gmp and vesnarinone

We studied the effects of various phosphodiesterase (PDE) III inhibitors: amrinone, pimobendan and vesnarinone: a PDE IV inhibitor (Ro 20-1724) and a PDE V inhibitor (E-4021) on the production of cytokines which have been shown to depress myocardial function. Recently developed inotropic agents which inhibit PDE III activity have produced short-term hemodynamic benefits in patients with advanced heart failure, but long-term treatment with these agents has an adverse effect on survival. However, vesnarinone, which has been shown to improve survival dramatically, has an immunomodulating effect and inhibits the production of cytokines. Peripheral blood mononuclear cells obtained from healthy human subjects were stimulated with lipopolysaccharide and each PDE inhibitor 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 supernatants were measured by an enzyme-linked immunosorbent assay. All three PDE III inhibitors, amrinone, pimobendan and vesnarinone, inhibited 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 production and pimobendan slightly decreased IL-6 production, whereas amrinone 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 also tended to inhibit IL-6 production; its modulation of cytokine production 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. Differential modulation of cytokine production may play a role in the therapeutic 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 immunomodulating properties.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; 8-Bromo Cyclic Adenosine Monophosphate; Amrinone; Cells, Cultured; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Failure; Humans; Interleukin-1; Interleukin-6; Kinetics; Leukocytes, Mononuclear; Lipopolysaccharides; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperidines; Pyrazines; Pyridazines; Quinazolines; Quinolines; Tumor Necrosis Factor-alpha

We examined the inhibitory effects of vesnarinone, a new cardiotonic agent, on human cyclic nucleotide phosphodiesterase (PDE). Vesnarinone selectively inhibited the activity of human cardiac cGMP-inhibited PDE with a Ki value of 8.5 microM. The inhibition of human cardiac cGMP-inhibited PDE by vesnarinone was not competitive but was of the mixed type with respect to cAMP. Although the activities of the cGMP-inhibited PDE from human heart, aorta, platelets, and kidney were inhibited to the same extent by cGMP, enoximone, and cilostazole, vesnarinone inhibited the activities of cardiac and kidney cGMP-inhibited PDE with 10 times greater potency than those of platelet and aorta cGMP-inhibited PDE. These results suggest that there exist, in human tissues, two isoforms of cGMP-inhibited PDE that can be distinguished by reference to the inhibitory effects of vesnarinone.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Aorta; Blood Platelets; Calcium; Calmodulin; Cardiotonic Agents; Cilostazol; Cyclic AMP; Cyclic GMP; Enoximone; Humans; Isoenzymes; Kidney; Myocardium; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyrazines; Quinolines; Tetrazoles

Possible cAMP-dependent and cAMP-independent mechanisms of action for the cardiac effects of OPC-8212, a novel piperazinyl-quinolinone derivative, were evaluated. OPC-8212 was tested for in vitro potency as an inhibitor of soluble bovine cardiac phosphodiesterases using a rapid isolation and assay method involving monoclonal antibodies that distinguish among isozymes. The drug was selective for a low-Km, cGMP-inhibited phosphodiesterase (CGI-PDE) with an IC50 (half-maximal inhibition concentration) of 7.4 mumol/l when measured at a substrate level of 0.35 mumol/l cAMP. Under the conditions used, sulfolane, the solvent for OPC-8212, did not affect CGI-PDE activity. In electrophysiological measurements, OPC-8212 prolonged the action potential duration in canine Purkinje strand preparations up to 148% (APD90) at 10 mumol/l. Concomitantly, OPC-8212 produced a 100% increase in developed force. Both prolongation of the action potential duration and the positive inotropic effect were readily reversed after exposure to tetrodotoxin, 3 mumol/l. Using Na-selective microelectrodes, intracellular Na+ ion activity increased 225% upon exposure to 10 mumol/l OPC-8212. OPC-8212 represents a novel type of positive inotropic agent, possessing both cAMP-dependent (selective PDE isozyme inhibition) and cAMP-independent (activation of intracellular Na+) mechanism of action.

Topics: Action Potentials; Animals; Cardiotonic Agents; Cattle; Cyclic AMP; Cyclic GMP; Electrophysiology; In Vitro Techniques; Membrane Potentials; Phosphodiesterase Inhibitors; Purkinje Fibers; Pyrazines; Quinolines; Sodium; Solvents; Time Factors