FK 409

FK409 was discovered during a screening program for prostaglandin like compounds from microbial products by measuring inhibition of platelet aggregation and vasodilation. FK409, a semisynthetic compound derived from acidic nitrosation of microbial broth, was shown to be a potent vasodilator with a similar pharmacological profile to organic nitrates such as nitroglycerin (NTG). FK409 dilated the larger diameter coronary vascular vessels more potently than those with a smaller diameter in vitro, and was more potent than NTG in a dog angina pectoris model. Clinical development of FK409 for angina pectoris included a preliminary open efficacy study in about twenty patients with angina pectoris showing an improvement in 60-70 % of patients. Anemia proved a drug related adverse event. A new study was carried out on around 20 patients with ischemic heart disease, but in the longer term the anemia remained. It was concluded that FK409 had a comparable efficacy to organic nitrates, but an undesirable adverse effect, and development was terminated. Back-up compounds for FK409, explored improvement of the pharmacokinetic profile: an increase in duration of action and a reduction of the risk of anemia. The pharmacological action of FK409 was associated with increased cGMP levels in aortic smooth muscle; and release of NO was observed by physicochemical methods. Synthesis of chemically more stable derivatives of FK409 with slower NO release was aimed at longer pharmacokinetic profiles and a lower incidence of anemia. FR144220 and FR146881 were identified as chemically more stable compounds with a longer duration of pharmacological action.

The interactions between neuronal, glial, and vascular cells play a key role in regulating blood flow in the retina. In the present study, we examined the role of the interactions between neuronal and glial cells in regulating the retinal vascular tone in rats upon stimulation of retinal neuronal cells by intravitreal injection of N-methyl-d-aspartic acid (NMDA). The retinal vascular response was assessed by measuring the diameter of the retinal arterioles in the in vivo fundus images. Intravitreal injection of NMDA produced retinal vasodilation that was significantly diminished following the pharmacological inhibition of nitric oxide (NO) synthase (nNOS), loss of inner retinal neurons, or intravitreal injection of glial toxins. Immunohistochemistry revealed the expression of nNOS in ganglion and calretinin-positive amacrine cells. Moreover, glial toxins significantly prevented the retinal vasodilator response induced by intravitreal injection of NOR3, an NO donor. Mechanistic analysis revealed that NO enhanced the production of vasodilatory prostanoids and epoxyeicosatrienoic acids in glial cells in a ryanodine receptor type 1-dependent manner, subsequently inducing the retinal vasodilator response. These results suggest that the NO released from stimulated neuronal cells acts as a key messenger in neuron-glia signaling, thereby causing neuronal activity-dependent and glial cell-mediated vasodilation in the retina.

Aim: In view of the central role of granulocytic neutrophils in the context of inflammatory reactions, the present study focuses on anti-inflammatory effects of drugs on activated neutrophils in neonates and adults. Methods: Sixteen blood samples of neonates and adults were investigated in a prospective study. Loss of deformability, morphological changes, and increases in neutrophil elastase were determined as measures of neutrophil activation due to incubation with the pro-inflammatory cytokine interleukin-8. For inhibition experiments, the blood samples were also incubated with the phosphodiesterase inhibitors milrinone and piclamilast, the protease inhibitor urinastatin, ketamine, protein C concentrate, and the nitric oxide donor FK 409. Changes in deformability were investigated with a cell transit analyzer, morphological changes by microscopic observation, and the extent of neutrophil elastase release with an enzyme immunoassay. Results: The drugs milrinone, piclamilast, urinastatin, ketamine, protein C concentrate and FK 409 showed deactivating effects on activated neutrophils in recommended clinical doses. They improved deformability as well as reduced pseudopod formation and the release of neutrophil elastase. The effects on neutrophils did not differ between neonates and adults despite their functional differences. Conclusion: We conclude that these drugs may reduce the inflammatory response and improve microcirculation in neonates and adults during inflammation.