YC-1 attenuates homotypic human neutrophil aggregation through inhibition of phosphodiesterase activity.
This study was undertaken to assess the effects of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a known activator of soluble guanylyl cyclase, on formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP) and complement component 5a (C5a)-induced homotypic human neutrophil aggregation. YC-1 as well as the phosphodiesterase (PDE)4 inhibitors rolipram and Ro 20-1724, but not the PDE3 inhibitor milrinone, inhibited the aggregation responses stimulated by FMLP and C5a. In contrast, sodium nitroprusside (SNP) had no effect on FMLP- or C5a-induced neutrophil aggregation. Moreover, SNP together with YC-1 failed to modify the YC-1-induced responses. In addition, YC-1 and rolipram, but not milrinone, induced substantial increases in cAMP levels, which occurred through the inhibition of PDE activity but not an increase in adenylate cyclase function. Interestingly, adenosine deaminase abolished the inhibitory effects and cAMP levels of YC-1, rolipram, and Ro 20-1724. In conclusion, these results indicate that the inhibitory effect of YC-1 on homotypic neutrophil aggregation is attributed to an elevation in the cAMP concentration through inhibition of the activity of PDE, which may potentiate the autocrine functions of endogenous adenosine.
Hwang
Tsong-Long
TL
Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan. htl@mail.cgu.edu.tw
Zhuo
Shi-Kai
SK
Pan
Yen-Lin
YL
D000241:Adenosine / Q000378:metabolism; D000328:Adult; D002449:Cell Aggregation / Q000187:drug effects; D015936:Complement C5a; D000242:Cyclic AMP / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects* / Q000378:metabolism
D020536:Enzyme Activators; D007191:Indazoles; D010726:Phosphodiesterase Inhibitors; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000241:Adenosine