Cyclic GMP mediates SIN-1-induced inhibition of human polymorphonuclear leukocytes

Molsidomine inhibits the chemoattractant-induced respiratory burst in human neutrophils via a no-independent mechanism

“…Table 1). In agreement with these data, bet-Lee-Phe-indu~d rS_ glucuronidase release is substantially inhibited by SIN-10 [5,7]. The lack of synergism between SIN-10 and SIN-1 in the inhibition of Met-Leu-Pheinduced 0, formation indicates that sydnonimines act through a common mechanism (see Fig.…”

“…Guanylyl cyclase is activated by the NO-releasing compounds, sodium nitroprusside (SNP) and 3-morpholino-sydnonimine (SIN-l) [ll-131. In agreement with the above data, SNP and SIN-l increase cGMP levels in neutrophils [5]. Additionally, NO-releasing compounds activate ADP-ribosylation of a 39-kDa protein and modulate various cell functions in a cGMP-independent manner [14-181.…”

“…Thus, it cannot be ruled out that the effects of sydnonimines are of clinical relevance. Similarly, the clinical importance of the effects of SIN-10 on other cell functions is not yet known [5,7,23,341.…”

“…Similar to other cell types, neutrophils generate NO [19-211, and NO-releasing compounds mimic, in part, the effects of Bt,cGMP on chemoattractant-induced P_glucuronidase release [5,71. SIN-10 is a prodrug and is converted to SIN-l in the liver [12,22]. Accordingly, SIN-10 does not increase cGMP levels in neutrophils [5]. Surprisingly, SIN-10inhibitsPglucuronidasereleaseinneutrophils more effectively than SIN-l [5,7].…”

“…Accordingly, SIN-10 does not increase cGMP levels in neutrophils [5]. Surprisingly, SIN-10inhibitsPglucuronidasereleaseinneutrophils more effectively than SIN-l [5,7]. Interestingly, an analogue of SIN-10 induces vasodilation, indicating that this substance does not only serve as a prodrug for a NO-releasing substance but is a pharmacologically active substance per se [23].…”