title: Soluble guanylyl cyclase activation by HMR-1766 (ataciguat) in cells exposed to oxidative stress.
abstract: Many vascular diseases are characterized by increased levels of ROS that destroy the biological activity of nitric oxide and limit cGMP formation. In the present study, we investigated the cGMP-forming ability of HMR-1766 in cells exposed to oxidative stress. Pretreatment of smooth muscle cells with H(2)O(2) reduced cGMP production stimulated by sodium nitroprusside (SNP) or BAY 41-2272. However, pretreatment with H(2)O(2) significantly increased HMR-1766 responses. Similar results were obtained with SIN-1, menadione, and rotenone. In addition, HMR-1766 was more effective in stimulating heme-free sGC compared with the wild-type enzyme. Interestingly, in cells expressing heme-free sGC, H(2)O(2) inhibited instead of potentiated HMR-1766 responses, suggesting that the ROS-induced enhancement of cGMP formation was heme dependent. Moreover, using truncated forms of sGC, we observed that the NH(2)-terminus of the beta(1)-subunit is required for the action of HMR-1766. Finally, to study tolerance development to HMR-1766, cells were pretreated with this sGC activator and reexposed to HMR-1766 or SNP. Results from these experiments demonstrated lack of tolerance development to HMR-1766 as well as lack of cross-tolerance with SNP. We conclude that HMR-1766 is an improved sGC activator as it has the ability to activate oxidized/heme-free sGC and is resistant to the development of tolerance; these observations make HMR-1766 a promising agent for treating diseases associated with increased vascular tone combined with enhanced ROS production.
authors.affiliation: George P. Livanos and Marianthi Simou Laboratories, Department of Critical Care and Pulmonary Services, Evangelismos Hospital, University of Athens, Athens, Greece.
authors.forename: Zongmin
authors.initials: Z
authors.lastname: Zhou
authors.forename: Anastasia
authors.initials: A
authors.lastname: Pyriochou
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kotanidou
authors.forename: Georgios
authors.initials: G
authors.lastname: Dalkas
authors.forename: Martin
authors.initials: M
authors.lastname: van Eickels
authors.forename: Georgios
authors.initials: G
authors.lastname: Spyroulias
authors.forename: Charis
authors.initials: C
authors.lastname: Roussos
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos