Figure - available from: Journal of Cardiovascular Pharmacology and Therapeutics
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The Janus effect: 2 faces of nitric oxide. Janus, an ancient Roman god depicted as having one head with 2 faced back to back looking in opposite directions. Similarly, NO has 2 opposite aspects in GTN tolerance, NO is the mediator of vasodilation by GTN but also may be the underlying cause of GTN tolerance, caused by uncoupling of mitochondrial complex I (Cx I) and glutathione (GSH) depletion in response to NO from GTN. Cascade is described in text and Figure 1.
Source publication
Our paper highlights the past 50 years of research focusing solely on tolerance involving nitroglycerin (glyceryl trinitrate, GTN). It also identifies and discusses inconsistencies in previous mechanistic explanations that have failed to provide a way to administer GTN continuously, free of limitations from tolerance and without the requirement of...
Citations
... Superoxide further depletes GSH via S-glutathiolation (11) with oxidation of GSH to GSSG thereby completing a depleting the cellular GSH pool (12). 3]Superoxide from the uncoupling of complex I leads to the formation of reactive oxygen and nitrogen species, ROS and RNS, which subsequently lead to ALDH II and eNOS uncoupling (13). This is followed by PKC activation that leads to the final step in superoxide production from GSH depletion, NADPH oxidase activation (13). ...
... 3]Superoxide from the uncoupling of complex I leads to the formation of reactive oxygen and nitrogen species, ROS and RNS, which subsequently lead to ALDH II and eNOS uncoupling (13). This is followed by PKC activation that leads to the final step in superoxide production from GSH depletion, NADPH oxidase activation (13). 4] Superoxide from the above steps 1-3 combines further with NO from GTN to produce peroxynitrite, OONO-(13) 5] repleting and maintaining the GSH pool suppresses superoxide production thereby preventing OONO and maintaining GTN as a donor and generator of NO (13) which explains the results of the above studies (3,4,5,6,7,8). ...
... This is followed by PKC activation that leads to the final step in superoxide production from GSH depletion, NADPH oxidase activation (13). 4] Superoxide from the above steps 1-3 combines further with NO from GTN to produce peroxynitrite, OONO-(13) 5] repleting and maintaining the GSH pool suppresses superoxide production thereby preventing OONO and maintaining GTN as a donor and generator of NO (13) which explains the results of the above studies (3,4,5,6,7,8). This is illustrated in figure 1. ...
The purpose of this article is to illustrate how the solution to the long standing problem of nitroglycerin tolerance may open the door to treatment opportunities for diseases with similar underlying mechanisms. Following a review of the cascade of reactions whereby nitric oxide from nitroglycerin causes tolerance mediated by superoxide, this paper proceeds to identify novel treatments for preventing diseases whose underlying pathogenesis is vessel wall inflammation resulting from activation of the NLRP3 inflammasome by superoxide. The paper identifies a list of diseases that may benefit from the treatments discussed. It concludes by suggesting studies involving patients with heart failure.
