Pharmacological inhibition ofS-nitrosoglutathione reductase improves endothelial vasodilatory function in rats in vivo

Abstract

Nitric oxide (NO) exerts a wide range of cellular effects in the cardiovascular system. NO is short lived, but S-nitrosoglutathione (GSNO) functions as a stable intracellular bioavailable NO pool. Accordingly, increased levels can facilitate NO-mediated processes, and conversely, catabolism of GSNO by the regulatory enzyme GSNO reductase (GSNOR) can impair these processes. Because dysregulated GSNOR can interfere with processes relevant to cardiovascular health, it follows that inhibition of GSNOR may be beneficial. However, the effect of GSNOR inhibition on vascular activity is unknown. To study the effects of GSNOR inhibition on endothelial function, we treated rats with a small-molecule inhibitor of GSNOR (N6338) that has vasodilatory effects on isolated aortic rings and assessed effects on arterial flow-mediated dilation (FMD), an NO-dependent process. GSNOR inhibition with a single intravenous dose of N6338 preserved FMD (15.3 ± 5.4 vs. 14.2 ± 6.3%, P = nonsignificant) under partial NO synthase inhibition that normally reduces FMD by roughly 50% (14.1 ± 2.9 vs. 7.6 ± 4.4%, P < 0.05). In hypertensive rats, daily oral administration of N6338 for 14 days reduced blood pressure (170.0 ± 5.3/122.7 ± 6.4 vs. 203.8 ± 1.9/143.7 ± 7.5 mmHg for vehicle, P < 0.001) and vascular resistance index (1.5 ± 0.4 vs. 3.2 ± 1.0 mmHg · min · l(-1) for vehicle, P < 0.001), and restored FMD from an initially impaired state (7.4 ± 1.7%, day 0) to a level (13.0 ± 3.1%, day 14, P < 0.001) similar to that observed in normotensive rats. N6338 also reversed the pathological kidney changes exhibited by the hypertensive rats. GSNOR inhibition preserves FMD under conditions of impaired NO production and protects against both microvascular and conduit artery dysfunction in a model of hypertension.

S-Nitrosoglutathione Reductase Deficiency Confers Improved Survival and Neurological Outcome in Experimental Cerebral Malaria

“…However, GSNO administration was associated with a decrease in mean arterial pressure (62), which may be problematic in hypovolemic critically ill patients. GSNOR inhibitors, on the other hand, have demonstrated minimal side effects in preclinical models (63), including limited effects on blood pressure (64), and are currently in phase I and phase II clinical trials for the treatment of cystic fibrosis. Future studies are required to determine if inhibitors of GSNOR can improve outcomes in preclinical models of ECM.…”

S-nitrosoglutathione reductase (GSNOR) inhibitor as an immune modulator in experimental autoimmune encephalomyelitis

“…N6022 is a first-in-class very potent, specific, and reversible inhibitor of GSNOR [50]. N6022 has been found to be beneficial in animal models of experimental asthma [51], allergic airway inflammation [52] and endothelial vasodilatory dysfunction [53]. In addition, safety of N6022 for human use is proven by Phase I and II studies for asthma and cystic fibrosis (ClinicalTrials.gov) [50].…”

Brief Exposure to Secondhand Smoke Reversibly Impairs Endothelial Vasodilatory Function

“…To study how SHS affects endothelial function in a physiologically consistent study population, we used a method that we previously developed to measure FMD by micro-ultrasound in the hindlimbs of living rats (Heiss et al, 2008b). FMD measured in rats is similar to human FMD with respect to factors that impair or improve the response and underlying mechanisms, and has provided us with unprecedented insight into the roles played by mediators of NO bioavailability (Chen et al, 2013;Heiss et al, 2008b).…”