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

Chen Q, Sievers RE, Varga M, Kharait S, Haddad DJ, Patton AK, Delany CS, Mutka SC, Blonder JP, Dube GP, Rosenthal GJ, Springer ML. Pharmacological inhibition of S-nitrosoglutathione reductase improves endothelial vasodilatory function in rats in vivo. J Appl Physiol 114: 752-760, 2013. First published January 24, 2013; doi: 10.1152/japplphysiol.01302.2012.-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.