Table 1.

Current and emerging therapies to ameliorate and circumvent nitric oxide resistance.

Therapy	Properties	Limitations	References
Amelioration strategies
ACE inhibitors: Ramipril & Perindopril	•Decrease angiotensin II formation •Improve endothelial function by decreasing bradykinin degradation	•Benefits observed following prolonged use (days to months) •Limited utility during cardiovascular emergencies	(Murphey et al., 2003; Chirkov et al., 2004; Lob et al., 2006; Willoughby et al., 2012)
Perhexiline	•Anti-ischemic •Inhibits mitochondrial enzyme carnitine palmitoyltransferase	•Potential neuro- & hepato-toxicity •Variable pharmacokinetics: close therapeutic monitoring required	(Ashrafian et al., 2007; Chong et al., 2016)
Statins	•Lower cholesterol •Increase hepatic LDL uptake •Enhance eNOS gene expression •Enhance eNOS activity by reducing caveolin-1 expression	•Benefits observed following prolonged use (days to months) •Limited utility during cardiovascular emergencies	(Willoughby et al., 2002; Stepien et al., 2003; Chirkov et al., 2004; Lundberg et al., 2015; Go et al., 2019)
Insulin (in presence of severe hyperglycemia)	•Lower plasma glucose •Reduce oxidative stress and superoxide production	•NO• resistance can persist following acute, aggressive glycaemic control •Beneficial effects on mortality unclear	(Vehkavaara and Yki-Järvinen, 2004; Mehta et al., 2005; Worthley et al., 2007)
Circumvention strategies
sGC activators	•Bind to heme pocket of sGC •Heme-independent •Activate sGC if heme is oxidized or detached	•Can cause hypotension	(Follmann et al., 2013; Buys et al., 2018; Elgert et al., 2019)
Nitrite	•Converted to NO• via reductases •Vasodilator & anti-aggregatory actions potentiated in hypoxia	•Anti-platelet effect diminished in patients with IHD •Does not reduce infarct size post-acute myocardial infarction	(Dautov et al., 2013; Siddiqi et al., 2014; Jones et al., 2015)
Nitroxyl donors	•Vasodilator, anti-aggregatory, positive cardiac inotropic/lusitropic actions •sGC-dependent & -independent signaling •Resistant to oxidative stress	•May cause coronary steal •Long-term benefits remain to be elucidated	(Irvine et al., 2007; Kemp-Harper, 2011; Dautov et al., 2013)