gms | German Medical Science


Figure 1: Improvement of NO bioactivity by preventing eNOS uncoupling and enhancing eNOS expression.

The renin inhibitor aliskiren, angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor 1 blockers (ARB), as well as the selective aldosterone antagonist eplerenone enhance the expression of eNOS. In addition, these drugs prevent eNOS uncoupling by downregulating NADPH oxidase (NOX) expression and activity, and by preventing tetrahydrobiopterin (BH4) oxidation. Statins (3-hydroxy-3-methylgulutaryl-coenzyme A reductase inhibitors) stabilize eNOS mRNA, downregulate NOX, and increase BH4 biosynthesis by upregulating GTP cyclohydrolase 1 (GCH1). Betulinic acid and ursolic acid are compounds that enhance eNOS expression and, at the same time, downregulate NOX expression. Resveratrol stimulates the expression of eNOS, upregulates antioxidant enzymes (such as superoxide dismutases (SOD) and glutathione peroxidase 1 (GPx1) and downregulates NOX. This leads to a reduction of peroxynitrite (ONOO-)-mediated BH4 oxidation and NO inactivation by superoxide O2-•. Resveratrol also stimulates the expression of GCH1.