The Effects of Dihydrobiopterin and Tetrahydrobiopterin on Hydrogen Peroxide and Nitric Oxide Release During Extracorporeal Shockwave Lithotripsy

Extracorporeal shockwave lithrotripsy (ESWL) is an effective, non-invasive clinical therapy utilized to break up stones in the kidney and urinary tract. A lithotripter generates high-energy acoustic pulses and propagates those shock waves through a lens on a region that focuses on the location of the stone, in turn breaking up the stone. The successive pulses generate shearing forces and cavitation bubbles. Cavitation bubbles are the formation and implosion of liquid free zones. The cavitation bubbles implode rapidly to create their own shockwaves that also put pressure on the stone. After treatment, fragmentation of the stone allows the debris to be cleared by the flow of the urinary tract. The problem is that to break up the kidney stone, it requires many repetitive shock waves that not only hit the kidney stone but also the surrounding tissue. Although lithotripsy provides a safer alternative to invasive treatments for removing harmful stones, ESWL may cause prolonged vasoconstriction after ESWL treatment, reducing renal blood flow, and subsequent endothelial dysfunction, which may cause kidney damage leading to acute to chronic hypertension clinically. ESWL-induced vascular oxidative stress and further endothelial dysfunction may be mediated by reduced levels of endothelial-derived nitric oxide (NO) and/or increased reactive oxygen species. Previous studies have shown that ESWL can induce oxidative stress, which can cause an increase in blood hydrogen peroxide (H2O2) and a decrease in endothelial-derived NO bioavailability release. Under normal conditions, tetrahydrobiopterin (BH4) is the cofactor to promote eNOS coupling, and endothelial-derived NO is produced. When the dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4) ratio is increased during oxidative stress, such as ESWL, BH2 promotes eNOS uncoupling and produces superoxide (SO) instead of NO. (1,2) (Figure 1) SO is then later converted to H2O2 by superoxide dismutase. BH4 and BH2 bind to eNOS with equal affinity, therefore the ratio will determine whether eNOS principally produces NO or SO