Targeting eNOS Uncoupling

BH4, an essential NOS cofactor, and its precursor sepiapterin, are commonly used to prevent eNOS uncoupling and oxidative stress and to prevent the development or progression of cardiovascular diseases in animal models [24]. Several large clinical trials are testing the efficacy of the oral formulation of BH[ in the treatment of systemic hypertension, peripheral arterial disease, coronary artery disease, pulmonary arterial hypertension, and SCD [23]. In addition, several agents are being tested for their ability to increase BH4 bioavailability as a more rational therapeutic strategy to improve eNOS coupling than BH4 supplementation per se. Therapeutic agents currently employed in cardiovascular medicine, such as statin-based drugs [165], erythropoietin [166]. folic acid (or its active metabolite 5-methyltetrahydrofolate [167]), insulin [168], ascorbic acid [169], or inhibitors of angiotensin II signaling [170]. recouple eNOS by stimulating the binding of BH. to NOS, promoting the biosynthesis of BH4, or protecting BH4 from oxidation.

Data supporting the improvement in penile erection by targeting eNOS uncoupling in the penis are very scarce. Treatment of diabetic rabbits with folic acid was found to decrease oxidative stress in the cavernosal tissue [50] . Recent basic science findings have demonstrated that pharmacologic supplementation with sepiapterin, a BH4 precursor, prevented an increase in oxidative stress in the penis and preserved erectile function in aged rats [40]. Further studies are warranted to examine the therapeutic effect of controlling eNOS uncoupling on penile erection in disease states.

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