L-arginine, tetrahydrobiopterin, nitric oxide and diabetes

The endothelial isoform of nitric oxide synthase (eNOS) is constitutively expressed but dynamically regulated by a number of factors. Building our knowledge of this regulation is necessary to understand and modulate the bioavailability of nitric oxide, central to the cardiovascular complications of diabetes and other diseases. This review will focus on the eNOS substrate (L-arginine), its cofactor (tetrahydrobiopterin), and mechanisms related to the uncoupling of eNOS activity.

The global arginine bioavailability ratio has been proposed as a biomarker reflective of L-arginine availability, arginase activity, and citrulline cycling, as all of these processes impact eNOS activity. The failure of oral supplementation of tetrahydrobiopterin to recouple eNOS has emphasized the importance of the tetrahydrobiopterin to dihydrobiopterin ratio. Identification of transporters for biopterin species as well as signals that regulate endogenous arginine production have provided insight for alternative strategies to raise endothelial tetrahydrobiopterin levels while reducing dihydrobiopterin and alter eNOS activity. Finally, new information about redox regulation of eNOS itself may point to ways of controlling oxidative stress in the vasculature.

Restoring proper eNOS activity is key to ameliorating or preventing cardiovascular complications of diabetes. Continued investigation is needed to uncover new means for maintaining endothelial nitric oxide bioavailability.