Tetrahydrobiopterin rescues impaired responses of cerebral resistance arterioles during type 1 diabetes

Abstract

Our goal was to test the hypothesis that administration of tetrahydrobiopterin (BH 4 ) would improve impaired endothelial nitric oxide synthase-dependent dilation of cerebral arterioles during type 1 diabetes. In addition, we examined the influence of BH 4 on levels of superoxide in brain tissue. In vivo diameter of cerebral arterioles in nondiabetic and diabetic rats was measured in response to endothelial nitric oxide synthase-dependent agonists (acetylcholine and adenosine 5′-diphosphate) and an endothelial nitric oxide synthase-independent agonist (nitroglycerine) before and during application of BH 4 (1.0 µM). We also measured levels of superoxide from cortex tissue in nondiabetic and diabetic rats under basal states and during BH 4 . Acetylcholine and adenosine 5′-diphosphate dilated cerebral arterioles in nondiabetic rats, but this vasodilation was significantly impaired in diabetic rats. In contrast, nitroglycerine produced similar vasodilation in nondiabetic and diabetic rats. Application of BH 4 did not enhance vasodilation in nondiabetic rats but improved impaired cerebral vasodilation in diabetic rats. Basal superoxide levels were increased in cortex tissue from diabetic rats, and BH 4 reduced these levels to that found in nondiabetic rats. Thus, BH 4 is an important mediator of endothelial nitric oxide synthase-dependent responses of cerebral arterioles in diabetes and may have therapeutic potential for the treatment of cerebral vascular disease.

Tetrahydrobiopterin Improves Recognition Memory in the Triple-Transgenic Mouse Model of Alzheimer’s Disease, Without Altering Amyloid-β and Tau Pathologies

“…Santhanam et al[34] observed a decreased BH4 level and NO production in isolated microvessels of the Tg2576 mouse model of AD, whereas these impairments are reversed by a ten-day BH4 treatment. BH4 has been shown in several studies to increase cerebral blood flow[93,94]. In accordance with the impairment of cerebral blood flow and endothelial NO signalingdysfunctions previously described in 3xTg-AD mice [90], a beneficial effect of BH4 supplementation on brain vascularization could be involved in the memory improvement we observed in transgenic treated mice.…”

Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences

“…Through a series of studies, Arrick and colleagues showed that T1D impairs endothelium-dependent vasorelaxation by dysregulation of both eNOS and nNOS in an oxidative stress manner (9, 12–15, 169, 170). They did not observe any differences in the relaxation response upon stimulation with a NOS-independent agonist.…”

“…Furthermore, inhibition of ET-1 signaling by blockade of ET A receptors, as well as exercise or resveratrol treatment, reduced oxidative stress and restored cerebrovascular function (12, 15, 170). Enhancement of NOS activity by tetrahydrobiopterin treatment also improved vascular function (169). Involvement of NOS dysregulation in cerebral endothelial dysfunction was also shown in the Akita T1D mouse model.…”

Tetrahydrobiopterin Restores Microvascular Dysfunction in Young Adult Binge Drinkers

“…We have previously found no differences between ABs and BDs in microvascular responsiveness to sodium nitroprusside (Goslawski et al, ), suggesting the effect of binge drinking is endothelium‐specific. Animal studies have demonstrated that BH 4 decreases superoxide (Franco MDo et al, ; Mayhan and Arrick, ) and increases eNOS activity (Franco MDo et al, ), eNOS dimer‐to‐monomer ratios (eNOS coupling), and NO levels (Dikalova et al, ). While this study did not measure BH 4 , BH 4 :BH 2 ratio, reactive oxygen species within the adipose/arterioles, and/or use eNOS inhibitor (LNAME) or stereoisomer BH 4 , future studies to further dissect the mechanisms by which BH 4 improves microvascular dysfunction in binge drinking appear warranted.…”