Sepiapterin Improves Vascular Reactivity and Insulin-Stimulated Glucose in Wistar Rats

Abstract EN

In the vasculature, sedentary behavior leads to endothelial abnormalities, resulting in elevated cardiovascular disease risk.

Endothelial nitric oxide synthase (eNOS) aberrations characterize endothelial dysfunction; eNOS also regulates mitochondrial function.

We hypothesized that sepiapterin (a precursor to eNOS cofactor tetrahydrobiopterin (BH4)) supplementation would improve endothelium-dependent vascular relaxation in sedentary animals via modulation of NOS function and mitochondrial activity.

Sedentary male Wistar rats were fed ad libitum for a total of 10 weeks.

Sepiapterin was administered in diet during the final 5 weeks.

Intraperitoneal insulin and glucose tolerance tests (IP-ITT/IP-GTT) were conducted at baseline and endpoint.

Aorta was assessed for vasoreactivity and mitochondrial respiration.

Insulin tolerance, determined by IP-ITT, significantly improved in rats treated with sepiapterin (p<0.05, interaction of time and treatment).

Acetylcholine- (ACh-) driven vasodilation was significantly greater in aorta from sepiapterin-treated rats as compared with control (76.4% versus 54.9% of phenylephrine contraction at 20 μM ACh, p<0.05).

Sepiapterin treatment resulted in significantly elevated state 3 (9.00 oxygen pmol/sec∗mg versus 8.17 oxygen pmol/sec∗mg, p<0.05) and 4 (7.28 oxygen pmol/sec∗mg versus 5.86 oxygen pmol/sec∗mg, p<0.05) aortic mitochondrial respiration with significantly lower respiratory control ratio (p<0.05) during octanoylcarnitine-driven respiration.

Vasodilation and insulin sensitivity were improved through targeting NOS via sepiapterin supplementation.