Acute localized administration of tetrahydrobiopterin and chronic systemic atorvastatin treatment restore cutaneous microvascular function in hypercholesterolaemic humans

Elevated oxidized low-density lipoproteins (LDL) are associated with vascular dysfunction in the cutaneous microvasculature, induced in part by upregulated arginase activity and increased globalized oxidant stress. Since tetrahydrobiopterin (BH ₄) is an essential cofactor for endothelial nitric oxide synthase (NOS3), decreased bioavailability of the substrate l-arginine and/or BH ₄ may contribute to decreased NO production with hypercholesterolaemia. We hypothesized that (1) localized administration of BH ₄ would augment NO-dependent vasodilatation in hypercholesterolaemic human skin, which would be further increased when combined with arginase inhibition and (2) the improvement induced by localized BH ₄ would be attenuated after a 3 month oral atorvastatin intervention (10 mg). Four microdialysis fibres were placed in the skin of nine normocholesterolaemic (NC: LDL = 95 ± 4 mg dl ^-1) and nine hypercholesterolaemic (HC: LDL = 177 ± 6 mg dl ^-1) men and women before and after 3 months of systemic atorvastatin. Sites served as control, NOS inhibited, BH ₄, and arginase inhibited + BH ₄ (combo). Skin blood flow was measured while local skin heating (42°C) induced NO-dependent vasodilatation. After the established plateau l-NAME was perfused in all sites to quantify NO-dependent vasodilatation (NO). Data were normalized to maximum cutaneous vascular conductance (CVC). Vasodilatation at the plateau and NO-dependent vasodilatation were reduced in HC subjects (plateau HC: 70 ± 5% CVC _maxvs. NC: 95 ± 2% CVC _max; NO HC: 45 ± 5% CVC _maxvs. NC: 64 ± 5% CVC _max; both P < 0.001). Localized BH ₄ alone or combo augmented the plateau (BH ₄: 93 ± 3% CVC _max; combo 89 ± 3% CVC _max, both P < 0.001) and NO-dependent vasodilatation in HC (BH ₄: 74 ± 3% CVC _max; combo 76 ± 3% CVC _max, both P < 0.001), but there was no effect in NC subjects (plateau BH ₄: 90 ± 2% CVC _max; combo 95 ± 3% CVC _max; NO-dependent vasodilatation BH ₄: 68 ± 3% CVC _max; combo 58 ± 4% CVC _max, all P > 0.05 vs. control site). After the atorvastatin intervention (LDL = 98 ± mg * dl ^-1) there was an increase in the plateau in HC (96 ± 4% CVC _max, P < 0.001) and NO-dependent vasodilatation (68 ± 3% CVC _max, P < 0.001). Localized BH ₄ alone or combo was less effective at increasing NO-dependent vasodilatation after the drug intervention (BH ₄: 60 ± 5% CVC _max; combo 58 ± 2% CVC _max, both P < 0.001). These data suggest that decreased BH ₄ bioavailability contributes in part to cutaneous microvascular dysfunction in hypercholesterolaemic humans and that atorvastatin is an effective systemic treatment for improving NOS coupling mechanisms in the microvasculature.