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.
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