Tetrahydrobiopterin increases myocardial blood flow in healthy volunteers: a double-blind, placebo-controlled study.

The crucial role of the vascular endothelium in vasomotor control is well recognised [1]. One important vasoactive mediator released by the endothelium, the so-called endothelium-derived relaxing factor [2], has been identified as nitric oxide (NO) [3]. Basal release of NO contributes significantly to resting macrovascular and coronary microvascular tone [4]. Furthermore, NO is critical for epicardial and microvascular vasodilatation during metabolic stimulation of the human heart [5]. Tetrahydrobiopterin (BH4) is an obligatory cofactor for all NO synthase isoforms. The precise role of BH4 in NO synthesis is incompletely understood, but several mechanisms are suggested: BH4 allosterically effects NO synthases, thereby stabilizing the active state of the enzyme [6] and increasing the affinity of the substrate L-arginine [7]. Furthermore, BH4 prevents feedback inhibition of NOS by NO itself [8]. Activation of NO synthases under suboptimal concentrations of BH4 leads to increased formation of oxygen radicals [9] and may represent an important mechanism of oxidative vascular injury [10]. BH4, like all reduced pteridines, is a potent antioxidant and scavenger of oxygen-derived free radicals [11]. There is increasing evidence for BH4 vasoactivity in vivo in both the vasculature of healthy individuals and patients with risk factors for or manifest atherosclerosis [12–20], suggesting potential therapeutic implications of BH4. However, in vivo data suggest that under physiological conditions endogenous BH4 levels are nearly saturating and barely a limiting factor for optimal or near optimal vascular NOS activity. For example, intraarterial infusion of BH4 in a dose of 500 μg/min over 10 minutes influenced neither mean arterial blood pressure nor basal or stimulated forearm blood flow in healthy volunteers [13]. Similarly, inhalation of 500 mg BH4 did not affect systemic haemodynamics in healthy volunteers despite elevated systemic arterial and venous BH4 levels [21]. In contrast, high doses of BH4 (8–32 mg/min) in the brachial artery induced marked local vasodilatation in the perfused limb of healthy subjects, whereas blood flow in the non-perfused limb, systemic blood pressure, and heart rate remained unchanged [12], and BH4 (250 nmol/min for 20 min) also caused Objectives: Tetrahydrobiopterin (BH4) is a regulatory cofactor for the activity of nitric oxide synthases. Vasodilating properties of BH4 have been reported in vitro and in vivo. The influence of BH4 on myocardial blood flow (MBF), however, is largely unknown. We therefore performed a double-blind, placebo-controlled study to investigate the effect of intravenous BH4 on MBF in healthy volunteers. Methods and Results: Resting MBF was assessed in 15 subjects receiving either intravenous BH4 (10 mg/kg) or placebo using positron emission tomography (PET) and [13N]ammonia. From a mean baseline MBF of 0.91 ± 0.09 ml/min/g, MBF increased to 1.18 ± 0.10 ml/min/g after BH4 (n = 10; p = 0.0042). In contrast, in the group receiving placebo mean MBF remained unchanged (non-significant decrease from 0.97 ± 0.19 to 0.84 ± 0.11 ml/min/g; n = 5; p = 0.36). Systemic haemodynamics and ECGs remained unaffected in both groups. BH4 was very well tolerated. Conclusion: Systemically administered BH4 is safe and effectively increases resting MBF in healthy volunteers.