Tetrahydrobiopterin as a Therapeutic Target

Given the complex pathophysiology of pulmonary hypertension, targeting of multiple pathways with combination drug therapy may be necessary. The ability of BH4 to both augment NO synthesis and decrease superoxide production addresses two pathogenic mechanisms simultaneously. The data support evaluation of pharmacological or molecular strategies that target endothelial BH4 availability in patients with pulmonary hypertension. In this context it is interesting to note that HMG-CoA inhibitors (statins), currently generating significant interest after their reversal of experimental pulmonary hypertension in rats [25], upregulate GTPCH mRNA and BH4 levels in vascular endothelial cells [31]. A more direct approach would be to examine the clinical efficacy of oral BH4 supplementation in suitable patients.

We cannot exclude the possibility that the pulmonary changes in the hph-1 mice occur at the transition from birth to neonatal life, or that BH4 has a particularly critical role in lung development. As such, BH4 deficiency may have a more important role in the pathogenesis of persistent pulmonary hypertension of the newborn rather than adult pulmonary hypertension. As discussed earlier, eNOS is known to play a critical role in lung development, as revealed in a recent study showing alveolar capillary dysplasia in eNOS-KO mice [29]. Furthermore, mice lacking 6-pyruvoyl-tetrahydropterin synthase (PTPS), the second enzyme in the synthetic pathway for BH4, die from an undefined cause within 48 hours following birth [18,76]. A recent study in lambs has shown that the normal foetal pulmonary endothelium has high levels of BH4 and NO production but BH4 levels fall postnatally, with evidence of eNOS uncoupling and the production of reactive oxygen species in addition to NO [55]. The data suggest that BH4 availability may have an important role in regulating pulmonary eNOS function during development and the adaptation of the pulmonary vasculature to extra-uterine life.

BH4 deficiency in hph-1 mice did not reproduce the severe pulmonary hypertension with plexiform lesions seen in humans [43] even after exposure to hypoxia, and the mice appear to have a normal life expectancy. Other recently published genetic mouse models of pulmonary hypertension have also failed to recapitulate this extreme phenotype [5,51,87]. Even in mice overexpressing S100A4/Mts1, only 5% of aging mice develop plexiform arteriopathy [27]. These observations imply that additional pathways need to be invoked for the full pathogenic expression of the human disease and reinforce the idea for combination therapy in the treatment of pulmonary hypertensive patients.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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