Abstract
Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthases (NOS). This study investigated the effect of increasing BH4 levels on hypoxia-induced pulmonary vasoconstriction (HPV).
Sprague Dawley rats and hph-1 (BH4 deficient) mice were given BH4 before and during HPV in an isolated perfused lung preparation. BH4 inhibited HPV in a concentration-dependent manner and increased NO metabolites in the perfusate. Bradykinin-induced reductions in HPV were blunted in hph-1 mice and pre-administration of BH4 restored the response. The effect of BH4 was attenuated by l-NAME (NOS inhibitor), PTIO (NO scavenger), and catalase (H2O2 catalyser) administered prior to HPV but enhanced by MnTMPyP (superoxide dismutase mimetic). The effect of BH4 on HPV was partially recapitulated by NH4, a stereoisomer that shares antioxidant properties with BH4 but is not a NOS cofactor.
The bioavailability of BH4 is an important determinant of the pulmonary vascular response to hypoxia. Its effects are mediated via nitric oxide, hydrogen peroxide and its antioxidant properties, and are attenuated by oxidant stress. Pharmacological administration of BH4 may have therapeutic potential in pulmonary hypertension.
- Animal models
- hypoxia
- pulmonary vasoconstriction
- pulmonary hypertension
- nitric oxide
- superoxide
- tetrahydrobiopterin
Footnotes
Support Statement
This work is supported by the British Heart Foundation (London, UK), BioMarin Pharmaceuticals, Inc. (Novato, CA, USA) and PULMOTENSION (European Commission under the 6th Framework Programme, contract numbers LSHM-CT-2005-018725, Brussels, Belgium).
Statement of Interest
A statement of interest for M.R. Wilkins and for the study itself can be found at www.erj.ersjournals.com/misc/statements.dtl
This article has supplementary material available from www.erj.ersjournals.com
- Received November 26, 2009.
- Accepted February 28, 2010.
- ©ERS 2010