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(Circulation. 2005;111:2086-2090.)
© 2005 American Heart Association, Inc.

Hypertension

Pulmonary Hypertension in a GTP-Cyclohydrolase 1–Deficient Mouse

Manasi Nandi, PhD; Alyson Miller, PhD; Raymond Stidwill; Thomas S. Jacques, PhD, MRCP; Amanda A.J. Lam, PhD; Sheila Haworth, FRCP; Simon Heales, PhD, FRCPath; Patrick Vallance, FRCP, FMed Sci

From the Centre for Clinical Pharmacology (M.N., A.M., R.S., S. Haworth, P.V.), British Heart Foundation Laboratories, The Rayne Institute, University College London, and the Division of Neuropathology (T.S.J.), Neurometabolic Unit and Division of Neurochemistry (A.A.J.L., S. Heales), Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom.

Correspondence to Manasi Nandi, Centre for Clinical Pharmacology, British Heart Foundation Laboratories, The Rayne Institute, University College London, 5 University St, London WC1E 6JJ, United Kingdom. E-mail m.nandi{at}ucl.ac.uk

Received June 15, 2004; revision received January 14, 2005; accepted January 20, 2005.

Background— GTP-cyclohydrolase 1 (GTP-CH1) catalyzes the first step for the de novo production of tetrahydrobiopterin (BH₄), a cofactor for nitric oxide synthase (NOS). The hyperphenylalaninemic mutant mouse (hph-1) displays a 90% reduction in GTP-CH1 activity. Reduced BH₄ decreases NOS activity and may lead to endothelial dysfunction, and there is increasing evidence that a dysfunction of the NOS pathway may be implicated in pulmonary hypertension. The aim of the study was to investigate whether reduced BH₄ in the hph-1 mouse results in a pulmonary hypertensive phenotype.

Methods and Results— Morphological characterization of the heart, lung, and kidney and measurements of systemic and right ventricular blood pressures were performed in both hph-1 and wild-type mice. BH₄ and NO_x levels were also measured. Hph-1 mice had significantly lower NO_x and BH₄ levels, consistent with previous findings. Both morphological and in vivo data were indicative of a pulmonary but not systemic hypertensive phenotype. We observed increased right ventricle–left ventricle plus septum ratios attributable only to an increase in right ventricular mass, increased smooth muscle medial area in pulmonary resistance vessels, and significantly higher right ventricular pressures in vivo. There were no significant differences between left ventricular masses and systemic pressures, and there was no observed evidence of systemic hypertension in kidney sections between wild-type and hph-1.

Conclusions— This study demonstrates that mice deficient in GTP-CH1/BH₄ display a pulmonary hypertensive but not systemic hypertensive phenotype.

Key Words: hypertension, pulmonary • nitric oxide synthase • remodelling

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Kirkwood A. Pritchard, Jr, Yang Shi, and G. Ganesh Konduri
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