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Circulation Research. 2001
Published online before print October 18, 2001, doi: 10.1161/hh2401.100426
A more recent version of this article appeared on December 7, 2001
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Submitted on June 11, 2001
Revised on September 5, 2001
Accepted on October 10, 2001

Contribution of the 5-HT1B Receptor to Hypoxia-Induced Pulmonary Hypertension. Converging Evidence Using 5-HT1B--Receptor Knockout Mice and the 5-HT1B/1D-Receptor Antagonist GR127935

Alan Keegan , Ian Morecroft , Diane Smillie , Martin N. Hicks , and Margaret R. MacLean *

From the Department of Neuroscience and Biomedical Systems (A.K., I.M., M.R.M.), Institute of Biomedical and Life Sciences and the Department of Medical Cardiology (D.S., M.N.H.), University of Glasgow, Scotland.

* To whom correspondence should be addressed. E-mail: m.maclean{at}bio.gla.ac.uk.

5-Hydroxytryptamine (5-HT)1B receptors mediate contraction in human pulmonary arteries, and 5-HT1B receptor--mediated contraction is enhanced in pulmonary arteries from hypoxic rats. Here we further examine the role of this receptor in the development of pulmonary hypertension (PHT) by examining (1) the effects of a 5-HT1B/1D--receptor antagonist (GR127935) on hypoxia-induced PHT (CHPHT) in rats and (2) CHPHT in 5-HT1B--receptor knockout mice. In rats, hypoxia increased right ventricular pressure and right ventricular hypertrophy and induced pulmonary vascular remodeling associated with an increase in pulmonary arterial wall thickness. GR127935 (3 mg · kg-1 · d-1) reduced all of these indices. 5-HT1--mediated contraction was enhanced in pulmonary arteries of the CHPHT rats. The effects of GR127935 on PHT indices were associated with an attenuation of the enhanced contractile responses to 5-HT and the 5-HT1--receptor agonist, 5-carboxamidotryptamine (5-CT), in isolated pulmonary arteries. In wild-type mice, hypoxia increased right ventricular hypertrophy, which was absent in 5-HT1B--receptor knockout mice. Hypoxia increased pulmonary vascular remodeling in wild-type mice, and this was reduced in the 5-HT1B--receptor knockout mice. Hypoxia increased 5-HT1--mediated contraction in pulmonary arteries from the wild-type mice and this was attenuated in the 5-HT1B--receptor knockout mice. In conclusion, the 5-HT1B receptor plays a role in the development of CHPHT. One possible mechanism may be via enhanced 5-HT1 receptor--mediated contraction of the pulmonary arterial circulation.


Key words: 5-HT1B--receptor knockout mice • 5-HT1B--receptor antagonist • pulmonary hypertension






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