Contribution of the 5-HT(1B) receptor to hypoxia-induced pulmonary hypertension: converging evidence using 5-HT(1B)-receptor knockout mice and the 5-HT(1B/1D)-receptor antagonist GR127935.
5-Hydroxytryptamine (5-HT)(1B) receptors mediate contraction in human pulmonary arteries, and 5-HT(1B) 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-HT(1B/1D)-receptor antagonist (GR127935) on hypoxia-induced PHT (CHPHT) in rats and (2) CHPHT in 5-HT(1B)-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-HT(1)-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-HT(1)-receptor agonist, 5-carboxamidotryptamine (5-CT), in isolated pulmonary arteries. In wild-type mice, hypoxia increased right ventricular hypertrophy, which was absent in 5-HT(1B)-receptor knockout mice. Hypoxia increased pulmonary vascular remodeling in wild-type mice, and this was reduced in the 5-HT(1B)-receptor knockout mice. Hypoxia increased 5-HT(1)-mediated contraction in pulmonary arteries from the wild-type mice and this was attenuated in the 5-HT(1B)-receptor knockout mice. In conclusion, the 5-HT(1B) receptor plays a role in the development of CHPHT. One possible mechanism may be via enhanced 5-HT(1) receptor-mediated contraction of the pulmonary arterial circulation.
Keegan
A
A
Department of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, University of Glasgow, Scotland.
Morecroft
I
I
Smillie
D
D
Hicks
M N
MN
MacLean
M R
MR
D000818:Animals; D001273:Atmosphere Exposure Chambers; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism*; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D010069:Oxadiazoles / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D018497:Ventricular Dysfunction, Right / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology
D010069:Oxadiazoles; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C090701:GR 127935