Serotonin Transporter Inhibition Prevents and Reverses Monocrotaline-Induced Pulmonary Hypertension in Rats (original) (raw)
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Serotonin Transporter Inhibitors Protect against Hypoxic Pulmonary Hypertension
American Journal of Respiratory and Critical Care Medicine, 2003
Pulmonary hypertension (PH) results from constriction and remodeling of pulmonary vessels. Serotonin contributes to both phenomena through different signaling pathways. The mitogenic effect of serotonin on pulmonary vascular smooth muscle cells is mediated by the serotonin transporter (5-hydroxytryptamine transporter [5-HTT]), whereas its constricting effect is mediated by 5-HT 1B/1D and 5-HT 2A receptors. Here, we investigated the respective roles of 5-HTT and 5-HT receptors on the development of chronic hypoxic PH in mice. During exposure to hypoxia (10% O 2 for 2 weeks), the animals received one of the specific 5-HTT inhibitors citalopram and fluoxetine (10 mg/kg/day), the selective 5-HT 1B/1D receptor antagonist GR127935 (2 and 10 mg/kg/day), or the 5-HT 2A receptor antagonist ketanserin (2 mg/kg/day). Mice treated with the 5-HTT inhibitors showed less right ventricle hypertrophy (ratio of right ventricle/left ventricle ϩ septum ϭ 36.7 Ϯ 2.0% and 35.8 Ϯ 1.3% in citalopram-and fluoxetine-treated mice, respectively, vs. 41.5 Ϯ 1.5% in vehicle-treated mice) and less pulmonary vessel muscularization (p Ͻ 0.01) than those receiving the vehicle. Neither GR127935 nor ketanserin affected these parameters. These data indicate that 5-HTT plays a key role in hypoxia-induced pulmonary vascular remodeling. The effects of serotonin transporter inhibitors on PH in humans deserve investigation.
In vivo effects of a combined 5-HT1B receptor/SERT antagonist in experimental pulmonary hypertension
Cardiovascular Research, 2010
A mechanism for co-operation between the serotonin (5-hydroxytryptamine, 5-HT) transporter and 5-HT1B receptor in mediating pulmonary artery vasoconstriction and proliferation of pulmonary artery smooth muscle cells has been demonstrated in vitro. Here we determine, for the first time, the in vivo effects of a combined 5-HT1B receptor/serotonin transporter antagonist (LY393558) with respect to the development of pulmonary arterial hypertension (PAH) and its in vitro effects in human pulmonary artery smooth muscle cells (hPASMCs) derived from idiopathic PAH (IPAH) patients. We determined the effects of LY393558 as well as a selective serotonin transporter inhibitor, citalopram, on right ventricular pressure, right ventricular hypertrophy, and pulmonary vascular remodelling in wildtype mice and mice over-expressing serotonin transporter (SERT+ mice) before and after hypoxic exposure. We also compared their effectiveness at reversing PAH in SERT+ mice and hypoxic mice. Further, we examined the proliferative response to serotonin in IPAH hPASMCs. We also clarified the pharmacology of serotonin-induced vasoconstriction and 5-HT1B receptor/serotonin transporter interactions in mouse isolated pulmonary artery. Citalopram had a moderate effect at preventing and reversing experimental PAH in vivo whereas LY393558 was more effective. LY393558 was more effective than citalopram at reversing serotonin-induced proliferation in IPAH hPASMCs. There is synergy between 5-HT1B receptor and serotonin transporter inhibitors against serotonin-induced vasoconstriction in mouse pulmonary arteries. 5-HT1B receptor and serotonin transporter inhibition are effective at preventing and reversing experimental PAH and serotonin-induced proliferation of PASMCs derived from IPAH patients. Targeting both the serotonin transporter and 5-HT1B receptor may be a novel therapeutic approach to PAH.
Circulation Research, 2006
One intrinsic abnormality of pulmonary artery smooth muscle cells (PA-SMCs) in human idiopathic pulmonary hypertension (iPH) is an exaggerated proliferative response to internalized serotonin (5-HT) caused by increased expression of the 5-HT transporter (5-HTT). To investigate whether 5-HTT overexpression in PA-SMCs is sufficient to produce PH, we generated transgenic mice overexpressing 5-HTT under the control of the SM22 promoter. Studies in SM22-LacZ ϩ mice showed that the transgene was expressed predominantly in SMCs of pulmonary and systemic vessels. Compared with wild-type mice, SM22-5-HTT ϩ mice exhibited a 3-to 4-fold increase in lung 5-HTT mRNA and protein, together with increased lung 5-HT uptake activity, but no changes in platelet 5-HTT activity or blood 5-HT levels. At 8 weeks of age, SM22-5-HTT ϩ mice exhibited PH, with marked increases in right ventricular systolic pressure (RVSP), right ventricle/left ventricleϩseptum ratio, and muscularization of distal pulmonary vessels, but no changes in systemic arterial pressure. PH worsened with age. Except a marked decrease in Kv channels, no changes in the lung expression of mediators of pulmonary vascular remodeling were observed in SM22-5-HTT ϩ mice. Compared with wild-type mice, SM22-5-HTT ϩ mice showed depressed hypoxic pulmonary vasoconstriction contrasting with greater severity of hypoxia-or monocrotaline-induced PH. These results show that increased 5-HTT expression in PA-SMCs, to a level close to that found in human iPH, lead to PH in mice. They further support a central role for 5-HTT in the pathogenesis of PH, making 5-HTT a potential therapeutic target. (Circ Res. 2006;98:1323-1330.)
Journal of Pharmacology and Experimental Therapeutics, 2004
Pulmonary arterial 5-hydroxytryptamine (serotonin) (5-HT) transporter (SERT)-, 5-HT receptor expression, and 5-HTinduced vasoconstriction can be increased in pulmonary hypertension. These variables were studied in normoxic and hypoxic Fawn-Hooded (FH) and Sprague-Dawley (SD) rats. Furthermore, we compared the functional effects of SERT inhibitors and 5-HT receptor antagonists against 5-HTinduced vasoconstriction of pulmonary arteries. SERT and 5-HT 1B expression was greater in FH rat lungs than in SD rats, as was 5-HT-mediated vasoconstriction. The 5-HT 2A receptor antagonist ketanserin and the 5-HT 1B receptor antagonist SB224289 (1Ј-methyl-5-[[2Ј-methyl-4Ј-(5-methyl-1,2,4oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro-spiro-[furo] 2, 3-f]indole-3,4Ј-piperidine]) inhibited responses to 5-HT in all vessels. The combined 5-HT 1B receptor/SERT antagonist LY393558 (1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)pyridinyl]ethyl]-3-isopropyl-6-(methylsulfonyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide) was the most potent inhibitor of constriction in all vessels. SERT inhibitors citalopram and fluoxetine inhibited responses to 5-HT in SD vessels. However, these inhibitors potentiated responses to 5-HT in FH vessels. After exposure of rats to 2 weeks of hypoxia, there was increased 5-HTmediated vasoconstriction and a profound decrease in SERT expression in both the FH and SD rat lung. Accordingly, citalopram had no effect on 5-HT-induced constriction in SD rat vessels and markedly less effect in FH rat vessels. Ketanserin, SB224289, and LY393558 inhibited responses to 5-HT in all hypoxic rat vessels. LY393558 was the most potent antagonist, and there was synergy between the effects of fluoxetine and SB224289 when given simultaneously. The results suggest that, in FH rats, SERT inhibitors may increase pulmonary vasoconstriction, but this can be inhibited by simultaneous 5-HT 1B receptor antagonism. There is synergy between the inhibitory effects of 5-HT 1B receptor antagonists and SERT inhibitors on 5-HT-induced pulmonary vasoconstriction.
European Journal of Pharmacology, 2011
Pulmonary arterial hypertension (PAH) is a chronic disease characterized by sustained elevation of pulmonary arterial pressure that leads to right ventricle failure and death. Pulmonary resistance arterioles in PAH undergo progressive narrowing and/or occlusion. Currently approved therapies for PAH are directed primarily at relief of symptoms by interfering with vasoconstrictive signals, but do not halt the microvascular cytoproliferative process. In this study we show that C-122 (2-amino-N-(2-{4-[3-(2-trifluoromethylphenothiazin-10-yl)-propyl]-piperazin-1-yl}-ethyl)-acetamide trihydrochloride, a novel antagonist of serotonin receptor 5-HT 2B (Ki = 5.2 nM, IC 50 = 6.9 nM), when administered to rats for three weeks in daily oral 10 mg/kg doses, prevents not only monocrotaline (MCT)-induced elevations in pressure in the pulmonary arterial circuit (19 ± 0.9 mm Hg vs. 28 ± 2 mm Hg in MCT-vehicle group, P b 0.05) and hypertrophy of the right ventricle (right ventricular wt./body wt. ratio 0.52 ± 0.02 vs. 0.64 ± 0.04 in MCT-vehicle group, P b 0.05), but also muscularization of pulmonary arterioles (23% vs. 56% fully muscularized in MCT-vehicle group, P b 0.05), and perivascular fibrosis in the lung. C-122 is orally absorbed in the rat, and partitions strongly into multiple tissues, including heart and lung. C-122 has significant off-target antagonist activity for histamine H-1 and several dopamine receptors, but shows no evidence of crossing the blood-brain barrier after a single 10 mg/kg oral dose in rats. We conclude that C-122 can prevent microvascular remodeling and associated elevated pressures in the rat MCT model for PAH, and offers promise as a new therapeutic entity to suppress vascular smooth muscle cell proliferation in PAH patients.
European Journal of …, 2011
Pulmonary arterial hypertension (PAH) is a chronic disease characterized by sustained elevation of pulmonary arterial pressure that leads to right ventricle failure and death. Pulmonary resistance arterioles in PAH undergo progressive narrowing and/or occlusion. Currently approved therapies for PAH are directed primarily at relief of symptoms by interfering with vasoconstrictive signals, but do not halt the microvascular cytoproliferative process. In this study we show that C-122 (2-amino-N-(2-{4-[3-(2-trifluoromethylphenothiazin-10-yl)-propyl]-piperazin-1-yl}-ethyl)-acetamide trihydrochloride, a novel antagonist of serotonin receptor 5-HT 2B (Ki = 5.2 nM, IC 50 = 6.9 nM), when administered to rats for three weeks in daily oral 10 mg/kg doses, prevents not only monocrotaline (MCT)-induced elevations in pressure in the pulmonary arterial circuit (19 ± 0.9 mm Hg vs. 28 ± 2 mm Hg in MCT-vehicle group, P b 0.05) and hypertrophy of the right ventricle (right ventricular wt./body wt. ratio 0.52 ± 0.02 vs. 0.64 ± 0.04 in MCT-vehicle group, P b 0.05), but also muscularization of pulmonary arterioles (23% vs. 56% fully muscularized in MCT-vehicle group, P b 0.05), and perivascular fibrosis in the lung. C-122 is orally absorbed in the rat, and partitions strongly into multiple tissues, including heart and lung. C-122 has significant off-target antagonist activity for histamine H-1 and several dopamine receptors, but shows no evidence of crossing the blood-brain barrier after a single 10 mg/kg oral dose in rats. We conclude that C-122 can prevent microvascular remodeling and associated elevated pressures in the rat MCT model for PAH, and offers promise as a new therapeutic entity to suppress vascular smooth muscle cell proliferation in PAH patients.
The FASEB Journal, 2009
and in experimental models including mice with SM22␣-targeted overexpression of the serotonin transporter (5-HTT). The mechanisms underlying these abnormalities, however, remain unknown. Dichloroacetate (DCA) inhibits chronic hypoxia-or monocrotaline-induced PAH by inhibiting nuclear factor of activated T-cells (NFAT)c2 and increasing Kv1.5. Therefore, we hypothesized that DCA could regress established PAH in SM22-5-HTT ؉ mice. We evaluated pulmonary hemodynamics, vascular remodeling, NFATc2, and Kv1.5 protein in 20-wk-old SM22-5-HTT ؉ or wild-type mice treated for 1, 7, and 21 d with DCA, cyclosporine-A (NFAT inhibitor), or vehicle. DCA partially reversed PAH in SM22-5-HTT ؉ mice by decreasing proliferation and increasing apoptosis in muscularized PAs. Furthermore, serotonin 10 ؊8 -10 ؊6 M) dose-dependently increased PA-smooth muscle cell (PA-SMC) proliferation in culture (EC 50 01؋79.0؍ ؊7 M) and DCA (5؋10 ؊4 M) vs. PBS markedly reduced the growth of PA-SMC from IPAH and control patients treated with the highest dose of serotonin by 50 and 30%, respectively. Finally, although serotonin induces NFATc2 activation in PA-SMCs, inhibition of NFATc2 alone with cyclosporine-A was not sufficient for reversing PAH in this model. Our results support the possibility that DCA may be an interesting agent for investigation in patients with PAH.-Guignabert, C., Tu, L., Izikki, M., Dewachter, L., Zadigue, P., Humbert, M., Adnot, S., Fadel, E., Eddahibi, S. Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22␣-targeted overexpression of the serotonin transporter. FASEB J. 23, 000 -000 (2009). www.fasebj.org Key Words: pulmonary vascular remodeling ⅐ serotonin pathway ⅐ NFAT/Kv1.5 axis ⅐ PDK inhibitor ⅐ Bcl-2/Bax ratio
Circulation Research, 2001
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/1Dreceptor 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 Ϫ1 · d Ϫ1 ) 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. (Circ Res. 2001;89:1231-1239.) Key Words: 5-HT 1B -receptor knockout mice Ⅲ 5-HT 1B -receptor antagonist Ⅲ pulmonary hypertension Original
2010
221 words Introduction: 659 words Discussion: 1232 words Abbreviations 5-HT 5-hydroxytryptamine AE alveolar edema AMI alveolar macrophage infiltration DF dexfenfluramine ECG electrocardiogram EDTA ethylenediaminetetraacetic acid FOV field of view iPAH idiopathic pulmonary arterial hypertension LVP left ventricular pressure LVSB left ventricular septal bowing MAP mean arterial pressure MAPK mitogen-activated protein kinase MCT Monocrotaline OLP overall lung pathology PA pulmonary artery PAH pulmonary arterial hypertension PAP peak pulmonary artery pressures PASMC pulmonary arterial smooth muscle cell PBS phosphate buffered saline PE perivascular edema RVP right ventricular pressure RVSP right ventricular systolic pressure This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on April 29, 2010 as DOI: 10.1124/jpet.109.165001 at A PE T Jornals on N ovem er 3, 2017 jpet.asjournals.org D ow nladed from