5‐Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats

MacLean, Margaret R.; Sweeney, Gary; Baird, Michael G.; McCulloch, Kirsty; Houslay, Miles D.; Morecroft, Ian

doi:10.1111/j.1476-5381.1996.tb15760.x

Cited by 144 publications

(145 citation statements)

References 41 publications

(66 reference statements)

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“…In control lungs, 5-HT evoked only a moderate vascular pressor response, which is in line with previous studies [21]. Acute vasoconstriction to 5-HT was mediated by the 5-HT1B receptor in human pulmonary arteries ex vivo [37] and in vivo [38], whereas in normal rat pulmonary arteries, these responses were mediated predominantly by the 5-HT2A receptor [39]. In ex vivo perfused lungs of allergen-sensitised and -challenged mice, as well as control mice, the 5-HT-evoked Ppa responses were blocked by the 5-HT2A receptor antagonist ketanserin, whereas 5-HT1B receptor antagonism by GR127935 did not diminish vasoconstriction.…”

Section: Discussionsupporting

confidence: 77%

Allergic lung inflammation induces pulmonary vascular hyperresponsiveness

Witzenrath¹

2006

European Respiratory Journal

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Pulmonary arterial vasoconstriction is an important early component of pulmonary hypertension. Inflammatory mechanisms play a prominent role in the pathogenesis of pulmonary hypertension. The present authors investigated the potential role of acute allergic lung inflammation for alterations in pulmonary haemodynamics.BALB/c mice were intraperitoneally sensitised to ovalbumin and challenged by ovalbumin inhalation. Subsequently, lungs were ventilated and perfused ex vivo, and pulmonary arterial pressure (Ppa) was continuously monitored.Isolated perfused lungs of allergen-sensitised and -challenged mice showed five-fold enhanced Ppa responses to serotonin, which is reported to be a significant contributor to pulmonary hypertension in humans. This increase in Ppa was abolished by the serotonin receptor-2A antagonist ketanserin, but not the serotonin receptor-1B antagonist GR127935. Intracellular signalling to serotonin involved phosphatidylcholine-specific phospholipase C and protein kinase C, as well as Rho-kinase, as assessed by employing the specific inhibitors D609, bisindolylmaleimide and Y27632, respectively. In addition to serotonin, impressively enhanced Ppa increases in allergic lungs were also evoked by the thromboxane receptor agonist U46619, angiotensin II and endothelin-1.In conclusion, allergic lung inflammation was accompanied by impressive pulmonary vascular hyperresponsiveness. These results suggest a possible role for allergic inflammation in the development of pulmonary arterial hypertension.

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Section: Discussionsupporting

confidence: 77%

Allergic lung inflammation induces pulmonary vascular hyperresponsiveness

Witzenrath¹

2006

European Respiratory Journal

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“…In human pulmonary arteries, large and small, we have demonstrated that it is the 5-HT 1B/1D receptor which mediates vasoconstriction using GR 55562 (MacLean et al, 1996a;MacLean & Morecroft, 1998) and we have recently demonstrated that 5-HT 1B receptor expression is signi®cantly greater than 5-HT 1D receptor expression in these vessels (unpublished observation). We have previously shown, in the adult rat PRA, that both the 5-HT 2A receptor and the 5-HT 1B/1D receptor mediate vasoconstriction but that it is the 5-HT 2A receptor which dominates (MacLean et al, 1996b). Hence, there is species variation in the 5-HT receptor/s mediating vasoconstriction in small muscular pulmonary arteries.…”

Section: Vasoconstrictor Response To 5-htmentioning

confidence: 99%

5‐Hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries

Morecroft

MacLean

1998

British J Pharmacology

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1 Vasoconstrictor responses to 5-HT, 5-carboxamidotryptamine (5-CT, 5-HT 1 receptor agonist), amethyl-5-HT (5-HT 2 receptor agonist) and sumatriptan (5-HT 1D/1B receptor agonist) were studied in fetal, 0 ± 24 h, 4 day, 7 day and adult rabbit pulmonary resistance arteries (PRAs), alone and in the presence of the NO synthase inhibitor N o -nitro-L-arginine methylester (L-NAME). The e ect of the selective 5-HT receptor antagonists ketanserin (5-HT 2A receptor) and GR55562 (5-HT 1B/1D receptor) on vasoconstrictor responses to 5-HT were studied in the presence of L-NAME. Vasodilator responses to 5-CT were also studied in pre-contracted PRAs. 3 5-HT and a-methyl-5-HT were equipotent in causing contraction in the PRAs at each age (e.g. pEC 50 s for 5-HT and a-methyl-5-HT were 6.74+0.13 and 6.63+0.22 respectively in adult vessels). In the perinatal PRAs, sumatriptan and 5-CT produced negligible contractions, but in adult PRAs, 5-CT and sumatriptan were potent agonists with pEC 50 s of 6.05+0.3 and 5.70+0.20 respectively. 4 L-NAME markedly increased the maximum response to 5-HT in the 0 ± 24 h, 4 day and 7 day vessels and increased 5-HT potency in the 4-, 7-day-old and adult rabbit vessels. 5 In perinatal vessels, responses to 5-HT, with L-NAME present, were antagonized by ketanserin (30 nM and 0.1 mM) but not GR55562 (1 mM). A small ketanserin-resistant, GR55562-sensitive component was observed at 0 ± 24 h. In adult vessels, both ketanserin and GR55562 inhibited 5-HTinduced responses. 7 Vasodilator responses to 5-CT were observed in pre-contracted PRAs from 4-and 7-day-old rabbits but not in the fetus, 0 ± 24 h old or adult rabbit vessels. At 4 days the vasodilator response was inhibited both by L-NAME and GR55562. At 7 days the response was only partly blocked by L-NAME and resistant to GR55562. The L-NAME resistant component was antagonized by the 5-HT 7 receptor antagonist spiperone (1 mM). 8 The results suggest that 5-HT 2A -receptors mediate vasoconstriction in perinatal vessels whilst the 5-HT 1D or 5-HT 1B receptor contributes in adult rabbit vessels. The 5-HT 1D or 5-HT 1B receptor mediates NO-dependent vasodilation in vessels from rabbits at 4 days of age whilst 5-HT 7 receptors mediate NOindependent vasodilation by 7 days.

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“…In addition, 5-HT can interact with cells either by binding to specific cell surface receptors, which transduce intracellular signaling, or they can be transported into the cell through the SERT. The pulmonary vasoconstrictor effects of 5-HT are transmitted via binding to receptors, and the mitogenic actions of 5-HT are transduced via the SERT pathway (6,11,12).…”

mentioning

confidence: 99%

Serotonin Transporter Polymorphisms in Familial and Idiopathic Pulmonary Arterial Hypertension

Willers

Newman

Loyd

et al. 2006

Am J Respir Crit Care Med

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Rationale: Serotonin is a pulmonary vasoconstrictor and smooth muscle cell mitogen. The serotonin transporter (SERT) is abundant in pulmonary vascular smooth muscle. Compared with the short (S) allele, the long (L) SERT promoter allele is associated with increased SERT transcription and more severe pulmonary hypertension in a cohort of patients with chronic obstructive pulmonary disease, and was more prevalent in a cohort with idiopathic pulmonary arterial hypertension (IPAH), compared with control subjects. Objective: We hypothesized that the SERT L allele would associate with an earlier age at diagnosis and/or shorter survival interval in pulmonary arterial hypertension (PAH) than the S allele. Methods: SERT promoters from 166 familial PAH (FPAH), 83 IPAH, and 125 control subjects were sequenced. One hundred twentyseven of the patients with FPAH had a known mutation in bone morphogenetic protein receptor 2 (BMPR2). Results: The mean age at diagnosis was 35.8 yr in patients with FPAH and 41.1 yr in patients with IPAH (p ϭ 0.02). There were no significant differences in distribution of the LL, LS, or SS genotypes in IPAH, FPAH, or unaffected BMPR2 mutation carriers. In FPAH, the LL genotype was associated with an earlier age at diagnosis (p Ͻ 0.02). Conclusions:In patients with IPAH, these SERT genotypes do not correlate with age at diagnosis or survival interval. In patients with FPAH, the LL genotype correlates with an earlier age at diagnosis than SL or SS, although survival among the groups was similar. The correlation of the SERT promoter polymorphism with age at diagnosis in FPAH suggests a possible relationship between the SERT and BMPR2.Keywords: familial pulmonary arterial hypertension; 5-HT; 5-HTT; idiopathic pulmonary arterial hypertension; primary pulmonary hypertension; serotonin transporter Much of what is known about the genetic basis of pulmonary arterial hypertension (PAH) is related to mutations in bone morphogenetic protein receptor 2 (BMPR2), which have been identified in over 75% of patients with familial PAH (FPAH) (1-3), but are likely to be responsible for over 90% of FPAH. This discovery has provided a genetic explanation for PAH as

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5‐Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats

Cited by 144 publications

References 41 publications

Allergic lung inflammation induces pulmonary vascular hyperresponsiveness

Allergic lung inflammation induces pulmonary vascular hyperresponsiveness

5‐Hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries

Serotonin Transporter Polymorphisms in Familial and Idiopathic Pulmonary Arterial Hypertension

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