Role of basal extracellular Ca<sup>2+</sup> entry during 5‐HT‐induced vasoconstriction of canine pulmonary arteries

Wilson, Sean; Mason, Helen S.; Ng, Lih Chyuan; Montague, Stephen; Johnston, Louise; Nicholson, Neil; Mansfield, Sarah; Hume, Joseph R.

doi:10.1038/sj.bjp.0706077

Cited by 28 publications

(96 citation statements)

References 57 publications

(91 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because 5-HT 2A receptors are also important for PA reactivity, we inhibited these with 100 nmol/L ketanserin, a concentration that preferentially inhibits 5-HT 2A receptors. 16,42,43 The EC 50 for 5-HT was shifted approximately 2 log units by 100 nmol/L ketanserin in vessels from both normoxic and LTH fetuses, being À4.74 + 0.09 mol/L (N ¼ 11/3) and À4.13…”

Section: Resultsmentioning

confidence: 96%

“…Extracellular Ca 2þ entry was selectively reduced by treating arteries with 10 mmol/L Ni 2þ because at a high concentration, Ni 2þ blocks plasma membrane Ca 2þ entry without inhibiting intracellular Ca 2þ release. 16 …”

Section: Resultsmentioning

confidence: 99%

“…The Ca 2þ imaging studies were conducted because our previous work indicates that Ca 2þ signaling is central to 5-HT contraction of PAs. 16,55 In these experiments, arterial segments were stimulated with 10 mmol/L 5-HT and cytosolic Ca 2þ was monitored in single myocytes within the intact arterial wall. This in situ approach was achieved using the Ca 2þ reporter Fluo-4 and laser scanning confocal microscopy techniques, as described in the methods.…”

Section: -Ht-induced Contraction In Fetal Pas and Its Role Is Presermentioning

confidence: 99%

See 2 more Smart Citations

Long-Term Maternal Hypoxia

et al. 2011

View full text Add to dashboard Cite

Antenatal maternal long-term hypoxia (LTH) can alter serotonin (5-HT) and calcium (Ca 2þ ) signaling in fetal pulmonary arteries (PAs) and is associated with persistent pulmonary hypertension of the newborn (PPHN). In humans, the antenatal maternal hypoxia can be secondary to smoking, anemia, and chronic obstructive pulmonary disorders. However, the mechanisms of antenatal maternal hypoxia-related PPHN are unresolved. Because both LTH and 5-HT are associated with PPHN, we tested the hypothesis that antenatal maternal LTH can increase 5-HT-mediated PA contraction and associated extracellular Ca 2þ influx through L-type Ca 2þ channels (Ca L ), nonselective cation channels (NSCCs), and reverse-mode sodium-calcium exchanger (NCX) in the near-term fetus. We performed wire myography and confocal-Ca 2þ imaging approaches on fetal lamb PA (*140 days of gestation) from normoxic ewes or those acclimatized to high-altitude LTH (3801 m) for *110 days. Long-term hypoxia reduced the potency but not the efficacy of 5-HT-induced PA contraction. Ketanserin (100 nmol/L), a 5-HT 2A antagonist, shifted 5-HT potency irrespective of LTH, while GR-55562 (1 mmol/L), a 5-HT 1B/D inhibitor, antagonized 5-HT-induced contraction in normoxic fetuses only. Various inhibitors for Ca L , NSCC, and reverse-mode NCX were used in contraction studies. Contraction was reliant on extracellular Ca 2þ regardless of maternal hypoxia, NSCC was more important to contraction than Ca L , and reverse-mode NCX had little or no role in contraction. Long-term hypoxia also attenuated the effects of 2-APB and flufenamic acid and reduced Ca 2þ responses observed by imaging studies. Overall, LTH reduced 5HT 1B/D function and increased NSCC-related Ca 2þ -dependent contraction in ovine fetuses, which may compromise pulmonary vascular function in the newborn.

show abstract

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: -Ht-induced Contraction In Fetal Pas and Its Role Is Presermentioning

confidence: 99%

See 1 more Smart Citation

Long-Term Maternal Hypoxia

et al. 2011

View full text Add to dashboard Cite

show abstract

“…However the pulmonary vasoconstriction elicited by serotonin reverses quite rapidly when the serotonin is withdrawn. 25,26 This indicates that another component apart from inhibition of I K is necessary for the vasoconstriction. This could be a constitutively active basal calcium entry 25 and/or serotonin-induced activation of Rho kinase.…”

mentioning

confidence: 99%

“…On the one hand, serotonin inhibits I K in PASMCs, 23 probably by a PKC-dependent pathway. 24 In addition, serotonin increases cytosolic calcium concentration through voltagegated calcium channels, 25 suggesting a role for membranepotential regulated calcium entry. On the other hand, in isolated perfused rat lungs, 26 prior treatment with the K v blocker, 4-aminopyridine, did not reduce serotonin-induced vasoconstriction.…”

mentioning

confidence: 99%

Serotonin-Induced Inhibition of K _V Current

Varghese

Hong

Weir³

2006

Circulation Research

View full text Add to dashboard Cite

P ulmonary vascular tone is largely determined by potassium and calcium currents in the smooth muscle cells (SMCs) of the small resistance arteries. Under normoxic circumstances an outward potassium current (I K ) passes through voltage-gated (K v ), calcium-activated (K Ca ), and background tandem-pore domain (K 2P ) potassium channels. The latter (coded by the KCNK family of genes) include the twik-related acid sensitive K ϩ channel TASK and TASKlike channels. This current keeps the resting membrane potential in the range of Ϫ50 to Ϫ60 mV and inhibits calcium entry through L-type calcium channels. 1 Vasodilator substances such as nitric oxide and prostacyclin, released from the endothelium, increase I K , one of several actions that lead to further vasodilatation. 2,3 Vasoconstrictor substances, such as endothelin, can inhibit I K 4 and/or release calcium from the sarcoplasmic reticulum. 5 In addition to vasoactive effects, an increase in cytosolic potassium inhibits smooth muscle cell apoptosis, 6 and an increase in cytosolic calcium promotes cellular proliferation. 7 Consequently, the inhibition of I K is important not only in causing membrane depolarization and calcium entry but also in stimulating vascular remodeling and in the development of chronic pulmonary hypertension. Agents that can cause pulmonary hypertension, such as the anorectic drugs and hypoxia, inhibit I K 8,9 and also enhance calcium release from the sarcoplasmic reticulum, leading to subsequent repletion of calcium through store-operated channels. 10,11,12 The smooth muscle cells in the resistance pulmonary arteries of patients with pulmonary arterial hypertension (PAH) exhibit both reduced I K and decreased expression of K v channels, 13 and also increased expression of the TRPC (transient receptor potential, canonical) genes that code for store-operated and receptor-operated calcium channels. 14 The decreased expression and function of the K v channels may relate to a mutation in the gene for the bone morphogenetic protein receptor 2 observed in some PAH patients, 15 as the normal function of the receptor increases K v channel activity. 16 Serotonin and its receptors have been implicated in the pathogenesis of idiopathic pulmonary arterial hypertension for several reasons. Plasma serotonin levels have been reported to be elevated in these patients and have remained high even after lung transplantation, indicating that the levels are not secondary to the pulmonary hypertension. 17 This observation implies that either serotonin plays an etiologic role or is linked to an etiologic agent. Plasma serotonin levels are elevated in rats treated with the anorectic agent, dexfenfluramine, 18 which has been implicated in the onset of some cases of PAH. 19 The metabolite nor-dexfenfluramine itself is an agonist of the serotonin 2B receptor (5HT 2B ) and to a lesser extent of the 5HT 2A and 5HT 2C receptors. 20 There is strong evidence of overexpression of the 5HT transporter in the pulmonary arteries of patients with pulmonary hypertension. 21 T...

show abstract