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

Morecroft, Ian; MacLean, Margaret R.

doi:10.1038/sj.bjp.0702055

Cited by 38 publications

(26 citation statements)

References 37 publications

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“…In contrast, inhibition of fetal 5-HT 1B receptors had no significant effect on fetal pulmonary blood flow, whereas 5-HT 2A receptor inhibition decreased PVR. Prior studies in isolated rabbit pulmonary arteries have shown that 5-HT-induced fetal pulmonary vasoconstriction is mediated through the 5-HT 2A receptor (40).…”

Section: Discussionmentioning

confidence: 99%

Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late-gestation ovine fetus

Delaney

Gien

Grover

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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Delaney C, Gien J, Grover TR, Roe G, Abman SH. Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late-gestation ovine fetus. Am J Physiol Lung Cell Mol Physiol 301: L937-L944, 2011. First published September 9, 2011 doi:10.1152/ajplung.00198.2011.-Maternal use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) is associated with an increased risk for persistent pulmonary hypertension of the newborn (PPHN), but little is known about 5-HT signaling in the developing lung. We hypothesize that 5-HT plays a key role in maintaining high pulmonary vascular resistance (PVR) in the fetus and that fetal exposure to SSRIs increases 5-HT activity and causes pulmonary hypertension. We studied the hemodynamic effects of 5-HT, 5-HT receptor antagonists, and SSRIs in chronically prepared fetal sheep. Brief infusions of 5-HT (3-20 g) increased PVR in a dose-related fashion. Ketanserin, a 5-HT 2A receptor antagonist, caused pulmonary vasodilation and inhibited 5-HT-induced pulmonary vasoconstriction. In contrast, intrapulmonary infusions of GR127945 and SB206553, 5-HT 1B and 5-HT 2B receptor antagonists, respectively, had no effect on basal PVR or 5-HT-induced vasoconstriction. Pretreatment with fasudil, a Rho kinase inhibitor, blunted the effects of 5-HT infusion. Brief infusions of the SSRIs, sertraline and fluoxetine, caused potent and sustained elevations of PVR, which was sustained for over 60 min after the infusion. SSRI-induced pulmonary vasoconstriction was reversed by infusion of ketanserin and did not affect the acute vasodilator effects of acetylcholine. We conclude that 5-HT causes pulmonary vasoconstriction, contributes to maintenance of high PVR in the normal fetus through stimulation of 5-HT 2A receptors and Rho kinase activation, and mediates the hypertensive effects of SSRIs. We speculate that prolonged exposure to SSRIs can induce PPHN through direct effects on the fetal pulmonary circulation. persistent pulmonary hypertension of the newborn; ketanserin; SB206553; GR127935 THE FETAL PULMONARY CIRCULATION is characterized by high pulmonary vascular resistance (PVR) and low pulmonary blood flow. Mechanisms that maintain high PVR are poorly understood but include a low pulmonary artery PO 2 and an imbalance between vasoconstrictors and vasodilators (1, 9). After birth PVR falls, allowing for an increase in pulmonary blood flow. A failure of this decrease in PVR results in the clinical syndrome known as persistent pulmonary hypertension of the newborn (PPHN). Factors that contribute to the pathogenesis of PPHN are multifactorial, including altered vascular reactivity, vascular remodeling, and abnormal growth (18). Understanding the basic mechanisms that regulate pulmonary vascular resistance is crucial to the development of novel therapies for severe PPHN.Although the role of serotonin (5-HT) in the pathogenesis of adult pulmonary hypertension (PH) has been extensively studied, little is known about the role of 5-HT in the normal perinatal pulmonary circulation or in ...

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Section: Discussionmentioning

confidence: 99%

Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late-gestation ovine fetus

Delaney

Gien

Grover

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…13,59,60 More precisely, related studies in rats report that hypoxia increased 5-HT 1B/D activity and promoted pharmacologic synergism with 5-HT 2A in PAs. 12,61 Related to this, the 5HT 1B/D receptor also is thought to be important to the development of pulmonary hypertension in rats and mice. 13,58 This leads to the possibility that the change in 5-HT potency and restriction of 5-HT 1B/Dmediated contraction observed in sheep may be beneficial adaptations to maternal LTH that restrain the development of pulmonary hypertension in the newborn.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 Direct evidence of 5-HT as a causative agent for PPHN comes from recent studies demonstrating an increased risk of PPHN in infants born to mothers treated with selective serotonin reuptake inhibitors (SSRIs) during pregnancy. 10 Long-term hypoxia also enhances 5-HT-induced PA contraction in rats and mice [11][12][13] ; however, the mechanistic base of these changes is unclear. Nevertheless, 5-HT signaling is important for PA contraction and enhanced reactivity to this inflammatory substance is a feature of pulmonary hypertension.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Maternal Hypoxia

et al. 2011

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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.

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“…23) Histamine is also reported to exert pulmonary vasodilator actions preferentially during vasoconstriction and in other conditions of high PAP in animals [18][19][20] including rats. 20,24) However, our study showed no changes in PVR in response to histamine, indicating that histamine did not cause pulmonary vasoconstriction or vasodilatation in in vivo rat lungs.…”

Section: Discussionmentioning

confidence: 99%

“…Histamine causes pulmonary vasoconstriction in animals such as rabbits, 17,18) dogs, 19) cats, 20) guinea pigs, 21) pigs, 22) and horses. 23) Histamine is also reported to exert pulmonary vasodilator actions preferentially during vasoconstriction and in other conditions of high PAP in animals [18][19][20] including rats.…”

Section: Discussionmentioning

confidence: 99%

The Responses of Pulmonary and Systemic Circulation and Airway to Allergic Mediators in Anesthetized Rats

Wang

Shibamoto

Kuda

et al. 2016

Biological & Pharmaceutical Bulletin

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Lung allergic diseases sometimes accompany pulmonary vaso-and broncho-constriction. Rats are currently used for the experimental study of lung allergies. However, their hemodynamic mechanisms are not fully understood. Therefore the effects of allergic mediators were determined systematically in vivo in rats in terms of pulmonary vascular resistance (PVR), airway pressure (AWP) and total peripheral resistance (TPR). We directly measured pulmonary arterial pressure, left atrial pressure, systemic arterial pressure, central venous pressure and aortic blood flow to determine PVR and TPR, as well as AWP, following injections of platelet-activating factor (PAF), histamine, serotonin, leukotriene (LT) C 4 , and prostaglandin (PG) D 2 in anesthetized open-chest artificially ventilated Sprague-Dawley (SD) rats. PVR was dose-dependently increased by consecutive administration of PAF, LTC 4 , and PGD 2 , with the maximal responsiveness being PAF>LTC 4 >PGD 2 . However, neither histamine nor serotonin changed PVR. TPR was decreased by all agents except LTC 4 which actually increased it. PAF and serotonin, but not the other agents, increased AWP. In conclusion, allergic mediators exert non-uniform actions on pulmonary and systemic circulation and airways in anesthetized SD rats: PAF, LTC 4 and PGD 2 , but not histamine or serotonin, caused substantial pulmonary vasoconstriction; LTC 4 yielded systemic vasoconstriction, while the others caused systemic vasodilatation; only two mediators, PAF and serotonin, induce airway constriction.Key words peripheral resistance; pulmonary arterial pressure; anaphylaxis; left atrial pressure; vasodilation; pulmonary vasoconstriction Rats are currently used for investigations on pulmonary allergic diseases.1-4) However, the studies on physiological characteristics of the rat pulmonary circulation were limited. The rat pulmonary vascular responses to various endogenous allergic mediators were previously examined in isolated perfused lungs [5][6][7] : platelet-activating factor (PAF) and leukotriene (LT) C 4 cause substantial vasoconstriction. In rat isolated pulmonary arteries, 8,9) serotonin showed strong constriction. However, there is no systematic study in which the effects of allergic mediators on the rat pulmonary vascular resistance (PVR) and total peripheral resistance (TPR) were determined by measuring cardiac output (CO) and the inflow and outflow pressures of the systemic and pulmonary circulations. Therefore, we measured directly and continuously CO, pulmonary arterial pressure (PAP) and left atrial pressure (LAP), along with systemic arterial pressure (SAP) and central venous pressure (CVP), in order to determine the responses of PVR and TPR to allergic mediators including PAF, histamine, serotonin, LTC 4 , and prostaglandin (PG) D 2 in anesthetized Sprague-Dawley (SD) rats. Airway pressure (AWP) was also measured to determine whether the allergic mediators cause bronchoconstriction. We hypothesized that these mediators do not exert the same directional actions on pulmonary and s...

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

Cited by 38 publications

References 37 publications

Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late-gestation ovine fetus

Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late-gestation ovine fetus

Long-Term Maternal Hypoxia

The Responses of Pulmonary and Systemic Circulation and Airway to Allergic Mediators in Anesthetized Rats

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