Use of Prostacyclin in Persistent Fetal Circulation

Cassin, S.; Tod, M.; Frisinger, J. E.; Jordan, Jill; Philips, Joseph B.

doi:10.1016/s0140-6736(79)91698-2

Cited by 15 publications

(12 citation statements)

References 4 publications

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“…The failure of indomethacin to substantially reduce bradykinin-dependent relaxation in newborns was interesting and compares with previous studies. In studies performed in newborn sheep as well as goats, direct stimulation with prostacyclin agonists and precursors elicits pulmonary vascular vasorelaxation (15,28). One explanation is that bradykinin does not fully activate resident prostacyclin synthesis pathways.…”

Section: Discussionmentioning

confidence: 99%

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Blum-Johnston

Thorpe

Wee

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of largeconductance Ca 2ϩ -activated K ϩ (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca 2ϩ . Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCa channels during bradykinin-induced vasorelaxation by examining endothelial Ca 2ϩ signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (ϳ140 days gestation) and newborn, 10-to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for Ͼ100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca 2ϩ responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 M nitro-L-arginine methyl ester or 10 M 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2 pathways. BKCa channel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCa channel ␣1-subunit expression but increased ␤1-subunit expression. These results suggest that CH amplifies the contribution of BKCa channels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes. potassium channels; sheep; pulmonary artery; contractility; maturation; hypoxia REGULATION OF SMOOTH MUSCLE tone in pulmonary arteries during development is a delicate balance of vasoconstrictive and vasorelaxant pathways. Endothelial cells play a crucial role in determining the overall level of vasorelaxation (39, 67), and endothelium-dependent relaxation is partially mediated through bradykinin stimulation (31). Bradykinin is a potent vasodilator that is important in the fetal pulmonary circulation, as well as during inflammation, and its relationship to pulmonary hypertension has been explored (5, 31, 83).Endothelial bradykinin receptor activation induces vasorelaxation through modulation of several different intracellular signaling pathways that are largely dependent on a rise of endothelial intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (67). The most widely studied pathway is bradykinin-induced activation of endothelial nitric oxide (NO) synthase (eNOS), an enzyme that generates NO (64). NO acts on nearby smooth muscle cells to cause downstream stimulation of soluble guanylate cyclase (sGC) pathways that leads to vasorelaxation (3,45). Previous studies have shown that regulatio...

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Section: Discussionmentioning

confidence: 99%

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Blum-Johnston

Thorpe

Wee

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Prostacyclin is a potent vasodilator in the fetal lung (5,10,14). Elevated intrapulmonary synthesis may result in high tissue levels of this prostanoid which could contribute to the pulmonary vasodilation at the onset of ventilation and, thus, perinatal circulatory transition.…”

Section: Discussionmentioning

confidence: 99%

“…This evidence, gathered using anesthetized preparations and mechanical ventilation, includes 1) removal of a dilator influence from the neonatal pulmonary circulation by prostaglandin cyclooxygenase inhibition (28), 2) abolition of the slow decline phase of pulmonary vasodilation by indomethacin pretreatment of fetal goats (1 3). 3) net production of prostacyclin-like material following ventilation of fetal lungs perfused with blood ( 1 5), 4) stimulation of prostacyclin synthesis by mechanical ventilation of fetal lungs perfused with Krebs solution (1 7), and 5) pulmonary vasodilation of fetal lamb lungs by infusion of authentic prostacyclin (5,10,14).…”

Section: Pc Prostaglandinmentioning

confidence: 99%

The Onset of Breathing at Birth Stimulates Pulmonary Vascular Prostacyclin Synthesis

1984

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“…128,129 These endothelial-derived substances dilate vessels and attenuate PASMC proliferation. Prostacyclins are released from the vascular endothelium and activate G s -coupled GPCRs on smooth muscle cells.…”

Section: Prostacyclinmentioning

confidence: 99%

Prenatal Programming of Pulmonary Hypertension Induced by Chronic Hypoxia or Ductal Ligation in Sheep

et al. 2013

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Pulmonary hypertension of the newborn is caused by a spectrum of functional and structural abnormalities of the cardiopulmonary circuit. The existence of multiple etiologies and an incomplete understanding of the mechanisms of disease progression have hindered the development of effective therapies. Animal models offer a means of gaining a better understanding of the fundamental basis of the disease. To that effect, a number of experimental animal models are being used to generate pulmonary hypertension in the fetus and newborn. In this review, we compare the mechanisms associated with pulmonary hypertension caused by two such models: in utero ligation of the ductus arteriosus and chronic perinatal hypoxia in sheep fetuses and newborns. In this manner, we make direct comparisons between ductal ligation and chronic hypoxia with respect to the associated mechanisms of disease, since multiple studies have been performed with both models in a single species. We present evidence that the mechanisms associated with pulmonary hypertension are dependent on the type of stress to which the fetus is subjected. Such an analysis allows for a more thorough evaluation of the disease etiology, which can help focus clinical treatments. The final part of the review provides a clinical appraisal of current treatment strategies and lays the foundation for developing individualized therapies that depend on the causative factors.

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Use of Prostacyclin in Persistent Fetal Circulation

Cited by 15 publications

References 4 publications

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

The Onset of Breathing at Birth Stimulates Pulmonary Vascular Prostacyclin Synthesis

Prenatal Programming of Pulmonary Hypertension Induced by Chronic Hypoxia or Ductal Ligation in Sheep

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