Interaction of KATP Channels and Endothelin-1 in Lambs With Persistent Pulmonary Hypertension of the Newborn

Abstract

Persistent pulmonary hypertension of the newborn is a life-threatening condition in which half of infants fail to respond to inhaled nitric oxide. Development of new therapeutic pathways is crucial. The adenosine triphosphate (ATP)-sensitive potassium channels (K ATP ) may be important in this condition. Concentrationresponse curves to the K ATP channel opener (SR47063) were performed in isolated pulmonary arterial rings from normal newborn lambs (n ϭ 8) and pulmonary hypertensive lambs (n ϭ 7) induced by intrauterine ductus arteriosus ligation. The effect of endothelin (ET) receptor antagonists was analyzed. Expression in the lung of the subunit Kir 6.1 of the K ATP channel and of ET were analyzed using Western blot and immunohistochemistry. Relaxation to SR47063 was increased in ligated animals compared with the control group. Endothelium removal enhanced this response in ligated animals (p Ͻ 0.01). The inhibitory effect of the endothelium was reversed by the Endothelin-A receptor (ET-A) antagonist BQ 123 (p Ͻ 0.01). Kir 6.1 expression was not different between groups and that of endothelin-1 (ET-1) was increased threefold in ligated animals (p ϭ 0.007). In pulmonary hypertensive lambs, vasodilation to K ATP channel openers was enhanced compared with controls and further potentiated by ET-A blockade. These data might lead to new therapeutic strategies in infants with pulmonary hypertension. (Pediatr Res 60: 252-257, 2006) P ersistent pulmonary hypertension of the newborn (PPHN) is a severe disease characterized by sustained elevation of pulmonary vascular resistance after birth, resulting in significant morbidity and mortality in term and near-term infants (1,2). The pathophysiology of PPHN remains poorly understood. Endothelial dysfunction has been suggested to be partly responsible for this syndrome through an imbalance between the release of vasorelaxant substances and vasoconstrictive ones with an excess of ET-1 production (3-5).ET-1 is a potent vasoactive agent that is produced by a number of cell types including pulmonary vascular endothelial cells. It produces its vasoactive effects through its interactions with at least two receptor subtypes, ET-A and ET-B, located on the vascular smooth muscle and endothelium. ET receptors are also present in other structures within the lung, such as fibroblasts, bronchial smooth muscle, and epithelial cells, but their respective distribution remains unknown (6). The pulmonary vasoconstrictor effect of ET-1 results mainly from activation of the ET-A receptor, whereas activation of the endothelial ET-B receptor has been shown to induce relaxation (5,7). Plasma levels and expression of ET-1 are increased in models of pulmonary hypertension as well as in children with PPHN (8 -10).The nitric oxide (NO) pathway, involved in endotheliumdependent pulmonary vasodilation has been shown to be deficient in PPHN (4,11-13). Although inhaled NO (iNO) has modified the poor prognosis of PPHN, half of the affected children are either refractory to iNO or remain dependent on...

The role of interleukin‐6, endothelins, and apoptotic genes in small bowel transplantation, in a swine model of ischemia and reperfusion injury

“…These findings suggest that any intervention aiming at reducing IRI that involves IL‐6 or ET‐1 must take place during organ retrieval or even earlier. Further studies designed to more precisely delineate the role of these cytokines in IRI could include already‐available antagonists (26–29). Longer CI times, such as those reported in clinical practice, may increase the benefit of early intervention and interruption of the inflammatory cascade, but this hypothesis needs to be tested in further studies.…”

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

“…ET B vasodilatory effects were maintained during the first few days after the onset of PH, but these eventually became suppressed. Around the same time period, ET A ‐mediated vasoconstriction became more pronounced, and this was concomitant with an increase in pulmonary resistance 80 . In PAs of newborn sheep that were born and maintained at high altitude, chronic hypoxia increased the sensitivity of contraction to ET‐1 7 .…”

“…Around the same time period, ET A -mediated vasoconstriction became more pronounced, and this was concomitant with an increase in pulmonary resistance. 80 In PAs of newborn sheep that were born and maintained at high altitude, chronic hypoxia increased the sensitivity of contraction to ET-1. 7 Yet such programming may occur after birth because ET-1 constriction was maintained in PAs from fetal sheep exposed to maternal chronic hypoxia.…”

Association of E23K polymorphism of Kir6.2 gene with coronary artery disease

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