Chronic intrauterine pulmonary hypertension decreases calcium-sensitive potassium channel mRNA expression.

Calcium-sensitive potassium (K(Ca)) channels play a critical role in mediating perinatal pulmonary vasodilation. Because infants with persistent pulmonary hypertension of the newborn (PPHN) have blunted vasodilator responses to birth-related stimuli, we hypothesized that lung K(Ca) channel gene expression is decreased in PPHN. To test this hypothesis, we measured K(Ca) channel gene expression in distal lung homogenates from both fetal lambs with severe pulmonary hypertension caused by prolonged compression of the ductus arteriosus and age-matched, sham-operated animals (controls). After at least 9 days of compression of the ductus arteriosus, fetal lambs were killed. To determine lung K(Ca) channel mRNA levels, primers were designed against the known sequence of the K(Ca) channel and used in semiquantitative RT-PCR, with lung 18S rRNA content as an internal control. Compared to that in control lambs, lung K(Ca) channel mRNA content in the PPHN group was reduced by 26 +/- 6% (P < 0.02), whereas lung voltage-gated K(+) 2.1 mRNA content was unchanged. We conclude that lung K(Ca) channel mRNA expression is decreased in an ovine model of PPHN. Decreased K(Ca) channel gene expression may contribute to the abnormal pulmonary vascular reactivity associated with PPHN.

[1]  D. Cornfield,et al.  NO causes perinatal pulmonary vasodilation through K+-channel activation and intracellular Ca2+release. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[2]  D. Cornfield,et al.  K+-channel blockade inhibits shear stress-induced pulmonary vasodilation in the ovine fetus. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[3]  S. Archer,et al.  Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes. , 1998, The Journal of clinical investigation.

[4]  Y. Kuryshev,et al.  Cloning and Expression of a Novel K+ Channel Regulatory Protein, KChAP* , 1998, The Journal of Biological Chemistry.

[5]  A. Hudetz,et al.  Increased expression of Ca2+-sensitive K+ channels in the cerebral microcirculation of genetically hypertensive rats: evidence for their protection against cerebral vasospasm. , 1998, Circulation research.

[6]  N. Rusch,et al.  Increased expression of Ca2+-sensitive K+ channels in aorta of hypertensive rats. , 1997, Hypertension.

[7]  M. Lazdunski,et al.  Kv2.1/Kv9.3, a novel ATP‐dependent delayed‐rectifier K+ channel in oxygen‐sensitive pulmonary artery myocytes , 1997, The EMBO journal.

[8]  L. Conforti,et al.  Selective inhibition of a slow‐inactivating voltage‐dependent K+ channel in rat PC 12 cells by hypoxia , 1997, The Journal of physiology.

[9]  A. Halbower,et al.  Chronic intrauterine pulmonary hypertension impairs endothelial nitric oxide synthase in the ovine fetus. , 1997, The American journal of physiology.

[10]  I. Yuhanna,et al.  Pulmonary endothelial NO synthase gene expression is decreased in fetal lambs with pulmonary hypertension. , 1997, The American journal of physiology.

[11]  D. Cornfield,et al.  Ventilation-induced pulmonary vasodilation at birth is modulated by potassium channel activity. , 1996, The American journal of physiology.

[12]  D. Cornfield,et al.  Oxygen causes fetal pulmonary vasodilation through activation of a calcium-dependent potassium channel. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[13]  S. Archer,et al.  Differential distribution of electrophysiologically distinct myocytes in conduit and resistance arteries determines their response to nitric oxide and hypoxia. , 1996, Circulation research.

[14]  S. Abman,et al.  Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn. , 1995, The Journal of pediatrics.

[15]  J. Tseng-Crank,et al.  Cloning, expression, and distribution of functionally distinct Ca2+-activated K+ channel isoforms from human brain , 1994, Neuron.

[16]  A. Halayko,et al.  Fetal ductus arteriosus ligation. Pulmonary vascular smooth muscle biochemical and mechanical changes. , 1993, Circulation research.

[17]  M. Blaustein,et al.  Hypoxia reduces potassium currents in cultured rat pulmonary but not mesenteric arterial myocytes. , 1993, The American journal of physiology.

[18]  D. Cornfield,et al.  Effects of birth-related stimuli on L-arginine-dependent pulmonary vasodilation in ovine fetus. , 1992, The American journal of physiology.

[19]  S. Abman,et al.  Role of endothelium-derived relaxing factor during transition of pulmonary circulation at birth. , 1990, The American journal of physiology.

[20]  F. Accurso,et al.  Failure of postnatal adaptation of the pulmonary circulation after chronic intrauterine pulmonary hypertension in fetal lambs. , 1989, The Journal of clinical investigation.

[21]  F. C. Morin.  Ligating the Ductus Arteriosus before Birth Causes Persistent Pulmonary Hypertension in the Newborn Lamb , 1989, Pediatric Research.

[22]  L. Wild,et al.  Ligating the Ductus Arteriosus before birth Remodels the Pulmonary Vasculature of the Lamb , 1989, Pediatric Research.

[23]  B. Rudy,et al.  Diversity and ubiquity of K channels , 1988, Neuroscience.

[24]  A. Rudolph.  Distribution and regulation of blood flow in the fetal and neonatal lamb. , 1985, Circulation research.

[25]  A. Hyman,et al.  Fetal hypertension and the development of increased pulmonary vascular smooth muscle: a possible mechanism for persistent pulmonary hypertension of the newborn infant. , 1978, The Journal of pediatrics.

[26]  D. Ivy,et al.  Chronic pulmonary hypertension in utero impairs endothelium-dependent vasodilation. , 1995, The American journal of physiology.

[27]  O. Pongs,et al.  Cloning and characterization of a human delayed rectifier potassium channel gene. , 1993, Receptors & channels.