Altered endothelium-dependent relaxations in lambs with high pulmonary blood flow and pulmonary hypertension

2001 ◽  
Vol 280 (1) ◽  
pp. H311-H317 ◽  
Author(s):  
Robin H. Steinhorn ◽  
James A. Russell ◽  
Satyan Lakshminrusimha ◽  
Sylvia F. Gugino ◽  
Stephen M. Black ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Vascular Graft ◽  
Pulmonary Blood Flow ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
No Synthase ◽  
A 23187 ◽  
Endothelium Dependent Relaxation

Congenital heart disease associated with increased pulmonary blood flow produces pulmonary hypertension. To characterize vascular alterations in the nitric oxide (NO)-cGMP cascade induced by increased pulmonary blood flow and pulmonary hypertension, 10 fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). When the lambs were 4–6 wk of age, we assessed responses of pulmonary arteries (PAs) and pulmonary veins (PVs) isolated from lungs of control and shunted lambs. PVs from control and shunted lambs relaxed similarly to exogenous NO ( S-nitrosyl-acetyl-penicillamine), to NO produced endogenously (zaprinast and A-23187), and to cGMP (atrial natriuretic peptide). In contrast, relaxations to A-23187 and zaprinast were blunted in PAs isolated from shunted lambs relative to controls. Inhibitors of NO synthase (NOS) and soluble guanylate cyclase constricted control but not shunt PAs, indicating reduced basal NOS activity in shunt PAs. Pretreatment of shunt PAs with the substratesl-arginine and sepiapterin, a precursor for tetrahydrobiopterin synthesis, did not augment A-23187 relaxations. However, pretreatment with superoxide dismutase and catalase significantly enhanced A-23187 relaxations in shunt PAs. We conclude that increased pulmonary blood flow induces an impairment of endothelium-dependent relaxation that is selective to PAs. The impaired relaxation may be mediated in part by excess superoxide production.

Disruption of cGMP production in pulmonary arteries isolated from fetal lambs with pulmonary hypertension

1995 ◽  
Vol 268 (4) ◽  
pp. H1483-H1489 ◽  
Author(s):  
R. H. Steinhorn ◽  
J. A. Russell ◽  
F. C. Morin
Keyword(s):  
Pulmonary Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Ductus Arteriosus ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Fourth Generation ◽  
Response Curves ◽  
Fetal Sheep ◽  
A 23187 ◽  
Arteries And Veins

Ligation of the ductus arteriosus of the fetal sheep produces severe pulmonary hypertension at birth. Standard tissue bath techniques were used to study third- and fourth-generation pulmonary arteries and veins isolated from fetal sheep with pulmonary hypertension created by ligation of the ductus arteriosus 11–12 days before birth as well as from age-matched control sheep. Vessels pretreated with indomethacin and propranolol were submaximally preconstricted with norepinephrine before exposure to A-23187 (10(-8) to 3 x 10(-7) M), sodium nitroprusside (SNP; 10(-9) to 10(-5) M), and nitric oxide (NO) gas (1-973 ppm). Pulmonary veins in both control and ligated animals relaxed similarly and completely to A-23187, SNP, and NO. Control pulmonary arteries relaxed by 16 +/- 2% to A-23187 and relaxed completely to SNP and NO, with concentration-response curves shifted rightward of those observed in pulmonary veins. Pulmonary arteries from ligated animals did not relax at all to A-23187. SNP relaxations in ligated arteries were shifted rightward of control. Ligated arteries relaxed by only 11 +/- 5% to the highest dose of NO. However, control and ligated pulmonary arteries relaxed similarly to 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP; 10(-5) to 10(-3) M) and atrial natriuretic peptide (10(-9) to 10(-7) M). These data are most simply explained by decreased arterial vascular smooth muscle sensitivity to NO at the level of soluble guanylate cyclase.

sGC and PDE5 are elevated in lambs with increased pulmonary blood flow and pulmonary hypertension

2001 ◽  
Vol 281 (5) ◽  
pp. L1051-L1057 ◽  
Author(s):  
Stephen M. Black ◽  
Lucienne S. Sanchez ◽  
Eugenia Mata-Greenwood ◽  
Janine M. Bekker ◽  
Robin H. Steinhorn ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Vascular Graft ◽  
Pulmonary Blood Flow ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Vasodilation ◽  
Phosphodiesterase Type ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Expression And Activity

Utilizing aortopulmonary vascular graft placement, we established a lamb model of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow. We previously demonstrated that endothelial nitric oxide synthase (eNOS) is increased in lambs at age 4 wk. However, these lambs display a selective impairment of endothelium-dependent pulmonary vasodilation that is suggestive of a derangement downstream of NO release. Thus our objective was to characterize potential alterations in the expression and activity of soluble guanylate cyclase (sGC) and phosphodiesterase type 5 (PDE5) induced by increased pulmonary blood flow and pulmonary hypertension. Late-gestational fetal lambs ( n = 10) underwent in utero placement of an aortopulmonary vascular graft (shunt). Western blotting analysis on lung tissue from 4-wk-old shunted lambs and age-matched controls showed that protein for both subunits of sGC was increased in shunted lamb lungs compared with age-matched controls. Similarly, cGMP levels were increased in shunted lamb lungs compared with age-matched controls. However, PDE5 expression and activity were also increased in shunted lambs. Thus although cGMP generation was increased, concomitant upregulation of PDE5 expression and activity may have (at least partially) limited and accounted for the impairment of endothelium-dependent pulmonary vasodilation in shunted lambs.

Increased endothelial NOS in lambs with increased pulmonary blood flow and pulmonary hypertension

1998 ◽  
Vol 275 (5) ◽  
pp. H1643-H1651 ◽  
Author(s):  
Stephen M. Black ◽  
Jeffrey R. Fineman ◽  
Robin H. Steinhorn ◽  
James Bristow ◽  
Scott J. Soifer
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Vascular Graft ◽  
Pulmonary Blood Flow ◽  
Congenital Heart ◽  
Vascular Reactivity ◽  
Heart Defects ◽  
Pulmonary Arteries ◽  
Enos Gene ◽  
Rnase Protection

Altered pulmonary vascular reactivity is a source of morbidity and mortality for children with congenital heart defects and increased pulmonary blood flow. Nitric oxide (NO) is an important mediator of pulmonary vascular reactivity. The objective of this study was to characterize potential early alterations in expression, localization, and activity of endothelial NO synthase (eNOS) induced by increased pulmonary blood flow and pulmonary hypertension. Utilizing aortopulmonary vascular graft placement in the fetal lamb, we have established a unique animal model of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow. Ten fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). RNase protection assays and Western blotting were performed on lung tissue prepared from 4-wk-old shunt lambs and age-matched controls. eNOS mRNA (2.4:1, P < 0.05) and protein (2.08:1, P < 0.05) were increased in lungs of shunt lambs. In situ hybridization and immunohistochemistry revealed that the increase was confined to the endothelium of pulmonary arteries. eNOS protein (1.55:1, P < 0.05) and tissue cGMP concentrations (2.1:1, P < 0.05) were also increased in isolated fifth-generation pulmonary arteries of shunt lambs. In addition, total lung eNOS activity was increased (2.9:1, P < 0.05). Thus we report a previously undescribed, early upregulation of eNOS gene expression and activity in lambs with increased pulmonary blood flow and pulmonary hypertension.

scholarly journals The role of nitric oxide synthase-derived reactive oxygen species in the altered relaxation of pulmonary arteries from lambs with increased pulmonary blood flow

2007 ◽  
Vol 293 (3) ◽  
pp. H1491-H1497 ◽  
Author(s):  
Satyan Lakshminrusimha ◽  
Dean Wiseman ◽  
Stephen M. Black ◽  
James A. Russell ◽  
Sylvia F. Gugino ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Nitric Oxide Synthase ◽  
Pulmonary Blood Flow ◽  
Pulmonary Arteries ◽  
Nitric Oxide Donor ◽  
Superoxide Anions ◽  
A 23187 ◽  
Oxide Synthase

Congenital cardiac defects associated with increased pulmonary blood flow (Qp) produce pulmonary hypertension. We have previously reported attenuated endothelium-dependent relaxations in pulmonary arteries (PA) isolated from lambs with increased Qp and pulmonary hypertension. To better characterize the vascular alterations in the nitric oxide-superoxide system, 12 fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). Twin lambs served as controls. PA were isolated from these lambs at 4–6 wk of age. Electron paramagnetic resonance spectroscopy on fourth-generation PA showed significantly increased superoxide anion generation in shunt PA that were decreased to control levels following inhibition of nitric oxide synthase (NOS) with 2-ethyl-2-thiopseudourea. Preconstricted fifth-generation PA rings were relaxed with a NOS agonist (A-23187), a nitric oxide donor [ S-nitrosyl amino penicillamine (SNAP)], polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), or H2O2. A-23187-, PEG-SOD-, and H2O2-mediated relaxations were impaired in shunt PA compared with controls. Pretreatment with PEG-SOD significantly enhanced the relaxation response to A-23187 and SNAP in shunt but not control PA. Inhibition of NOS with nitro-l-arginine or scavenging superoxide anions with tiron enhanced relaxation to SNAP and inhibited relaxation to PEG-SOD in shunt PA. Pretreatment with catalase inhibited relaxation of shunt PA to A-23187, SOD, and H2O2. We conclude that NOS catalyzes the production of superoxide anions in shunt PA. PEG-SOD relaxes shunt PA by converting these anions to H2O2, a pulmonary vasodilator. The redox environment, influenced by the balance between production and scavenging of ROS, may have important consequences on pulmonary vascular reactivity in the setting of increased Qp.

Altered endothelium-dependent responses in lambs with pulmonary hypertension and increased pulmonary blood flow

1996 ◽  
Vol 271 (2) ◽  
pp. H562-H570 ◽  
Author(s):  
V. M. Reddy ◽  
J. Wong ◽  
J. R. Liddicoat ◽  
M. Johengen ◽  
R. Chang ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Endothelial Function ◽  
Pulmonary Blood Flow ◽  
Main Pulmonary Artery ◽  
Plasma Concentrations ◽  
Phosphodiesterase Inhibitor ◽  
No Synthase ◽  
Late Gestation ◽  
Fetal Sheep

To investigate early endothelial function associated with increased pulmonary blood flow, vascular shunts were placed between the ascending aorta and main pulmonary artery in 18 late-gestation fetal sheep. Four weeks after delivery, the lambs were instrumented to measure vascular pressures and blood flows, and blood was collected to measure plasma concentrations of guanosine 3',5'-cyclic monophosphate [cGMP, the second messenger to nitric oxide (NO)-mediated vasodilation] and L-arginine (the precursor for NO synthesis). The responses to the endothelium-dependent vasodilators acetylcholine (ACh, 1.0 microgram/kg) and ATP (0.1 mg.kg-1.min-1), the endothelium-independent vasodilators M & B-22948 (a cGMP-specific phosphodiesterase inhibitor, 2.5 mg/kg) and inhaled NO (40 ppm), and N omega-nitro-L-arginine (an inhibitor of NO synthase, 5 mg/kg) were then compared with responses in 12 age-matched controls. Vasodilator responses in control lambs were determined during pulmonary hypertension induced by U-46619 (a thromboxane A2 mimic). Shunted lambs displayed a selective impairment of endothelium-dependent pulmonary vasodilation, an augmented pulmonary vasoconstricting response to NO synthase inhibition, increased plasma cGMP concentrations, and decreased L-arginine concentrations. Taken together, these data suggest that lambs with pulmonary hypertension and increased pulmonary blood flow have early aberrations in endothelial function, as manifested by increased basal NO activity, that cannot be further increased by agonist-induced endothelium-dependent vasodilators.

Nitric oxide-endothelin-1 interactions after surgically induced acute increases in pulmonary blood flow in intact lambs

2006 ◽  
Vol 290 (5) ◽  
pp. H1922-H1932 ◽  
Author(s):  
Peter Oishi ◽  
Anthony Azakie ◽  
Cynthia Harmon ◽  
Robert K. Fitzgerald ◽  
Albert Grobe ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Vascular Graft ◽  
Pulmonary Blood Flow ◽  
Heart Defects ◽  
No Synthase ◽  
Before And After ◽  
Nos Inhibitor ◽  
Surgically Induced

Several congenital heart defects require surgery that acutely increases pulmonary blood flow (PBF). This can lead to dynamic alterations in postoperative pulmonary vascular resistance (PVR) and can contribute to morbidity and mortality. Thus the objective of this study was to determine the role of nitric oxide (NO), endothelin (ET)-1, and their interactions in the alterations of PVR after surgically induced increases in PBF. Twenty lambs underwent placement of an aortopulmonary vascular graft. Lambs were instrumented to measure vascular pressures and PBF and studied for 4 h. Before and after shunt opening, lambs received an infusion of saline ( n = 9), tezosentan, an ETA- and ETB-receptor antagonist ( n = 6), or Nω-nitro-l-arginine (l-NNA), a NO synthase (NOS) inhibitor ( n = 5). In control lambs, shunt opening increased PBF by 117.8% and decreased PVR by 40.7% ( P < 0.05) by 15 min, without further changes thereafter. Plasma ET-1 levels increased 17.6% ( P < 0.05), and total NOS activity decreased 61.1% ( P < 0.05) at 4 h. ET-receptor blockade (tezosentan) prevented the plateau of PBF and PVR, such that PBF was increased and PVR was decreased compared with controls at 3 and 4 h ( P < 0.05). These changes were associated with an increase in total NOS activity (+61.4%; P < 0.05) at 4 h. NOS inhibition (l-NNA) after shunt placement prevented the sustained decrease in PVR seen in control lambs. In these lambs, PVR decreased by 15 min ( P < 0.05) but returned to baseline by 2 h. Together, these data suggest that surgically induced increases in PBF are limited by vasoconstriction, at least in part by an ET-receptor-mediated decrease in lung NOS activity. Thus NO appears to be important in maintaining a reduction in PVR after acutely increased PBF.

Noninvasive Investigation of Pulmonary Blood Flow in Children with Pulmonary Hypertension Using the TRV/RVOT VTI Ratio

2017 ◽  
Vol 65 (S 02) ◽  
pp. S111-S142
Author(s):  
M. Koestenberger ◽  
D. Baumgartner ◽  
G. Hansmann ◽  
S. Schweintzger ◽  
G. Grangl ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Pulmonary Blood Flow

Newborn rat response to single vs. combined cGMP-dependent pulmonary vasodilators

2014 ◽  
Vol 306 (2) ◽  
pp. L207-L215 ◽  
Author(s):  
Masahiro Enomoto ◽  
Amish Jain ◽  
Jingyi Pan ◽  
Yulia Shifrin ◽  
Todd Van Vliet ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Synergistic Effect ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Small Heat Shock Protein ◽  
No Donor ◽  
Clinical Exposure ◽  
Pulmonary Vasodilators ◽  
Pulmonary Vasodilator

Inhaled nitric oxide (NO) and other cGMP- or cAMP-dependent pulmonary vasodilators are often used in combination for the treatment of the persistent pulmonary hypertension of the newborn syndrome. There is in vitro evidence to indicate that NO downregulate the pulmonary vascular response to cGMP-dependent agonists raising concern as to whether a synergistic effect is observed when employing a combined strategy in newborns. Hypothesizing that a synergistic effect is absent, we evaluated newborn and juvenile rat pulmonary arteries to determine the individual and combined vasodilatory effect of cGMP- and cAMP-dependent agonists. In precontracted near-resistance pulmonary arteries, the addition of sildenafil reduced vasorelaxation response to NO donor S-nitroso- N-acetyl penicillamine (SNAP). A similar decrease in SNAP-induced vasodilation was observed in arteries pretreated with BAY 41–2272 (10−9 M), a soluble guanylate cyclase stimulator cGMP, and its downstream protein kinase activator. cGMP also reduced the vasorelaxant response to the cAMP-dependent forskolin. Inhibition of endogenous vascular NO generation enhanced SNAP-induced relaxation. The present data suggest that the mechanism involved in the cGMP desensitization to other relaxant agonists involves downregulation of the small heat shock protein HSP20 and is evident in rat pulmonary and systemic vascular smooth muscle cells. In newborn rats with chronic hypoxia-induced pulmonary hypertension, the combination of sildenafil and inhaled NO resulted in a lesser reduction in pulmonary vascular resistance compared with their individual effect. These data suggest that clinical exposure to one cGMP-dependent pulmonary vasodilator may affect the response to other cGMP- or cAMP-mediated agonists.

Importance of adhesion molecules for children with congenital heart disease

2012 ◽  
Vol 23 (1) ◽  
pp. 35-40
Author(s):  
Ayşe Yıldırım ◽  
Aysu T. Karaağaç ◽  
Fusun Güzelmeriç ◽  
Nihat Çine ◽  
Naci C. Öner
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Adhesion Molecules ◽  
Adhesion Molecule ◽  
Pulmonary Blood Flow ◽  
Congenital Heart ◽  
Heart Diseases ◽  
Cellular Adhesion ◽  
Mean Values ◽  
Cellular Adhesion Molecule

AbstractBackgroundThe aim of our study was to compare the blood levels of adhesion molecules in children with different heart diseases and pulmonary flow rates.MethodsIn this study, we evaluated the levels of soluble intercellular adhesion molecule-1 and soluble vascular cellular adhesion molecule-1 in blood samples of 65 children with different congenital heart diseases. The patients were divided into four groups according to their pulmonary blood flow. The first group had increased pulmonary blood flow with pulmonary hypertension and left-to-right shunt. The second group had increased pulmonary blood flow without pulmonary hypertension and left-to-right shunt. The third group had decreased pulmonary blood flow with cyanotic congenital heart disease and the fourth group had normal pulmonary blood flow with left ventricle outflow tract obstruction and aortic stenosis.ResultThe highest soluble intercellular and vascular cellular adhesion molecule-1 levels with the mean values of 420.2 nanograms per millilitre and 1382.1 nanograms per millilitre, respectively, were measured in the first group and the lowest levels with the mean values of 104.4 and 358.6 nanograms per millilitre, respectively, were measured in the fourth group. The highest pulmonary blood pressure levels were found in the first group.ConclusionEndothelial activity is influenced not only by left-to-right shunt with pulmonary hypertension, but also by decreased pulmonary blood flow in cyanotic heart diseases. Adhesion molecules are valuable markers of endothelial activity in congenital heart diseases, and they are influenced by pulmonary blood flow rate.

scholarly journals Mechanisms of calcitonin gene-related peptide-induced increases of pulmonary blood flow in fetal sheep

2000 ◽  
Vol 279 (4) ◽  
pp. H1654-H1660 ◽  
Author(s):  
Yasushi Takahashi ◽  
Maartje De Vroomen ◽  
Christine Roman ◽  
Michael A. Heymann
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Pulmonary Blood Flow ◽  
Pulmonary Arteries ◽  
Calcitonin Gene Related Peptide ◽  
Fetal Sheep ◽  
Nitric Oxide Synthase Inhibitor ◽  
Flow Transducer ◽  
Related Peptide ◽  
Calcitonin Gene

Fetal pulmonary blood flow is regulated by various vasoactive substances. One, calcitonin gene-related peptide (CGRP), increases pulmonary blood flow. We examined four key physiological mechanisms underlying this response using the blocker drugs CGRP receptor blocker (CGRP8–37), nitric oxide synthase inhibitor [ N ω-nitro-l-arginine (l-NNA)], adenosine triphosphate-dependent potassium (KATP) channel blocker (glibenclamide), and cyclooxygenase inhibitor (indomethacin) in 17 near-term fetal sheep. Catheters were placed in the left (LPA) and main pulmonary arteries, and an ultrasonic flow transducer was placed around the LPA to measure flow continuously. CGRP was injected directly into the LPA (mean 1.02 μg/kg) before and after blockade, and responses to CGRP were statistically compared. Before blockade, CGRP increased LPA blood flow from 23 ± 25 to 145 ± 77 ml/min (means ± SD), and these increases were significantly attenuated by CGRP8–37( n = 6; 91% inhibition), l-NNA ( n = 6; 86% inhibition), and glibenclamide ( n = 6; 69% inhibition). No significant changes were found with indomethacin ( n = 6; 4% inhibition). Thus, in the fetal pulmonary circulation, CGRP increases pulmonary blood flow not only through its specific receptor but also, in part, through nitric oxide release and KATP channel activation.

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