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.

Endothelin-1 vasoactive responses in lambs with pulmonary hypertension and increased pulmonary blood flow

1995 ◽  
Vol 269 (6) ◽  
pp. H1965-H1972 ◽  
Author(s):  
J. Wong ◽  
V. M. Reddy ◽  
K. Hendricks-Munoz ◽  
J. R. Liddicoat ◽  
R. Gerrets ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Blood Flow ◽  
Heart Diseases ◽  
Main Pulmonary Artery ◽  
Similar Degree ◽  
Fetal Sheep ◽  
Endothelin 1

Increased concentrations of endothelin-1 (ET-1) are found in children with congenital heart diseases that produce increased pulmonary blood flow and pulmonary hypertension, but the role of ET-1 in the pathophysiology of pulmonary hypertension is unclear. Therefore, we investigated ET-1-induced vasoactive responses and ET-1 concentrations in an animal model of pulmonary hypertension and increased pulmonary blood flow. Vascular shunts were placed between the ascending aorta and main pulmonary artery in seven late-gestation fetal sheep. Four weeks after spontaneous delivery, ET-1 increased pulmonary vascular resistance by 29.7 +/- 34.4% (P < 0.05), the ETb-receptor agonist [Ala1,3,11,15]ET-1 (4AlaET-1) had no effect, and the ETa-receptor antagonist cyclo(D-Asp-L-Pro-D-Val-L-Leu-D-Trp) (BQ-123) decreased pulmonary vascular resistance by -16.0 +/- 5.6% (P < 0.05). In contrast, in six control lambs with a similar degree of pulmonary hypertension induced by U-46619, ET-1 and 4AlaET-1 decreased pulmonary vascular resistance by 24.8 +/- 17.6, and 20.0 +/- 13.8%, respectively (P < 0.05). In addition, systemic arterial concentrations of immunoreactive ET-1 were elevated in lambs with pulmonary hypertension (29.2 +/- 9.6 vs. 15.2 +/- 10.7 pg/ml, P < 0.05). Pulmonary hypertension and increased pulmonary blood flow alters the response of ET-1 from pulmonary vasodilation to vasoconstriction. These altered responses suggest a role for ET-1 and its receptors in the pathogenesis of pulmonary hypertension secondary to increased pulmonary blood flow.

scholarly journals Chronic intrauterine pulmonary hypertension increases main pulmonary artery stiffness and adventitial remodeling in fetal sheep

2014 ◽  
Vol 307 (11) ◽  
pp. L822-L828 ◽  
Author(s):  
R. Blair Dodson ◽  
Matthew R. Morgan ◽  
Csaba Galambos ◽  
Kendall S. Hunter ◽  
Steven H. Abman
Keyword(s):  
Pulmonary Hypertension ◽  
Main Pulmonary Artery ◽  
Pulmonary Arteries ◽  
Clinical Syndrome ◽  
Late Gestation ◽  
Biaxial Testing ◽  
Mechanical Stiffness ◽  
Sheep Model ◽  
Fetal Sheep ◽  
Ecm Remodeling

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that is characterized by high pulmonary vascular resistance due to changes in lung vascular growth, structure, and tone. PPHN has been primarily considered as a disease of the small pulmonary arteries (PA), but proximal vascular stiffness has been shown to be an important predictor of morbidity and mortality in other diseases associated with pulmonary hypertension (PH). The objective of this study is to characterize main PA (MPA) stiffness in experimental PPHN and to determine the relationship of altered biomechanics of the MPA with changes in extracellular matrix (ECM) content and orientation of collagen and elastin fibers. MPAs were isolated from control and PPHN fetal sheep model and were tested by planar biaxial testing to measure stiffness in circumferential and axial vessel orientations. Test specimens were fixed for histological assessments of the vascular wall ECM constituents collagen and elastin. MPAs from PPHN sheep had increased mechanical stiffness ( P < 0.05) and altered ECM remodeling compared with control MPA. A constitutive mathematical model and histology demonstrated that PPHN vessels have a smaller contribution of elastin and a greater role for collagen fiber engagement compared with the control arteries. We conclude that exposure to chronic hemodynamic stress in late-gestation fetal sheep increases proximal PA stiffness and alters ECM remodeling. We speculate that proximal PA stiffness further contributes to increased right ventricular impedance in experimental PPHN, which contributes to abnormal transition of the pulmonary circulation at birth.

Increased right ventricular output and central pulmonary reservoir function support rise in pulmonary blood flow during adenosine infusion in the ovine fetus

2012 ◽  
Vol 302 (12) ◽  
pp. R1450-R1457 ◽  
Author(s):  
Joseph J. Smolich ◽  
Daniel J. Penny ◽  
Jonathan P. Mynard
Keyword(s):  
Blood Flow ◽  
Right Ventricular ◽  
Pulmonary Blood Flow ◽  
Ductus Arteriosus ◽  
Late Gestation ◽  
Adenosine Infusion ◽  
Flow Profile ◽  
Fetal Sheep ◽  
Time Flow ◽  
Flow Interactions

Although adenosine markedly increases fetal pulmonary blood flow, the specific changes in pulmonary trunk (PT), ductus arteriosus (DA), and conduit pulmonary artery (PA) flow interactions that support this increased flow are unknown. To address this issue, seven anesthetized late-gestation fetal sheep were instrumented with PT, DA, and left PA micromanometer catheters and transit-time flow probes. Blood flow profile and wave intensity analyses were performed at baseline and after adenosine infusion to increase PA flow approximately fivefold. With adenosine infusion, DA mean and phasic flows were unchanged, but increases in mean PT (500 ± 256 ml/min, P = 0.002) and the combined left and right PA flow (479 ± 181 ml/min, P < 0.001) were similar ( P > 0.7) and related to a larger flow-increasing forward-running compression wave arising from right ventricular (RV) impulsive contraction. Moreover, while the increased PT flow was confined to systole, the rise in PA flow spanned systole (316 ml/min) and diastole (163 ml/min). This elevated PA diastolic flow was accompanied by a 170% greater discharge from a PT and main PA reservoir filled in systole ( P < 0.001), but loss of retrograde blood discharge from a conduit PA reservoir that was evident at baseline. These data suggest that 1) an increase in fetal pulmonary blood flow produced by adenosine infusion is primarily supported by a higher PT blood flow (i.e., RV output); 2) about two-thirds of this increased RV output passes into the pulmonary circulation during systole; and 3) the remainder is transiently stored in a central PT and main PA systolic reservoir, from where it discharges into the lungs in diastole.

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.

rhVEGF treatment preserves pulmonary vascular reactivity and structure in an experimental model of pulmonary hypertension in fetal sheep

2005 ◽  
Vol 289 (2) ◽  
pp. L315-L321 ◽  
Author(s):  
Theresa R. Grover ◽  
Thomas A. Parker ◽  
Neil E. Markham ◽  
Steven H. Abman
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Experimental Model ◽  
Vascular Remodeling ◽  
Ductus Arteriosus ◽  
Main Pulmonary Artery ◽  
Left Lung ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Pulmonary Vascular Remodeling

We have previously shown that lung VEGF expression is decreased in a fetal lamb model of PPHN and that VEGF165 inhibition causes severe pulmonary hypertension in fetal lambs. Therefore, we hypothesized that treatment with rhVEGF165 would preserve endothelium-dependent vasodilation and reduce the severity of pulmonary vascular remodeling in an experimental model of PPHN. We studied the effects of daily intrapulmonary infusions of rhVEGF after partial ligation of the ductus arteriosus (DA). We performed surgery in 24 late-gestation fetal lambs and placed catheters in the main pulmonary artery, left atrium, and aorta for pressure measurements and in the left pulmonary artery for drug infusions. A pressure transducer was placed around the LPA to measure blood flow to the left lung (Qp), and the DA was surgically constricted to induce pulmonary hypertension. rhVEGF165 or vehicle was infused for 7 or 14 days. ACh or 8-BrcGMP was infused on days 2 and 13 to assess endothelium-dependent and -independent vasodilation, respectively. ACh-induced vasodilation was reduced in PPHN lambs after 14 days (change in Qp from baseline, 106% vs. 11%). In contrast, the response to ACh was preserved in lambs treated with rhVEGF (change in Qp, 94% vs. 90%). Pulmonary vasodilation to 8-BrcGMP was not altered in PPHN lambs or enhanced by VEGF treatment. rhVEGF treatment increased expression of lung eNOS protein and decreased pulmonary artery wall thickness by 34% vs. PPHN lambs. We conclude that VEGF165 preserves endothelium-dependent vasodilation, upregulates eNOS expression, and reduces the severity of pulmonary vascular remodeling in experimental PPHN.

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

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.

scholarly journals Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

2015 ◽  
Vol 308 (4) ◽  
pp. E306-E314 ◽  
Author(s):  
Satya S. Houin ◽  
Paul J. Rozance ◽  
Laura D. Brown ◽  
William W. Hay ◽  
Randall B. Wilkening ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Hepatic Glucose Production ◽  
Plasma Concentrations ◽  
Glucose Production ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Hepatic Glucose ◽  
Molar Percent ◽  
Glucose Output

Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 ( P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 μmol/min) to output by d4 (2.8 ± 1.4 μmol/min; P < 0.05 vs. basal). The [U-13C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 ( P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia ( P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

scholarly journals Serotonin contributes to high pulmonary vascular tone in a sheep model of persistent pulmonary hypertension of the newborn

2013 ◽  
Vol 304 (12) ◽  
pp. L894-L901 ◽  
Author(s):  
Cassidy Delaney ◽  
Jason Gien ◽  
Gates Roe ◽  
Nicole Isenberg ◽  
Jenai Kailey ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Tryptophan Hydroxylase ◽  
Late Gestation ◽  
Persistent Pulmonary Hypertension ◽  
Sheep Model ◽  
Pulmonary Hemodynamics ◽  
Fetal Sheep ◽  
Pulmonary Arterial

Although past studies demonstrate that altered serotonin (5-HT) signaling is present in adults with idiopathic pulmonary arterial hypertension, whether serotonin contributes to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) is unknown. We hypothesized that 5-HT contributes to increased pulmonary vascular resistance (PVR) in a sheep model of PPHN and that selective 5-HT reuptake inhibitor (SSRI) treatment increases PVR in this model. We studied the hemodynamic effects of 5-HT, ketanserin (5-HT2A receptor antagonist), and sertraline, an SSRI, on pulmonary hemodynamics of the late gestation fetal sheep with PPHN caused by prolonged constriction of the ductus arteriosis. Brief intrapulmonary infusions of 5-HT increased PVR from 1.0 ± 0.07 (baseline) to 1.4 ± 0.22 mmHg/ml per minute of treatment ( P < 0.05). Ketanserin decreased PVR from 1.1 ± 0.15 (baseline) to 0.82 ± 0.09 mmHg/ml per minute of treatment ( P < 0.05). Sertraline increased PVR from 1.1 ± 0.17 (baseline) to 1.4 ± 0.17 mmHg/ml per minute of treatment ( P = 0.01). In addition, we studied 5-HT production and activity in vitro in experimental PPHN. Compared with controls, pulmonary artery endothelial cells from fetal sheep with PPHN exhibited increased expression of tryptophan hydroxylase 1 and 5-HT production by twofold and 56%, respectively. Compared with controls, 5-HT2A R expression was increased in lung homogenates and pulmonary artery smooth muscle cell lysates by 35% and 32%, respectively. We concluded that increased 5-HT contributes to high PVR in experimental PPHN through activation of the 5-HT2A receptor and that SSRI infusion further increases PVR in this model.

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