Effects of oxygen and exogenous L-arginine on EDRF activity in fetal pulmonary circulation

1993 ◽  
Vol 264 (3) ◽  
pp. H865-H871 ◽  
Author(s):  
J. A. McQueston ◽  
D. N. Cornfield ◽  
I. F. McMurtry ◽  
S. H. Abman
Keyword(s):  
Blood Flow ◽  
Pulmonary Artery ◽  
Pulmonary Circulation ◽  
Fetal Lung ◽  
Left Pulmonary Artery ◽  
Late Gestation ◽  
Arginine Infusion ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasodilator ◽  
Vasodilator Activity

To determine whether L-arginine, the precursor of endothelium-derived relaxing factor (EDRF), increases vasodilator activity in the fetal pulmonary circulation, we studied its effects on basal pulmonary vascular tone and on pulmonary vasodilation stimulated by oxygen and acetylcholine (ACh) in chronically prepared late-gestation fetal lambs. L-Arginine infusion (30–300 mg over 10 min) into the left pulmonary artery (LPA) increased blood flow (18–57%) without changing pulmonary artery pressure. To determine whether O2-induced vasodilation involves EDRF and is augmented by L-arginine treatment, we infused L-arginine or NG-nitro-L-arginine (L-NNA), an inhibitor of EDRF synthesis, while increasing fetal PO2 6 Torr by delivering 100% O2 to the ewe for 120 min. In controls, LPA blood flow progressively increased from 106 +/- 13 ml/min (baseline) to 257 +/- 34 ml/min (peak) at 40 min of increased PO2 (P < 0.05, baseline vs. peak) but steadily returned toward baseline during the next hour. Treatment with L-NNA markedly attenuated O2-induced pulmonary vasodilation (P < 0.05 vs. control). L-Arginine infusion did not augment or sustain the O2-induced vasodilator response. We also examined whether L-arginine could sustain pulmonary vasodilation to ACh, another EDRF-dependent stimulus, and found that the EDRF substrate neither potentiated nor sustained the ACh response. We conclude that: in the fetal lung 1) exogenous L-arginine is a fetal pulmonary vasodilator, 2) increased PO2 augments EDRF activity in the fetal lung, and 3) supplemental L-arginine does not sustain either O2- or ACh-induced vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of ATP-sensitive potassium channels in ovine fetal pulmonary vascular tone

1992 ◽  
Vol 263 (5) ◽  
pp. H1363-H1368 ◽  
Author(s):  
D. N. Cornfield ◽  
J. A. McQueston ◽  
I. F. McMurtry ◽  
D. M. Rodman ◽  
S. H. Abman
Keyword(s):  
Blood Flow ◽  
Pulmonary Circulation ◽  
Pulmonary Blood Flow ◽  
Vascular Tone ◽  
Left Pulmonary Artery ◽  
Late Gestation ◽  
Flow Transducer ◽  
Pulmonary Vasodilation ◽  
Relaxing Factor

To study the potential role of ATP-sensitive K+ (K+ATP) channels in fetal pulmonary vasoregulation, we studied the effect of a K+ATP channel agonist, lemakalim, and antagonist, glibenclamide, on the fetal pulmonary circulation in nine chronically instrumented late-gestation fetal lambs. Left pulmonary artery (LPA) blood flow was measured with an electromagnetic flow transducer. Brief (10 min) infusions of lemakalim at 3, 10, and 30 micrograms/min into the LPA produced dose-dependent increases in flow from 68 +/- 7 to 96 +/- 11, 160 +/- 15, and 204 +/- 34 ml/min, respectively. The duration of pulmonary vasodilation after the 10-min infusions of lemakalim at 3, 10, and 30 micrograms/min was 20 +/- 3, 47 +/- 10, and 55 +/- 15 min, respectively. Pulmonary blood pressure and flow did not change with intrapulmonary infusion of glibenclamide (10 mg), a K+ATP channel antagonist. Lemakalim-induced pulmonary vasodilation was not affected by nitro-L-arginine (10 mg), a competitive inhibitor of endothelium-dependent relaxing factor, but was blocked by glibenclamide. Prolonged (2 h) intrapulmonary infusions of lemakalim (2-6 micrograms/min) increased pulmonary blood flow by 137%. The increase in pulmonary blood flow was sustained throughout the infusion. Systemic and pulmonary arterial pressures decreased during prolonged infusion. We conclude that K+ATP channels are present in the fetal pulmonary circulation, but do not participate in the regulation of basal pulmonary vascular tone. K+ATP channel activation produces sustained vasodilation that is not mediated by endothelium-derived relaxing factor. We speculate that birth-related stimuli activate K+ATP channels to enhance the pulmonary vasodilation that occurs at birth.

Effects of BAY 41–2272, a soluble guanylate cyclase activator, on pulmonary vascular reactivity in the ovine fetus

2005 ◽  
Vol 288 (4) ◽  
pp. L727-L733 ◽  
Author(s):  
Philippe Deruelle ◽  
Theresa R. Grover ◽  
Laurent Storme ◽  
Steven H. Abman
Keyword(s):  
Blood Flow ◽  
Pulmonary Artery ◽  
Guanylate Cyclase ◽  
Pulmonary Circulation ◽  
Soluble Guanylate Cyclase ◽  
Critical Role ◽  
No Production ◽  
Flow Transducer ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasodilator

Nitric oxide (NO)-cGMP signaling plays a critical role during the transition of the pulmonary circulation at birth. BAY 41–2272 is a novel NO-independent direct stimulator of soluble guanylate cyclase that causes vasodilation in systemic and local circulations. However, the hemodynamic effects of BAY 41–2272 have not been studied in the perinatal pulmonary circulation. We hypothesized that BAY 41–2272 causes potent and sustained fetal pulmonary vasodilation. We performed surgery on 14 fetal lambs (125–130 days gestation; term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery (LPA) to measure blood flow, and a catheter was placed in the LPA for drug infusion. Pulmonary vascular resistance (PVR) was calculated as pulmonary artery pressure minus left atrial pressure divided by LPA blood flow. BAY 41–2272 caused dose-related increases in pulmonary blood flow up to threefold above baseline and reduced PVR by 75% ( P < 0.01). Prolonged infusion of BAY 41–2272 caused sustained pulmonary vasodilation throughout the 120-min infusion period. The pulmonary vasodilator effect of BAY 41–2272 was not attenuated by Nω-nitro-l-arginine, a NO synthase inhibitor. In addition, compared with sildenafil, a phosphodiesterase 5 inhibitor, the pulmonary vasodilator response to BAY 41–2272 was more prolonged. We conclude that BAY 41–2272 causes potent and sustained fetal pulmonary vasodilation independent of NO release. We speculate that BAY 41–2272 may have therapeutic potential for pulmonary hypertension associated with failure to circulatory adaptation at birth, especially in the setting of impaired NO production.

Effects of catecholamines on the pulmonary circulation in the ovine fetus

2001 ◽  
Vol 281 (2) ◽  
pp. R607-R614 ◽  
Author(s):  
S. Jaillard ◽  
V. Houfflin-Debarge ◽  
Y. Riou ◽  
T. Rakza ◽  
S. Klosowski ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Pulmonary Circulation ◽  
Vascular Tone ◽  
Left Pulmonary Artery ◽  
Late Gestation ◽  
Dopamine Infusion ◽  
Pulmonary Vasodilator ◽  
Norepinephrine Infusion ◽  
Ovine Fetus ◽  
Oxide Synthase

High levels of circulating catecholamines are found in the fetus, and fetal stress and birth induce a marked surge in catecholamine secretion. Little is known about the role of catecholamines on the fetal pulmonary circulation. To determine the effects of catecholamines on the pulmonary vascular tone, we tested the hemodynamic response to norepinephrine and dopamine infusion in chronically prepared late-gestation fetal lambs. We found that norepinephrine infusion (0.5 μg · kg−1· min−1) increased pulmonary artery pressure (PAP) by 10 ± 1% ( P < 0.01), left pulmonary artery blood flow by 73 ± 14% ( P < 0.01), and decreased pulmonary vascular resistance (PVR) by 33 ± 6% ( P < 0.01). The pulmonary vasodilator effect of norepinephrine was abolished after nitric oxide synthase inhibition. Dopamine infusion at 5 μg · kg−1· min−1did not significantly change PVR. Conversely, dopamine infusion at 10 μg · kg−1· min−1increased PAP ( P < 0.01) and progressively increased PVR by 30 ± 14% ( P < 0.01). These results indicate that catecholamines may modulate basal pulmonary vascular tone in the ovine fetus. We speculate that catecholamines may play a significant role in the maintenance of the fetal pulmonary circulation and in mediating changes in the transitional pulmonary circulation.

scholarly journals Cinaciguat, a soluble guanylate cyclase activator, causes potent and sustained pulmonary vasodilation in the ovine fetus

2009 ◽  
Vol 297 (2) ◽  
pp. L318-L325 ◽  
Author(s):  
Marc Chester ◽  
Pierre Tourneux ◽  
Greg Seedorf ◽  
Theresa R. Grover ◽  
Jason Gien ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Left Pulmonary Artery ◽  
Flow Transducer ◽  
Pulmonary Vasodilation

Impaired nitric oxide-cGMP signaling contributes to severe pulmonary hypertension after birth, which may in part be due to decreased soluble guanylate cyclase (sGC) activity. Cinaciguat (BAY 58-2667) is a novel sGC activator that causes vasodilation, even in the presence of oxidized heme or heme-free sGC, but its hemodynamic effects have not been studied in the perinatal lung. We performed surgery on eight fetal (126 ± 2 days gestation) lambs (full term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery to measure blood flow, and a catheter was placed in the left pulmonary artery for drug infusion. Cinaciguat (0.1–100 μg over 10 min) caused dose-related increases in pulmonary blood flow greater than fourfold above baseline and reduced pulmonary vascular resistance by 80%. Treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an sGC-oxidizing inhibitor, enhanced cinaciguat-induced pulmonary vasodilation by >120%. The pulmonary vasodilator effect of cinaciguat was prolonged, decreasing pulmonary vascular resistance for >1.5 h after brief infusion. In vitro stimulation of ovine fetal pulmonary artery smooth muscle cells with cinaciguat after ODQ treatment resulted in a 14-fold increase in cGMP compared with non-ODQ-treated cells. We conclude that cinaciguat causes potent and sustained fetal pulmonary vasodilation that is augmented in the presence of oxidized sGC and speculate that cinaciguat may have therapeutic potential for severe neonatal pulmonary hypertension.

scholarly journals Inhaled carbon monoxide does not cause pulmonary vasodilation in the late-gestation fetal lamb

2000 ◽  
Vol 278 (4) ◽  
pp. L779-L784 ◽  
Author(s):  
Theresa R. Grover ◽  
Robyn L. Rairigh ◽  
Jeanne P. Zenge ◽  
Steven H. Abman ◽  
John P. Kinsella
Keyword(s):  
Carbon Monoxide ◽  
Blood Flow ◽  
Pulmonary Artery ◽  
Vascular Tone ◽  
Ductus Arteriosus ◽  
Protoporphyrin Ix ◽  
Left Lung ◽  
Late Gestation ◽  
Zinc Protoporphyrin ◽  
Pulmonary Vasodilation

As observed with nitric oxide (NO), carbon monoxide (CO) binds and may activate soluble guanylate cyclase and increase cGMP levels in smooth muscle cells in vitro. Because inhaled NO (INO) causes potent and sustained pulmonary vasodilation, we hypothesized that inhaled CO (ICO) may have similar effects on the perinatal lung. To determine whether ICOcan lower pulmonary vascular resistance (PVR) during the perinatal period, we studied the effects of ICOon late-gestation fetal lambs. Catheters were placed in the main pulmonary artery, left pulmonary artery (LPA), aorta, and left atrium to measure pressure. An ultrasonic flow transducer was placed on the LPA to measure blood flow to the left lung. After baseline measurements, fetal lambs were mechanically ventilated with a hypoxic gas mixture (inspired O2fraction < 0.10) to maintain a constant fetal arterial [Formula: see text]. After 60 min (baseline), the lambs were treated with ICO[5–2,500 parts/million (ppm)]. Comparisons were made with INO(5 and 20 ppm) and combined INO(5 ppm) and ICO(100 and 2,500 ppm). We found that ICOdid not alter left lung blood flow or PVR at any of the study doses. In contrast, low-dose INOdecreased PVR by 47% ( P < 0.005). The combination of INOand ICOdid not enhance the vasodilator response to INO. To determine whether endogenous CO contributes to vascular tone in the fetal lung, zinc protoporphyrin IX, an inhibitor of heme oxygenase, was infused into the LPA in three lambs. Zinc protoporphyrin IX had no effect on baseline PVR, aortic pressure, or the pressure gradient across the ductus arteriosus. We conclude that ICOdoes not cause vasodilation in the near-term ovine transitional circulation, and endogenous CO does not contribute significantly to baseline pulmonary vascular tone or ductus arteriosus tone in the late-gestation ovine fetus.

scholarly journals Fasudil inhibits the myogenic response in the fetal pulmonary circulation

2008 ◽  
Vol 295 (4) ◽  
pp. H1505-H1513 ◽  
Author(s):  
Pierre Tourneux ◽  
Marc Chester ◽  
Theresa Grover ◽  
Steven H. Abman
Keyword(s):  
Blood Flow ◽  
Pulmonary Circulation ◽  
Ductus Arteriosus ◽  
Fetal Lung ◽  
Late Gestation ◽  
Time Dependent ◽  
Myogenic Response ◽  
Rock Inhibitor ◽  
Fetal Sheep ◽  
Rock Activity

In addition to high pulmonary vascular resistance (PVR) and low pulmonary blood flow, the fetal pulmonary circulation is characterized by mechanisms that oppose vasodilation. Past work suggests that high myogenic tone contributes to high PVR and may contribute to autoregulation of blood flow in the fetal lung. Rho-kinase (ROCK) can mediate the myogenic response in the adult systemic circulation, but whether high ROCK activity contributes to the myogenic response and modulates time-dependent vasodilation in the developing lung circulation are unknown. We studied the effects of fasudil, a ROCK inhibitor, on the hemodynamic response during acute compression of the ductus arteriosus (DA) in chronically prepared, late-gestation fetal sheep. Acute DA compression simultaneously induces two opposing responses: 1) blood flow-induced vasodilation through increased shear stress that is mediated by NO release and 2) stretch-induced vasoconstriction (i.e., the myogenic response). The myogenic response was assessed during acute DA compression after treatment with Nω-nitro-l-arginine, an inhibitor of nitric oxide synthase, to block flow-induced vasodilation and unmask the myogenic response. Intrapulmonary fasudil infusion (100 μg over 10 min) did not enhance flow-induced vasodilation during brief DA compression but reduced the myogenic response by 90% ( P < 0.05). During prolonged DA compression, fasudil prevented the time-dependent decline in left pulmonary artery blood flow at 2 h (183 ± 29 vs. 110 ± 11 ml/min with and without fasudil, respectively; P < 0.001). We conclude that high ROCK activity opposes pulmonary vasodilation in utero and that the myogenic response maintains high PVR in the normal fetal lung through ROCK activation.

The pulmonary vasculature in a neonatal porcine model with increased pulmonary blood flow and pressure

2001 ◽  
Vol 11 (4) ◽  
pp. 420-430 ◽  
Author(s):  
Elisabeth V. Stenbøg ◽  
Daniel A. Steinbrüchel ◽  
Anne Bloch Thomsen ◽  
Ulrik Baandrup ◽  
Lene Heickendorff ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Artery ◽  
Vascular Disease ◽  
Pulmonary Blood Flow ◽  
Left Pulmonary Artery ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Disease ◽  
Systolic Pulmonary Arterial Pressure ◽  
Pulmonary Arterial ◽  
Circulating Levels

Introduction: Hypertension and hyperperfusion of the pulmonary vascular bed in the setting of congenital cardiac malformations may lead to progressive pulmonary vascular disease. To improve the understanding of the basic mechanisms of this disease, there is a need for clinically relevant animal models which reflect the disease process. Material and Results: We randomly allocated 45 newborn pigs, at the age of 48 hrs, to groups in which there was either construction of a 3 mm central aorto-pulmonary shunt, undertaken in 9, or ligation of the left pulmonary artery, achieved in 13. Controls included sham operations in 13, or no operations in 10 pigs. Follow-up was continued for three months. The interventions were compatible with survival in most pigs. The shunts resulted in an acute 85% increase in systolic pulmonary arterial pressure, and a more than twofold increase in pulmonary blood flow. By three months of age, nearly all shunts had closed spontaneously, and haemodynamics were normal. Ligation of the left pulmonary artery resulted in a normal total pulmonary blood flow, despite only the right lung being perfused, and a 33% increase in systolic pulmonary arterial pressure. These haemodynamic changes were maintained throughout the period of study. In both groups, histomorphometry revealed markedly increased muscularity of the intra-acinar pulmonary arteries. Circulating levels of endothelin were normal in the shunted animals, and elevated in those with ligation of the left pulmonary artery. Conclusion: In neonatal porcine models of pulmonary vascular disease, created by construction of 3 mm central aorto-pulmonary shunts and ligation of one pulmonary artery, we observed histopathological changes of the pulmonary vasculature similar to early hypertensive pulmonary vascular disease in humans. Elevated circulating levels of endothelin were associated with abnormal haemodynamics rather than abnormal pathology. These findings could be valuable for future studies on the pathogenesis of hypertensive pulmonary vascular disease associated with congenital cardiac malformations.

scholarly journals The role of CXCR2 in systemic neovascularization of the mouse lung

2007 ◽  
Vol 103 (2) ◽  
pp. 594-599 ◽  
Author(s):  
Jesús Sánchez ◽  
Aigul Moldobaeva ◽  
Jessica McClintock ◽  
John Jenkins ◽  
Elizabeth Wagner
Keyword(s):  
Blood Flow ◽  
Pulmonary Artery ◽  
Left Lung ◽  
Neutralizing Antibody ◽  
Left Pulmonary Artery ◽  
Endothelial Cell Proliferation ◽  
Antibody Treatment ◽  
Pulmonary Artery Obstruction ◽  
Artery Obstruction ◽  
Deficient Mice

We previously showed increased expression of the ELR+, CXC chemokines in the lung after left pulmonary artery obstruction. These chemokines have been shown in other systems to bind their G protein-coupled receptor, CXCR2, and promote systemic endothelial cell proliferation, migration, and capillary tube formation. In the present study, we blocked CXCR2 in vivo using a neutralizing antibody and also studied mice that were homozygous null for CXCR2. To estimate the extent of neovascularization in this model, we measured systemic blood flow to the left lung 14 days after left pulmonary artery ligation (LPAL). We found blood flow significantly reduced (67% decrease) with neutralizing antibody treatment compared with controls. However, blood flow was not altered in the CXCR2-deficient mice compared with wild-type controls after LPAL. To test for ligand availability, we measured macrophage inflammatory protein (MIP)-2 in lung homogenates after LPAL, because this is the predominant CXC chemokine previously shown to be increased after LPAL ( 22 ). MIP-2 protein was two- to fourfold higher in the left lung relative to the right lung in all treatment groups 4 h after LPAL and this increase did not differ among groups. We speculate that the CXCR2-deficient mice have compensatory mechanisms that mitigate their lack of gene expression and conclude that CXCR2 contributes to chemokine-induced systemic angiogenesis after pulmonary artery obstruction.

Tone-dependent responses to endothelin in the isolated perfused fetal sheep pulmonary circulation in situ

1991 ◽  
Vol 70 (3) ◽  
pp. 1228-1234 ◽  
Author(s):  
S. Cassin ◽  
V. Kristova ◽  
T. Davis ◽  
P. Kadowitz ◽  
G. Gause
Keyword(s):  
Pulmonary Circulation ◽  
Vena Cava ◽  
Fetal Lung ◽  
Left Pulmonary Artery ◽  
Pulmonary Vasculature ◽  
Fetal Sheep ◽  
Vascular Responses ◽  
Arterial Perfusion ◽  
Ovine Fetal

Pulmonary vascular responses to endothelin (ET-1), a peptide derived from endothelial cells in culture, were investigated in the ovine fetus delivered by cesarean section from chloralose-anesthetized ewes with intact umbilical circulation. Circulation to the lower left lobe of the fetal lung was isolated in situ and perfused at constant flow with blood withdrawn from the inferior vena cava. Injection of graded doses of ET-1 into the left pulmonary artery decreased pulmonary arterial perfusion pressure in a dose-related manner. At doses of 100, 300, and 1,000 ng, pulmonary vascular resistance per kilogram body weight (PVR/kg) was decreased 30, 40, and 42%, respectively. However, when fetuses were ventilated with 100% oxygen, 100- and 300-ng doses of ET-1 decreased PVR/kg by 5 and 9%, respectively. In contrast, injection of 1,000 ng of ET-1 resulted in a reversal of the response, and PVR/kg was increased by 70%. Ventilation of the right lung alone resulted in a similar reversal of the vasodilator response to 1,000 ng of ET-1, and a 138% increase in PVR/kg was recorded. These studies demonstrate for the first time that ET-1 has vasodilator activity in the normally high-tone ovine fetal pulmonary circulation. In addition, these results show that ET-1 has vasoconstrictor activity in the newly ventilated low-tone pulmonary vasculature. The present data indicate the pulmonary vascular responses to ET-1 are tone dependent in the ovine fetal pulmonary circulation.

Blood Flow Velocity Profiles in Pulmonary Branch Arteries in Lambs

1995 ◽  
Vol 117 (2) ◽  
pp. 237-241
Author(s):  
H. Katayama ◽  
G. W. Henry ◽  
C. L. Lucas ◽  
B. Ha ◽  
J. I. Ferreiro ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Artery ◽  
Pulmonary Arteries ◽  
Maximum Velocity ◽  
Left Pulmonary Artery ◽  
Control Group ◽  
Pulsed Doppler Ultrasound ◽  
Right Pulmonary Artery ◽  
Blood Flow Velocities ◽  
The Right

We studied the detailed profiles of blood flow in the right and left pulmonary arteries using 20 MHz pulsed Doppler ultrasound equipment in a lamb model. Fourteen lambs aged four to six weeks were selected. In six lambs, monocrotaline pyrrole was injected parenterally to create pulmonary hypertension (PH group). Eight other lambs served as unaltered controls (control group). The blood flow velocities were sampled in 1mm increments along the anterior—posterior axis of the branch arteries. The maximum velocity of the forward flow in the left pulmonary artery was higher than that in the right pulmonary artery in the control group (71.7 ± 15.9cm/s vs 60.2 ± 13.5; p < 0.05). The fastest backward flow was located at the posterior position of the vessel in the right pulmonary artery in the control group. No significant bias in location was shown in the left pulmonary artery. Using indices of P90, acceleration time, P90*AcT, the velocity waveforms in the PH group were compared with those in the control group. In the left pulmonary artery, every index in the control group showed a significantly greater value that in the PH group. On the other hand, no significant differences were found between either group in the right pulmonary artery.

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