Chronic pulmonary hypertension in utero impairs endothelium-dependent vasodilation

1995 ◽  
Vol 268 (1) ◽  
pp. H288-H294 ◽  
Author(s):  
J. A. McQueston ◽  
J. P. Kinsella ◽  
D. D. Ivy ◽  
I. F. McMurtry ◽  
S. H. Abman
Keyword(s):  
Pulmonary Hypertension ◽  
Ductus Arteriosus ◽  
Left Lung ◽  
Late Gestation ◽  
Pulmonary Vasodilation ◽  
Mean Pulmonary Arterial Pressure ◽  
Chronic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Arterial O2 Saturation ◽  
Arterial Po2

To determine whether endothelium-dependent pulmonary vasodilation is selectively impaired by chronic intrauterine pulmonary hypertension, we compared the hemodynamic effects of an endothelium-dependent agonist, acetylcholine (ACh), with an endothelium-independent agonist, atrial natriuretic peptide (ANP), before, during, and after development of pulmonary hypertension in five late-gestation fetal lambs. Pulmonary hypertension was produced over 9–12 days by progressive inflation of a vascular occluder around the ductus arteriosus. Age-matched fetal lambs (n = 5) without occluders served as controls. Mean pulmonary arterial pressure increased from 44 +/- 2 (baseline) to 65 +/- 4 Torr after 10-12 days of inflation (P < 0.05). Left lung pulmonary vascular resistance (PVR) increased from 0.52 +/- 0.06 to 0.72 +/- 0.11 Torr.ml-1.min over 10 days (P < 0.05). O2 saturation remained at > 40% during the study period. Although brief intrapulmonary infusions of ACh (1.5 micrograms over 15 min) lowered left lung PVR by 29 +/- 8% before ductus arteriosus compression, ACh-induced pulmonary vasodilation was absent after 9–12 days of pulmonary hypertension. In contrast, the vasodilator response to ANP remained intact throughout the study period. ACh- and ANP-induced vasodilation did not change with time in control animals. In five hypertensive animals delivered by cesarean section, inhaled NO (20 ppm) reduced left lung PVR from levels achieved during ventilation with 100% O2 alone (0.61 +/- 0.31 to 0.24 +/- 0.007 Torr.ml-1.min), increased arterial O2 saturation from 51 +/- 14 to 84 +/- 13%, and increased arterial PO2 from 29 +/- 11 to 106 +/- 34 Torr.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Endothelin blockade augments pulmonary vasodilation in the ovine fetus

1996 ◽  
Vol 81 (6) ◽  
pp. 2481-2487 ◽  
Author(s):  
D. Dunbar Ivy ◽  
John P. Kinsella ◽  
Steven H. Abman
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Vascular Tone ◽  
Ductus Arteriosus ◽  
Left Lung ◽  
Late Gestation ◽  
Converting Enzyme ◽  
Pulmonary Vasodilation ◽  
Vasodilator Response ◽  
Ovine Fetus

Ivy, D. Dunbar, John P. Kinsella, and Steven H. Abman.Endothelin blockade augments pulmonary vasodilation in the ovine fetus. J. Appl. Physiol. 81(6): 2481–2487, 1996.—The physiological role of endothelin-1 (ET-1) in regulation of vascular tone in the perinatal lung is controversial. Recent studies suggest that ET-1 contributes to high basal pulmonary vascular resistance in the normal fetus, but its role in the modulation of pulmonary vascular tone remains uncertain. We hypothesized that high ET-1 activity opposes the vasodilator response to some physiological stimuli such as increased pressure. To test the hypothesis that ET-1 modulates fetal pulmonary vascular responses to acute and prolonged physiological stimuli, we performed a series of experiments in the late-gestation ovine fetus. We studied the hemodynamic effects of two ET-1 antagonists, BQ-123 (a selective ETA-receptor antagonist) and phosphoramidon (a nonselective ET-1-converting enzyme inhibitor) during mechanical increases in pressure due to partial ductus arteriosus compression in chronically prepared late-gestation fetal lambs. In control studies, partial ductus arteriosus compression decreased the ratio of pulmonary arterial pressure to pulmonary artery flow in the left lung 34 ± 6% from baseline. Intrapulmonary infusions of BQ-123 (0.5 μg/min for 10 min; 0.025 μg/min for 2 h) or phosphoramidon (1.0 mg/min for 10 min) augmented the peak vasodilator response during ductus arteriosus compression (52 ± 3 and 49 ± 6% from baseline, respectively, P < 0.05 vs. control). In addition, unlike the transient vasodilator response to ductus arteriosus compression in control studies, ET-1 blockade with BQ-123 or phosphoramidon prolonged the increase in flow caused by ductus arteriosus compression. In summary, ETA-receptor blockade and ET-1-converting enzyme inhibition augment and prolong fetal pulmonary vasodilation during partial compression of the ductus arteriosus. We conclude that ET-1 activity modulates acute and prolonged responses of the fetal pulmonary circulation to changes in vascular pressure. We speculate that ET-1 contributes to regulation and maintenance of high pulmonary vascular resistance in the normal ovine fetal lung.

Pulmonary vascular effects of nitric oxide-cGMP augmentation in a model of chronic pulmonary hypertension in fetal and neonatal sheep

2005 ◽  
Vol 289 (5) ◽  
pp. L798-L806 ◽  
Author(s):  
Philippe Deruelle ◽  
Theresa R. Grover ◽  
Steven H. Abman
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Ductus Arteriosus ◽  
Vascular Effects ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasodilator ◽  
Cgmp Signaling ◽  
Chronic Pulmonary Hypertension ◽  
Direct Activator

Persistent pulmonary hypertension of the newborn (PPHN) is partly due to impaired nitric oxide (NO)-cGMP signaling. BAY 41-2272 is a novel direct activator of soluble guanylate cyclase, but whether this drug may be an effective therapy for PPHN is unknown. We hypothesized that BAY 41-2272 would cause pulmonary vasodilation in a model of severe PPHN. To test this hypothesis, we compared the hemodynamic response of BAY 41-2272 to acetylcholine, an endothelium-dependent vasodilator, and sildenafil, a selective inhibitor of PDE5 in chronically instrumented fetal lambs at 1 and 5 days after partial ligation of the ductus arteriosus. After 9 days, we delivered the animals by cesarean section to measure their hemodynamic responses to inhaled NO (iNO), sildenafil, and BAY 41-2272 alone or combined with iNO. BAY 41-2272 caused marked pulmonary vasodilation, as characterized by a twofold increase in blood flow and a nearly 60% fall in PVR at day 1. Effectiveness of BAY 41-2272-induced pulmonary vasodilation increased during the development of pulmonary hypertension. Despite a similar effect at day 1, the pulmonary vasodilator response to BAY 41-2272 was greater than sildenafil at day 5. At birth, BAY 41-2272 dramatically reduced PVR and augmented the pulmonary vasodilation induced by iNO. We concluded that BAY 41-2272 causes potent pulmonary vasodilation in fetal and neonatal sheep with severe pulmonary hypertension. We speculate that BAY 41-2272 may provide a novel treatment for severe PPHN, especially in newborns with partial response to iNO therapy.

A model of embolic chronic pulmonary hypertension in the dog

1984 ◽  
Vol 56 (3) ◽  
pp. 810-815 ◽  
Author(s):  
I. Shelub ◽  
A. van Grondelle ◽  
R. McCullough ◽  
S. Hofmeister ◽  
J. T. Reeves
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Histological Study ◽  
Systemic Arterial Pressure ◽  
Right Atrial ◽  
Pulmonary Vasodilation ◽  
Reliable Model ◽  
Chronic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Wedge Pressure

Despite numerous efforts, a reliable model of chronic embolic pulmonary hypertension has not been established. To develop such a model five conscious mongrel dogs were embolized repeatedly over 16–30 wk with Sephadex microspheres 286 +/- 70 micron in diameter. Hemodynamic and respiratory measurements were obtained just prior to each embolization. Chronic pulmonary hypertension developed in all dogs. Pulmonary hypertension was not accounted for by increased cardiac output, wedge pressure, right atrial pressure, or systemic arterial pressure. Gas exchange was little altered. Lung histological study revealed microspheres clustered within vessels. In three dogs increased pulmonary arterial pressure was sustained despite cessation of embolization for up to 5 mo. Reembolization in one of these caused further pulmonary hypertension. In two dogs acute pulmonary vasodilation by O2 breathing and administration of prostaglandin E1 reduced, but did not abolish, the increased pulmonary vascular resistance, suggesting some vascular tone was present. An embolic model of chronic pulmonary hypertension in awake dogs allows further investigation into the evolution of pulmonary hypertension.

Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension

2006 ◽  
Vol 290 (4) ◽  
pp. L723-L729 ◽  
Author(s):  
Oleg V. Evgenov ◽  
Cornelius J. Busch ◽  
Natalia V. Evgenov ◽  
Rong Liu ◽  
Bodil Petersen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Selective Inhibition ◽  
Pulmonary Vasodilation ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Vasodilator ◽  
Pulmonary Arterial ◽  
Inhaled No

Phosphodiesterase 1 (PDE1) modulates vascular tone and the development of tolerance to nitric oxide (NO)-releasing drugs in the systemic circulation. Any role of PDE1 in the pulmonary circulation remains largely uncertain. We measured the expression of genes encoding PDE1 isozymes in the pulmonary vasculature and examined whether or not selective inhibition of PDE1 by vinpocetine attenuates pulmonary hypertension and augments the pulmonary vasodilator response to inhaled NO in lambs. Using RT-PCR, we detected PDE1A, PDE1B, and PDE1C mRNAs in pulmonary arteries and veins isolated from healthy lambs. In 13 lambs, the thromboxane A2 analog U-46619 was infused intravenously to increase mean pulmonary arterial pressure to 35 mmHg. Four animals received an intravenous infusion of vinpocetine at incremental doses of 0.3, 1, and 3 mg·kg−1·h−1. In nine lambs, inhaled NO was administered in a random order at 2, 5, 10, and 20 ppm before and after an intravenous infusion of 1 mg·kg−1·h−1 vinpocetine. Administration of vinpocetine did not alter pulmonary and systemic hemodynamics or transpulmonary cGMP or cAMP release. Inhaled NO selectively reduced mean pulmonary arterial pressure, pulmonary capillary pressure, and pulmonary vascular resistance index, while increasing transpulmonary cGMP release. The addition of vinpocetine enhanced pulmonary vasodilation and transpulmonary cGMP release induced by NO breathing without causing systemic vasodilation but did not prolong the duration of pulmonary vasodilation after NO inhalation was discontinued. Our findings demonstrate that selective inhibition of PDE1 augments the therapeutic efficacy of inhaled NO in an ovine model of acute chemically induced pulmonary hypertension.

Pulmonary vascular effects of sildenafil on the development of chronic pulmonary hypertension in the ovine fetus

2005 ◽  
Vol 288 (6) ◽  
pp. L1193-L1200 ◽  
Author(s):  
B. Larrue ◽  
S. Jaillard ◽  
M. Lorthioir ◽  
X. Roubliova ◽  
G. Butrous ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Ductus Arteriosus ◽  
Pulmonary Arteries ◽  
Late Gestation ◽  
Control Group ◽  
Vascular Effects ◽  
Chronic Pulmonary Hypertension ◽  
Ovine Fetus ◽  
Prophylactic Use ◽  
The Right

We investigated the pulmonary vascular effects of prophylactic use of sildenafil, a specific phosphodiesterase-5 inhibitor, in late-gestation fetal lambs with chronic pulmonary hypertension. Fetal lambs were operated on at 129 ± 1 days gestation (term = 147 days). Ductus arteriosus (DA) was compressed for 8 days to cause chronic pulmonary hypertension. Fetuses were treated with sildenafil (24 mg/day) or saline. Pulmonary vascular responses to increase in shear stress and in fetal PaO2 were studied at, respectively, day 4 and 6. Percent wall thickness of small pulmonary arteries (%WT) and the right ventricle-to-left ventricle plus septum ratio (RVH) were measured after completion of the study. In the control group, DA compression increased PA pressure (48 ± 5 to 72 ± 8 mmHg, P < 0.01) and pulmonary vascular resistance (PVR) (0.62 ± 0.08 to 1.15 ± 0.11 mmHg·ml−1·min−1, P < 0.05). Similar increase in PAP was observed in the sildenafil group, but PVR did not change significantly (0.54 ± 0.06 to 0.64 ± 0.09 mmHg·ml−1·min−1). Acute DA compression, after brief decompression, elevated PVR 25% in controls and decreased PVR 35% in the sildenafil group. Increased fetal PaO2 did not change PVR in controls but decreased PVR 60% in the sildenafil group. %WT and RVH were not different between groups. Prophylactic sildenafil treatment prevents the rise in pulmonary vascular tone and altered vasoreactivity caused by DA compression in fetal lambs. These results support the hypothesis that elevated PDE5 activity is involved in the consequences of chronic pulmonary hypertension in the perinatal lung.

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.

scholarly journals Under pressure: pulmonary hypertension associated with left heart disease

2015 ◽  
Vol 24 (138) ◽  
pp. 665-673 ◽  
Author(s):  
Harrison W. Farber ◽  
Simon Gibbs
Keyword(s):  
Pulmonary Hypertension ◽  
Heart Disease ◽  
Survival Rates ◽  
Left Ventricular ◽  
Left Heart ◽  
Mean Pulmonary Arterial Pressure ◽  
Left Heart Disease ◽  
Right Heart Catheterisation ◽  
Pulmonary Capillary ◽  
Pulmonary Arterial

Pulmonary hypertension (PH) associated with left heart disease (PH-LHD) is the most common type of PH, but its natural history is not well understood. PH-LHD is diagnosed by right heart catheterisation with a mean pulmonary arterial pressure ≥25 mmHg and a pulmonary capillary wedge pressure >15 mmHg. The primary causes of PH-LHD are left ventricular dysfunction of systolic and diastolic origin, and valvular disease. Prognosis is poor and survival rates are low. Limited progress has been made towards specific therapies for PH-LHD, and management focuses on addressing the underlying cause of the disease with supportive therapies, surgery and pharmacological treatments. Clinical trials of therapies for pulmonary arterial hypertension in patients with PH-LHD have thus far been limited and have provided disappointing or conflicting results. Robust, long-term clinical studies in appropriate target populations have the potential to improve the outlook for patients with PH-LHD. Herein, we discuss the knowledge gaps in our understanding of PH-LHD, and describe the current unmet needs and challenges that are faced by clinicians when identifying and managing patients with this disease.

scholarly journals Pulmonary Hypertension in Heart Failure Patients Presenting at OAUTHC, Ile-Ife, Nigeria

2016 ◽  
Vol 10 ◽  
pp. CMC.S38447
Author(s):  
Valentine N. Amadi ◽  
Olufemi E. Ajayi ◽  
Anthony O. Akintomide ◽  
Olugbenga O. Abiodun ◽  
Olaniyi J. Bamikole ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Left Ventricular ◽  
Systolic Volume ◽  
Heart Failure Patients ◽  
Mean Pulmonary Arterial Pressure ◽  
Diastolic Velocity ◽  
End Systolic Volume ◽  
Pulmonary Arterial ◽  
Systolic And Diastolic Function

Background Pulmonary hypertension (PH) is common in heart failure patients. Literature on PH in heart failure is sparse in Nigeria. This study was carried out to determine the prevalence of PH in heart failure patients and ascertain the relationship between left ventricular systolic and diastolic function and the degree of PH. Methods A total of 125 heart failure patients had echocardiography done. PH was diagnosed using tricuspid regurgitation jet and pulmonary ejection jet profile. Results PH was present in 70.4% of heart failure patients. Estimated mean pulmonary arterial pressure increased with increasing severity of systolic and diastolic dysfunction and had significantly negative correlation with ejection fraction, fractional shortening, and early mitral annular tissue diastolic velocity ( E′), but positive correlation with left ventricular end-systolic volume, right ventricular dimension, transmitral E to A ratio, and E/E′ ratio. Conclusion PH is very common in heart failure and has significant relationship with left ventricular function.

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