Alterations in Endogenous Nitric Oxide Production After Cardiopulmonary Bypass in Lambs With Normal and Increased Pulmonary Blood Flow

Circulation ◽  
2000 ◽  
Vol 102 (suppl_3) ◽  
Author(s):  
D. Michael McMullan ◽  
Janine M. Bekker ◽  
Andrew J. Parry ◽  
Michael J. Johengen ◽  
Alexander Kon ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Cardiopulmonary Bypass ◽  
Pulmonary Blood Flow ◽  
Vascular Reactivity ◽  
Pulmonary Arterial Pressure ◽  
No Production ◽  
Protein Levels ◽  
Pulmonary Arterial ◽  
Nitrite Nitrate

Background —After cardiopulmonary bypass (CPB), altered vascular reactivity is a major source of complications, particularly for children with increased pulmonary blood flow. Although changes in agonist-induced NO activity are well described after CPB, potential changes in basal NO production and their role in post-CPB pulmonary hypertension remain unclear. By using aortopulmonary vascular graft placement in the fetal lamb (shunt lambs), we established a unique model of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow. The objective of the present study was to investigate potential alterations in endogenous NO production after CPB in lambs with normal and increased pulmonary blood flow. Methods and Results —Vascular pressures and blood flows were monitored in 1-month-old lambs (n=7) with increased pulmonary blood flow and 6 age-matched control lambs. After shunt closure, hypothermic CPB (25°C) was performed for 2 hours. The hemodynamic variables were monitored for 4 hours after CPB. Before, during, and after CPB, peripheral lung biopsies were performed to determine tissue NO, nitrite, nitrate, and cGMP concentrations; total NO synthase (NOS) activity; and endothelial NOS protein levels. Hypothermic CPB increased both mean pulmonary arterial pressure and left pulmonary vascular resistance ( P <0.05). The increase in pulmonary arterial pressure induced in shunt lambs was greater than that induced in control lambs ( P <0.05). Four hours after CPB, tissue concentrations of NO, nitrite, nitrate, and cGMP were decreased to ≈70% of pre-CPB levels in both control and shunt lambs ( P <0.05). Total NOS activity and endothelial NOS protein levels were unchanged. Conclusions —Modest decreases in basal NO production, the inability to increase NO production, or both may play a role in the altered pulmonary vascular reactivity after CPB. The decrease in NO is independent of gene expression. However, other mechanisms for this decrease, such as substrate or cofactor availability, warrant further study.

Regional pulmonary blood flow during 96 hours of hypoxia in conscious sheep

1986 ◽  
Vol 61 (6) ◽  
pp. 2136-2143 ◽  
Author(s):  
D. C. Curran-Everett ◽  
K. McAndrews ◽  
J. A. Krasney
Keyword(s):  
Blood Flow ◽  
Arterial Pressure ◽  
Pulmonary Blood Flow ◽  
Pulmonary Arterial Pressure ◽  
Pressor Response ◽  
Superior Vena ◽  
Acute Hypoxia ◽  
Vena Cava ◽  
Normobaric Hypoxia ◽  
Pulmonary Arterial

The effects of acute hypoxia on regional pulmonary perfusion have been studied previously in anesthetized, artificially ventilated sheep (J. Appl. Physiol. 56: 338–342, 1984). That study indicated that a rise in pulmonary arterial pressure was associated with a shift of pulmonary blood flow toward dorsal (nondependent) areas of the lung. This study examined the relationship between the pulmonary arterial pressor response and regional pulmonary blood flow in five conscious, standing ewes during 96 h of normobaric hypoxia. The sheep were made hypoxic by N2 dilution in an environmental chamber [arterial O2 tension (PaO2) = 37–42 Torr, arterial CO2 tension (PaCO2) = 25–30 Torr]. Regional pulmonary blood flow was calculated by injecting 15-micron radiolabeled microspheres into the superior vena cava during normoxia and at 24-h intervals of hypoxia. Pulmonary arterial pressure increased from 12 Torr during normoxia to 19–22 Torr throughout hypoxia (alpha less than 0.049). Pulmonary blood flow, expressed as %QCO or ml X min-1 X g-1, did not shift among dorsal and ventral regions during hypoxia (alpha greater than 0.25); nor were there interlobar shifts of blood flow (alpha greater than 0.10). These data suggest that conscious, standing sheep do not demonstrate a shift in pulmonary blood flow during 96 h of normobaric hypoxia even though pulmonary arterial pressure rises 7–10 Torr. We question whether global hypoxic pulmonary vasoconstriction is, by itself, beneficial to the sheep.

Shear stress paradigm for perinatal fractal arterial network remodeling in lambs with pulmonary hypertension and increased pulmonary blood flow

2007 ◽  
Vol 292 (6) ◽  
pp. H3006-H3018 ◽  
Author(s):  
Zahra Ghorishi ◽  
Jay M. Milstein ◽  
Francis R. Poulain ◽  
Anita Moon-Grady ◽  
Theresa Tacy ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Shear Stress ◽  
High Resistance ◽  
Vascular Reactivity ◽  
Fractal Model ◽  
Pulmonary Hemodynamic ◽  
Pulmonary Arterial ◽  
Hemodynamic Reactivity ◽  
And Control

Congenital heart disease with increased blood flow commonly leads to the development of increased pulmonary vascular reactivity and pulmonary arterial hypertension by mechanisms that remain unclear. We hypothesized a shear stress paradigm of hemodynamic reactivity and network remodeling via the persistence and/or exacerbation of a fetal diameter bifurcation phenotype [parent diameter d0and daughters d1≥ d2with α < 2 in ( d1/ d0)α+ ( d2/ d0)αand area ratio β < 1 in β = ( d12+ d22)/ d02] that mechanically acts as a high resistance magnifier/shear stress amplifier to blood flow. Evidence of a hemodynamic influence on network remodeling was assessed with a lamb model of high-flow-induced secondary pulmonary hypertension in which an aortopulmonary graft was surgically placed in one twin in utero (Shunt twin) but not in the other (Control twin). Eight weeks after birth arterial casts were made of the left pulmonary arterial circulation. Bifurcation diameter measurements down to 0.010 mm in the Shunt and Control twins were then compared with those of an unoperated fetal cast. Network organization, cumulative resistance, and pressure/shear stress distributions were evaluated via a fractal model whose dimension D0≈ α delineates hemodynamic reactivity. Fetus and Control twin D0differed: fetus D0= 1.72, a high-resistance/shear stress amplifying condition; control twin D0= 2.02, an area-preserving transport configuration. The Shunt twin ( D0= 1.72) maintained a fetal design but paradoxically remodeled diameter geometry to decrease cumulative resistance relative to the Control twin. Our results indicate that fetal/neonatal pulmonary hemodynamic reactivity remodels in response to shear stress, but the response to elevated blood flow and pulmonary hypertension involves the persistence and exacerbation of a fetal diameter bifurcation phenotype that facilitates endothelial dysfunction/injury.

Alterations in ET-1, not nitric oxide, in 1-week-old lambs with increased pulmonary blood flow

2003 ◽  
Vol 284 (2) ◽  
pp. H480-H490 ◽  
Author(s):  
Boaz Ovadia ◽  
Olaf Reinhartz ◽  
Robert Fitzgerald ◽  
Janine M. Bekker ◽  
Michael J. Johengen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Congenital Heart Disease ◽  
Blood Flow ◽  
Heart Disease ◽  
Endothelial Function ◽  
Pulmonary Blood Flow ◽  
Congenital Heart ◽  
Vascular Reactivity ◽  
Protein Levels ◽  
Vasodilator Response

Altered pulmonary vascular reactivity is a source of morbidity and mortality for children with congenital heart disease and increased pulmonary blood flow. Nitric oxide (NO) and endothelin (ET)-1 are important mediators of pulmonary vascular reactivity. We hypothesize that early alterations in endothelial function contribute to the altered vascular reactivity associated with congenital heart disease. The objective of this study was to characterize endothelial function in our lamb model of increased pulmonary blood flow at 1 wk of life. Eleven fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 7 days after delivery. The pulmonary vasodilator response to both intravenous ACh (endothelium dependent) and inhaled NO (endothelium independent) was similar in shunted and control lambs. In addition, tissue NOx, NO synthase (NOS) activity, and endothelial NOS protein levels were similar. Conversely, the vasodilator response to both ET-1 and 4Ala-ET-1 (an ETBreceptor agonist) were attenuated in shunted lambs, and tissue ET-1 concentrations were increased ( P < 0.05). Associated with these changes were an increase in ET-converting enzyme-1 protein and a decrease in ETBreceptor protein levels ( P < 0.05). These data demonstrate that increased pulmonary blood flow induces alterations in ET-1 signaling before NO signaling and suggest an early role for ET-1 in the altered vascular reactivity associated with increased pulmonary blood flow.

Abstract 2305: Pulmonary Vascular Reactivity And Prognosis In Patients With Chronic Thromboembolic Pulmonary Hypertension

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Nika Skoro-Sajer ◽  
Nicklas Hack ◽  
Roela Sadushi ◽  
Johannes Jakowitsch ◽  
Diana Bonderman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Vascular Reactivity ◽  
Pulmonary Arterial Pressure ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Mean Pulmonary Arterial Pressure ◽  
Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Relative Change

Hemodynamic responder status defined as an acute decrease of mean pulmonary arterial pressure (mPAP)>10mmHg and below 40mmHg is associated with improved outcome in patients (pts) with pulmonary arterial hypertension (PAH). Pulmonary vascular reactivity to nitric oxide (NO) is controversial in chronic thromboembolic pulmonary hypertension (CTEPH). We speculated that the magnitude of the acute decrease in mean pulmonary artery pressure (mPAP) after exposure to NO might reflect the degree of small vessel disease in CTEPH and thus, affect long-term outcome. Methods: Right heart catheterization was performed in 62 (55  ± 15 years, 32 female) pts with major-vessel CTEPH, at baseline and during inhalation of 40ppm NO. Within 25±15 days patients underwent pulmonary endarterectomy (PEA). Pts were followed for 11.3±26 months. Predictors of survival were analyzed by Cox regression analysis, and survival was described by Kaplan-Meier curves. Results: Significant reductions in mean pulmonary arterial pressure (mPAP; p<0.001), pulmonary vascular resistance (PVR; p<0.001) and an increase in mixed venous oxygen saturation following NO inhalation were demonstrated (p<0.001) by a paired t-test. Stepwise multivariate analysis revealed the relative change of PVR after NO inhalation as a predictor of survival. Patients whose PVR during NO inhalation declined below 789.8 dynes.s.cm-5 had significantly better outcome than patients with above median PVR. There was a strong negative correlation between the relative change of PVR under NO and recurrent pulmonary hypertension after PEA (p=0.02). Conclusions: Patients with operable CTEPH demonstrated acute pulmonary vascular reactivity, mostly not corresponding to a complete responder status, but accounting for a wide range of decreases of mPAP [change of mPAP (%) (−10.9±14)] and PVR [change of PVR (%) (−17 ±15)]. Reduction of PVR under 800 dynes.s.cm-5 after inhalation of NO was associated with better outcome. Responsiveness to inhaled nitric oxide is a predictor for mid-term survival in adult patients with CTEPH undergoing PEA.

scholarly journals Pulmonary hypertension in infants with congenital heart defects: are leukotrienes involved?

1997 ◽  
Vol 6 (5-6) ◽  
pp. 323-326 ◽  
Author(s):  
A. Serraf ◽  
J-P. Gascard ◽  
J. Bruniaux ◽  
C. Labat ◽  
C. Planche ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Congenital Heart Defects ◽  
Pulmonary Blood Flow ◽  
Congenital Heart ◽  
Heart Defects ◽  
Blood Levels ◽  
Blood Samples ◽  
Number Of Patients ◽  
Pulmonary Arterial

The circulating levels of leukotriene E4in infants with congenital heart defects, increased pulmonary blood flow and pulmonary arterial hypertension, were determined and compared with infants with decreased pulmonary blood flow (Tetralogy of Fallot). There was no correlation (r=0.38) between the pulmonary arterial pressure (56 ± 4 mmHg) and the leukotriene E4levels (1.37 ± 0.67 ng/ml blood) measured in peripheral blood samples from the hypertensive group prior to surgery. There was considerable variation in the detectable leukotriene E4levels in blood samples from different patients. The levels detected in the blood samples between the two groups of patients was similar. These data suggest that neither the surgical repair during cardiopulmonary bypass nor the pulmonary hypertension appeared to modify the leukotriene E4blood levels in the small number of patients studied.

Effects of blood flow on lung ACE kinetics: evidence for microvascular recruitment

1991 ◽  
Vol 71 (6) ◽  
pp. 2244-2254 ◽  
Author(s):  
H. J. Toivonen ◽  
J. D. Catravas
Keyword(s):  
Blood Flow ◽  
Pulmonary Blood Flow ◽  
Pulmonary Arterial Pressure ◽  
Left Lung ◽  
In Vivo Assays ◽  
Vascular Bed ◽  
Pulmonary Arterial ◽  
Microvascular Recruitment ◽  
The Relationship

The parameter Amax/Km (product of reactant enzyme mass in perfused microvessels and the constant kcat/Km), calculated from in vivo assays of pulmonary endothelial ectoenzymes (e.g., angiotensin-converting enzyme, ACE), can provide estimates of the perfused pulmonary microvascular surface area (PMSA) in the absence of enzyme dysfunction. We examined the relationship between PMSA and pulmonary blood flow (Qb) in anesthetized rabbits placed on total heart bypass, using [3H]benzoyl-Phe-Ala-Pro (BPAP) as the ACE substrate. When Qb was increased from 250 to 1,100 ml/min, at zone 3 conditions, pulmonary arterial pressure increased, pulmonary vascular resistance (PVR) decreased, and Amax/Km increased linearly, reflecting increasing PMSA. When only the left lung was perfused, increasing Qb from 250 to 636 +/- 17 ml/min (the last value representing fully recruited and/or distended vascular bed), PVR decreased, while Amax/Km increased. When Qb was further increased to 791 +/- 44 ml/min, both PVR and Amax/Km remained unchanged, confirming the lack of additional changes in PMSA. We conclude that Amax/Km provides a sensitive indication of PMSA, because it 1) increases with increasing Qb and decreasing PVR, 2) reaches a maximum at Qb values that correspond to the minimal values in PVR, and 3) like PVR, did not change with further increases in Qb. Compared with predicted changes in PMSA produced by either microvascular recruitment alone or distension alone, our data indicate that recruitment is a larger contributor to the observed increase in PMSA.

Acetylcholine increases pulmonary blood flow in intact fetuses via endothelium-dependent vasodilation

1992 ◽  
Vol 262 (2) ◽  
pp. H406-H410 ◽  
Author(s):  
M. H. Tiktinsky ◽  
J. J. Cummings ◽  
F. C. Morin
Keyword(s):  
Blood Flow ◽  
Pulmonary Blood Flow ◽  
Pulmonary Arterial Pressure ◽  
Control Protocol ◽  
Relaxing Factor ◽  
Fetal Lamb ◽  
Pulmonary Arterial ◽  
Endothelium Derived Relaxing Factor ◽  
Near Term

In vitro, acetylcholine causes vasodilation by releasing endothelium-derived relaxing factor (EDRF) from endothelial cells. EDRF may be nitric oxide, derived from the amino acid L-arginine (L-Arg), by a process that is inhibited by NG-monomethyl-L-arginine (L-NMMA) and restored by L-Arg. We studied the effect of L-NMMA and L-Arg on the increase in pulmonary blood flow caused by acetylcholine in unanesthetized intrauterine near-term fetal lambs. Three protocols were employed. In each protocol, acetylcholine (0.48 +/- 0.15 micrograms/kg) was injected at 15-min intervals for 120 min. In the control protocol, nothing else was given. In the second protocol, L-NMMA (14 +/- 5 mg/kg) was given at 35 min. In the third protocol, L-NMMA was given at 35 min followed by L-Arg (138 +/- 73 mg/kg) at 80 min. In the control protocol, acetylcholine increased pulmonary blood flow 179 +/- 17% while it decreased pulmonary arterial pressure 15 +/- 1% and did not affect left atrial pressure. The response to each injection lasted less than 1 min and did not change throughout the experiment. L-NMMA completely blocked, whereas L-Arg completely restored, the effect of acetylcholine on pulmonary blood flow. We conclude that acetylcholine increases pulmonary blood flow in the fetal lamb via the release of EDRF derived from L-Arg. We speculate that endothelium-dependent vasodilation may play a role in the increase in pulmonary blood flow at birth.

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