Ontogeny of NO activity and response to inhaled NO in the developing ovine pulmonary circulation

1994 ◽  
Vol 267 (5) ◽  
pp. H1955-H1961 ◽  
Author(s):  
J. P. Kinsella ◽  
D. D. Ivy ◽  
S. H. Abman
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Circulation ◽  
Hemodynamic Effects ◽  
Fetal Sheep ◽  
Pulmonary Vasodilation ◽  
Ovine Fetus ◽  
Pulmonary Arterial ◽  
Inhaled No

To determine maturation-related changes in nitric oxide (NO) activity in the developing pulmonary circulation, we studied the hemodynamic effects of endogenous NO inhibition under basal conditions in the premature ovine fetus and the response to birth-related stimuli and exogenous NO in 30 fetal sheep at three different gestational ages. At 0.95 term, pulmonary vasodilation during inhaled NO (20 parts per million) was equivalent to the dilator response to 100% O2, but at 0.86 term vasodilation during inhaled NO was greater than the dilator response to 100% O2 (P < 0.05). At 0.78 term, left pulmonary arterial flow (QLPA) did not increase with exposure to either NO or 100% O2. Intrapulmonary infusion of nitro-L-arginine (L-NA) increased basal pulmonary vascular resistance 38% in the premature fetus at 0.78 term. L-NA treatment decreased the ventilation-induced rise in QLPA by 60% compared with controls (P < 0.05). Inhaled NO but not 100% O2 increased QLPA after L-NA treatment to levels achieved with ventilation alone in the controls. We conclude that in the premature pulmonary circulation (0.78 term) 1) basal pulmonary vascular resistance is modulated by endogenous NO, 2) pulmonary vasodilation at birth is partly mediated by endogenous NO activity, and 3) inhaled NO causes potent vasodilation.

Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension

1998 ◽  
Vol 84 (2) ◽  
pp. 435-441 ◽  
Author(s):  
Christophe Adrie ◽  
Fumito Ichinose ◽  
Alexandra Holzmann ◽  
Larry Keefer ◽  
William E. Hurford ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Vascular Resistance ◽  
Pulmonary Circulation ◽  
Half Life ◽  
Hemodynamic Effects ◽  
Pulmonary Vasodilation ◽  
Short Half Life ◽  
Acute Pulmonary Hypertension ◽  
Inhaled No

Adrie, Christophe, Fumito Ichinose, Alexandra Holzmann, Larry Keefer, William E. Hurford, and Warren M. Zapol. Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension. J. Appl. Physiol. 84(2): 435–441, 1998.—Sodium 1-( N, N-diethylamino)diazen-1-ium-1,2-diolate {DEA/NO; Et2N[N(O)NO]Na} is a compound that spontaneously generates nitric oxide (NO). Because of its short half-life (2.1 min), we hypothesized that inhaling DEA/NO aerosol would selectively dilate the pulmonary circulation without decreasing systemic arterial pressure. We compared the pulmonary selectivity of this new NO donor with two other reference drugs: inhaled NO and inhaled sodium nitroprusside (SNP). In seven awake sheep with pulmonary hypertension induced by the infusion of U-46619, we compared the hemodynamic effects of DEA/NO with those of incremental doses of inhaled NO gas. In seven additional awake sheep, we examined the hemodynamic effects of incremental doses of inhaled nitroprusside (i.e., SNP). Inhaled NO gas selectively dilated the pulmonary vasculature. Inhaled DEA/NO produced nonselective vasodilation; both systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were reduced. Inhaled SNP selectively dilated the pulmonary circulation at low concentrations (≤10−2 M), inducing a decrease of PVR of up to 42% without any significant decrease of SVR (−5%), but nonselectively dilated the systemic circulation at larger doses (>10−2 M). In conclusion, despite its short half-life, DEA/NO is not a selective pulmonary vasodilator compared with inhaled NO. Inhaled SNP appears to be selective to the pulmonary circulation at low doses but not at higher levels.

Selective Pulmonary Vasodilation by Intravenous Infusion of an Ultrashort Half-life Nucleophile/Nitric Oxide Adduct 

1998 ◽  
Vol 88 (1) ◽  
pp. 190-195 ◽  
Author(s):  
Christophe Adrie ◽  
Mona W. Hirani ◽  
Alexandra Holzmann ◽  
Larry Keefer ◽  
Warren M. Zapol ◽  
...  
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Circulation ◽  
Half Life ◽  
Pulmonary Vasculature ◽  
Prostaglandin F2alpha ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasodilator ◽  
Healthy Sheep ◽  
Inhaled No

Background PROLI/NO (C5H7N3O4Na2 x CH3OH) is an ultrashort-acting nucleophile/NO adduct that generates NO (half-life 2 s at 37 degrees C and pH 7.4). Because of its short half-life, the authors hypothesized that intravenous administration of this compound would selectively dilate the pulmonary vasculature but cause little or no systemic hypotension. Methods In eight awake healthy sheep with pulmonary hypertension induced by 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F2alpha, the authors compared PROLI/NO with two reference drugs-inhaled NO, a well-studied selective pulmonary vasodilator, and intravenous sodium nitroprusside (SNP), a nonselective vasodilator. Sheep inhaled 10, 20, 40, and 80 parts per million NO or received intravenous infusions of 0.25, 0.5, 1, 2, and 4 microg x kg-1 x min-1 of SNP or 0.75, 1.5, 3, 6, and 12 microg x kg-1 x min-1 of PROLI/NO. The order of administration of the vasoactive drugs (NO, SNP, PROLI/NO) and their doses were randomized. Results Inhaled NO selectively dilated the pulmonary vasculature. Intravenous SNP induced nonselective vasodilation of the systemic and pulmonary circulation. Intravenous PROLI/NO selectively vasodilated the pulmonary circulation at doses up to 6 microg x kg-1 x min-1, which decreased pulmonary vascular resistance by 63% (P &lt; 0.01) from pulmonary hypertensive baseline values without changing systemic vascular resistance. At 12 microg x kg-1 x min-1, PROLI/NO decreased systemic and pulmonary vascular resistance and pressure. Exhaled NO concentrations were higher during PROLI/NO infusion than during SNP infusion (P &lt; 0.01 with all data pooled). Conclusions The results suggest that PROLI/NO could be a useful intravenous drug to vasodilate the pulmonary circulation selectively.

scholarly journals Inhaled Nitric Oxide at Birth Reduces Pulmonary Vascular Resistance and Improves Oxygenation in Preterm Lambs

Children ◽  
2021 ◽  
Vol 8 (5) ◽  
pp. 378
Author(s):  
Satyan Lakshminrusimha ◽  
Sylvia F. Gugino ◽  
Krishnamurthy Sekar ◽  
Stephen Wedgwood ◽  
Carmon Koenigsknecht ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Preterm Infants ◽  
Vascular Resistance ◽  
Inhaled Nitric Oxide ◽  
Persistent Pulmonary Hypertension ◽  
Inhaled No ◽  
Birth Preterm

Resuscitation with 21% O2 may not achieve target oxygenation in preterm infants and in neonates with persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (iNO) at birth can reduce pulmonary vascular resistance (PVR) and improve PaO2. We studied the effect of iNO on oxygenation and changes in PVR in preterm lambs with and without PPHN during resuscitation and stabilization at birth. Preterm lambs with and without PPHN (induced by antenatal ductal ligation) were delivered at 134 d gestation (term is 147–150 d). Lambs without PPHN were ventilated with 21% O2, titrated O2 to maintain target oxygenation or 21% O2 + iNO (20 ppm) at birth for 30 min. Preterm lambs with PPHN were ventilated with 50% O2, titrated O2 or 50% O2 + iNO. Resuscitation with 21% O2 in preterm lambs and 50%O2 in PPHN lambs did not achieve target oxygenation. Inhaled NO significantly decreased PVR in all lambs and increased PaO2 in preterm lambs ventilated with 21% O2 similar to that achieved by titrated O2 (41 ± 9% at 30 min). Inhaled NO increased PaO2 to 45 ± 13, 45 ± 20 and 76 ± 11 mmHg with 50% O2, titrated O2 up to 100% and 50% O2 + iNO, respectively, in PPHN lambs. We concluded that iNO at birth reduces PVR and FiO2 required to achieve target PaO2.

Inhaled nitric oxide partially reverses hypoxic pulmonary vasoconstriction in the dog

1994 ◽  
Vol 76 (3) ◽  
pp. 1350-1355 ◽  
Author(s):  
J. A. Romand ◽  
M. R. Pinsky ◽  
L. Firestone ◽  
H. A. Zar ◽  
J. R. Lancaster
Keyword(s):  
Nitric Oxide ◽  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Canine Model ◽  
Systemic Arterial Pressure ◽  
Vasomotor Tone ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial

Nitric oxide (NO) inhaled during a hypoxia-induced increase in pulmonary vasomotor tone decreases pulmonary arterial pressure (Ppa). We conducted this study to better characterize the hemodynamic effects induced by NO inhalation during hypoxic pulmonary vasoconstriction in 11 anesthetized ventilated dogs. Arterial and venous systemic and pulmonary pressures and aortic flow probe-derived cardiac output were recorded, and nitrosylhemoglobin (NO-Hb) and methemoglobin (MetHb) were measured. The effects of 5 min of NO inhalation at 0, 17, 28, 47, and 0 ppm during hyperoxia (inspiratory fraction of O2 = 0.5) and hypoxia (inspiratory fraction of O2 = 0.16) were observed. NO inhalation has no measurable effects during hyperoxia. Hypoxia induced an increase in Ppa that reached plateau levels after 5 min. Exposure to 28 and 47 ppm NO induced an immediate (< 30 s) decrease in Ppa and calculated pulmonary vascular resistance (P < 0.05 each) but did not return either to baseline hyperoxic values. Increasing the concentration of NO to 74 and 145 ppm in two dogs during hypoxia did not induce any further decreases in Ppa. Reversing hypoxia while NO remained at 47 ppm further decreased Ppa and pulmonary vascular resistance to baseline values. NO inhalation did not induce decreases in systemic arterial pressure. MetHb remained low, and NO-Hb was unmeasurable. We concluded that NO inhalation only partially reversed hypoxia-induced increases in pulmonary vasomotor tone in this canine model. These effects are immediate and selective to the pulmonary circulation.

Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension

1999 ◽  
Vol 277 (5) ◽  
pp. H1849-H1856 ◽  
Author(s):  
Stephen M. Black ◽  
R. Scott Heidersbach ◽  
D. Michael McMullan ◽  
Janine M. Bekker ◽  
Michael J. Johengen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Inhaled Nitric Oxide ◽  
Protein Levels ◽  
Acute Withdrawal ◽  
Inhaled No

Life-threatening increases in pulmonary vascular resistance have been noted on acute withdrawal of inhaled nitric oxide (NO), although the mechanisms remain unknown. In vitro data suggest that exogenous NO exposure inhibits endothelial NO synthase (NOS) activity. Thus the objectives of this study were to determine the effects of inhaled NO therapy and its acute withdrawal on endogenous NOS activity and gene expression in vivo in the intact lamb. Six 1-mo-old lambs were mechanically ventilated and instrumented to measure vascular pressures and left pulmonary blood flow. Inhaled NO (40 ppm) acutely decreased left pulmonary vascular resistance by 27.5 ± 4.7% ( P < 0.05). This was associated with a 207% increase in plasma cGMP concentrations ( P < 0.05). After 6 h of inhaled NO, NOS activity was reduced to 44.3 ± 5.9% of pre-NO values ( P < 0.05). After acute withdrawal of NO, pulmonary vascular resistance increased by 52.1 ± 11.6% ( P < 0.05) and cGMP concentrations decreased. Both returned to pre-NO values within 60 min. One hour after NO withdrawal, NOS activity increased by 48.4 ± 19.1% to 70% of pre-NO values ( P < 0.05). Western blot analysis revealed that endothelial NOS protein levels remained unchanged throughout the study period. These data suggest a role for decreased endogenous NOS activity in the rebound pulmonary hypertension noted after acute withdrawal of inhaled NO.

Pulmonary vasodilator drugs decrease lung liquid production in fetal sheep

1995 ◽  
Vol 79 (4) ◽  
pp. 1212-1218 ◽  
Author(s):  
J. J. Cummings
Keyword(s):  
Blood Flow ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Blood Flow ◽  
Fetal Lung ◽  
Prostaglandin D2 ◽  
Fetal Sheep ◽  
Pulmonary Vasodilator ◽  
Pulmonary Arterial ◽  
Lung Liquid

To examine a potential relationship between pulmonary vasodilatation and fetal lung liquid production, I measured lung liquid production in 20 fetal sheep at 130 +/- 4 days gestation while using several agents known to increase pulmonary blood flow. Thirty-two studies were done in which left pulmonary arterial flow (Qlpa) was measured by an ultrasonic Doppler flow probe and net lung luminal liquid production (Jv) was measured by plotting the change in lung luminal liquid concentration of radiolabeled albumin, an impermeant tracer that was mixed into the lung liquid at the start of each study. Qlpa and Jv were measured during a 1- to 2-h baseline period and then during a 1- to 2-h infusion period in which the fetuses received either an intravenous infusion of acetylcholine (n = 8), prostaglandin D2 (n = 10), or the leukotriene blocker FPL-55712 (n = 7). These vasodilators work by different mechanisms, each mechanism having been implicated in the decrease in pulmonary vascular resistance seen at birth. Control (saline) infusions (n = 7) caused no change in either Qlpa or Jv over 4 h. All vasodilator agents significantly increased pulmonary blood flow and decreased Jv. Pulmonary arterial pressure did not change significantly in either the control, acetylcholine, prostaglandin, or leukotriene-blocker studies, indicating that pulmonary vascular resistance decreased. Thus agents that increase pulmonary blood flow by mechanisms that occur at birth also decrease lung liquid production in fetal lambs.

Effect of high intra-alveolar O2 tensions on pulmonary circulation in perfused lungs of dogs

1965 ◽  
Vol 208 (1) ◽  
pp. 130-138 ◽  
Author(s):  
G. J. A. Cropp
Keyword(s):  
Blood Flow ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Circulation ◽  
Time Course ◽  
Systemic Circulation ◽  
The Body ◽  
Arterial Blood ◽  
Pulmonary Parenchyma ◽  
Pulmonary Arterial

The resistance to blood flow in the pulmonary circulation of dogs (PVR) increased when their lungs were ventilated with 95–100% oxygen and were perfused with blood that recirculated only through the pulmonary circulation; the systemic circulation was perfused independently. This increase in PVR occurred even when nerves were cut or blocked but was abolished by inhaled isopropylarterenol aerosol. Elevation of intra-alveolar Po2 without increase in pulmonary arterial blood Po2 was sufficient to increase pulmonary vascular resistance. The pulmonary venules or veins were thought to be the likely site of the constriction. These reactions were qualitatively similar to those produced by injection of serotonin or histamine into the pulmonary circulation. The time course of the response and failure to obtain it when the blood was perfused through the remainder of the body before it re-entered the pulmonary circulation are compatible with a theory that high intra-alveolar O2 tension activates a vasoconstrictor material in the pulmonary parenchyma.

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.

Pregnancy blunts pulmonary vascular reactivity in dogs

1980 ◽  
Vol 239 (3) ◽  
pp. H297-H301 ◽  
Author(s):  
L. G. Moore ◽  
J. T. Reeves
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Circulation ◽  
Vascular Reactivity ◽  
Pulmonary Arterial Pressure ◽  
Acute Hypoxia ◽  
Limited Data ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Arterial

Pregnancy decreases systemic vascular reactivity but comparatively little is known about the effects of pregnancy on the pulmonary circulation. Pulmonary vascular resistance (PVR) during acute hypoxia was lower (P < 0.01) in eight intact anesthetized pregnant dogs compared to the same animals postpartum. Mean pulmonary arterial pressure (Ppa) and PVR during infusion of prostaglandin (PG) F2 alpha were also reduced during pregnancy. Nonpregnant female dogs (n = 5) treated with estrogen (0.001 mg x kg-1 x da-1) for 2 wk had decreased Ppa (P < 0.01) during acute hypoxia compared to control measurements, but PVR was unchanged during hypoxia and PGF2 alpha infusion. Treatment with progesterone in four dogs had no effect on pulmonary vascular reactivity to hypoxia or PGF2 alpha. Inhibition of circulating PG with meclofenamate in four dogs during pregnancy did not appear to restore pulmonary vascular reactivity. Blunted pulmonary vascular reactivity is suggested by the limited data available for women, but is not seen in pregnant cows. We conclude that pregnancy decreases pulmonary as well as systemic vascular reactivity in the dog, but the mechanism is unclear.

scholarly journals Pulmonary vascular resistance and compliance relationship in pulmonary hypertension

2015 ◽  
Vol 46 (4) ◽  
pp. 1178-1189 ◽  
Author(s):  
Denis Chemla ◽  
Edmund M.T. Lau ◽  
Yves Papelier ◽  
Pierre Attal ◽  
Philippe Hervé
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Circulation ◽  
Arterial Compliance ◽  
Pulmonary Arteries ◽  
Transpulmonary Pressure ◽  
Total Arterial Compliance ◽  
Arterial Load ◽  
Pulmonary Arterial

Right ventricular adaptation to the increased pulmonary arterial load is a key determinant of outcomes in pulmonary hypertension (PH). Pulmonary vascular resistance (PVR) and total arterial compliance (C) quantify resistive and elastic properties of pulmonary arteries that modulate the steady and pulsatile components of pulmonary arterial load, respectively. PVR is commonly calculated as transpulmonary pressure gradient over pulmonary flow and total arterial compliance as stroke volume over pulmonary arterial pulse pressure (SV/PApp). Assuming that there is an inverse, hyperbolic relationship between PVR and C, recent studies have popularised the concept that their product (RC-time of the pulmonary circulation, in seconds) is “constant” in health and diseases. However, emerging evidence suggests that this concept should be challenged, with shortened RC-times documented in post-capillary PH and normotensive subjects. Furthermore, reported RC-times in the literature have consistently demonstrated significant scatter around the mean. In precapillary PH, the true PVR can be overestimated if one uses the standard PVR equation because the zero-flow pressure may be significantly higher than pulmonary arterial wedge pressure. Furthermore, SV/PApp may also overestimate true C. Further studies are needed to clarify some of the inconsistencies of pulmonary RC-time, as this has major implications for our understanding of the arterial load in diseases of the pulmonary circulation.

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