Adenosine and hypoxic pulmonary vasodilation

1984 ◽  
Vol 247 (4) ◽  
pp. H541-H547 ◽  
Author(s):  
J. E. Gottlieb ◽  
M. D. Peake ◽  
J. T. Sylvester
Keyword(s):  
Arterial Pressure ◽  
Time Course ◽  
Pulmonary Arterial Pressure ◽  
Autologous Blood ◽  
Systemic Circulation ◽  
Constant Flow ◽  
Pulmonary Vasodilation ◽  
Pulmonary Arterial ◽  
Hypoxic Vasodilation ◽  
Isolated Lungs

We have previously shown that after exposure to an inspired O2 tension less than 25 Torr, isolated lungs perfused with autologous blood exhibit vasoconstriction followed by dilation. Because adenosine has been implicated as a mediator of hypoxic vasodilation in the systemic circulation and because the concentration of adenosine in the lung has been shown to increase with hypoxia, we tested the hypothesis that adenosine is the mediator of hypoxic pulmonary vasodilation. We first confirmed that adenosine was a vasodilator in isolated lungs of adult male ferrets. Next we added the enzyme adenosine deaminase (ADase), which inactivates adenosine by converting it to inosine, to the perfusate before exposure to one of two levels of hypoxia [inspiratory PO2 (PIO2) 18 or 0 Torr]. In comparison with untreated lungs, the time course of pulmonary arterial pressure at constant flow in lungs treated with ADase (24 mg protein or 6,000 U) was not different; however, when the vessels were constricted at PIO2 25 Torr, ADase prevented vasodilator responses to adenosine administered into either the perfusate or the airways, indicating penetration of active ADase into the interstitium. Unless adenosine released endogenously into the interstitium during hypoxia was somehow protected from the ADase which reached the interstitium, these results indicate that hypoxic pulmonary vasodilation was not mediated by adenosine.

L-Arginine, a precursor of EDRF in vitro, produces pulmonary vasodilation in lambs

1991 ◽  
Vol 261 (5) ◽  
pp. H1563-H1569 ◽  
Author(s):  
J. R. Fineman ◽  
R. Chang ◽  
S. J. Soifer
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Phosphodiesterase Inhibitor ◽  
Hemodynamic Effects ◽  
Synthesis Inhibitor ◽  
Pulmonary Vasodilation ◽  
Pulmonary Arterial ◽  
Rate Limiting

There is increasing evidence that resting pulmonary vascular tone is mediated in part by the release of endothelium-derived relaxing factors (EDRF). Because L-arginine may be a precursor for EDRF synthesis, we studied the pulmonary vasodilating effects of L-arginine at rest and during pulmonary hypertension in 16 intact newborn lambs. At rest, the intravenous infusions of L-arginine (150 mg/kg) had no hemodynamic effects. However, during pulmonary hypertension induced by hypoxia or the infusion of U-46619 (a thromboxane A2 mimic), L-arginine decreased pulmonary arterial pressure by 22 and 27%, respectively (P less than 0.05). The decrease in pulmonary arterial pressure produced by L-arginine was blocked by methylene blue, a guanylate cyclase inhibitor, and augmented by Zapranast, a guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor (-17.9 vs. -31.2%, P less than 0.05). In addition, L-arginine partially reversed the pulmonary hypertension induced by N omega-nitro-L-arginine, a competitive EDRF synthesis inhibitor, but D-arginine had no hemodynamic effects. This study suggests that L-arginine produces pulmonary vasodilation by increasing cGMP concentrations, supporting the in vitro hypothesis that L-arginine is a precursor for EDRF synthesis, whose availability may become rate limiting during pulmonary hypertension.

Pulmonary vasodilation to adrenomedullin: a novel peptide in humans

1995 ◽  
Vol 268 (6) ◽  
pp. H2211-H2215 ◽  
Author(s):  
J. Heaton ◽  
B. Lin ◽  
J. K. Chang ◽  
S. Steinberg ◽  
A. Hyman ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Vasomotor Tone ◽  
Pulmonary Vasodilation ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Vasodilator Activity ◽  
Pulmonary Arterial ◽  
Cgrp Receptor Antagonist ◽  
Pulmonary Vascular Bed

The present study investigates the effects of human adrenomedullin (ADM) on the pulmonary vascular bed of isolated, blood-perfused rat lung. Because pulmonary blood flow and left atrial pressure were constant, changes in pulmonary arterial pressure directly reflect changes in pulmonary vascular resistance. Under conditions of resting (low) pulmonary vasomotor tone, intra-arterial bolus injections of ADM-(1-52) and two truncated sequences of ADM-(1-52) [ADM-(1-12) and ADM-(13-52)] did not alter pulmonary arterial pressure. When pulmonary vasomotor tone was increased by U-46619, a thromboxane A2 mimic, intra-arterial bolus injections of ADM-(1-52) and ADM-(13-52) at similar doses produced similar, dose-dependent reductions in pulmonary arterial pressure. On a molar basis, ADM-(1-52) had greater pulmonary vasodilator activity than isoproterenol. In contrast, ADM-(1-12) had no activity. When pulmonary vasomotor tone was actively increased to the same level using KCl, the pulmonary vasodilator activity of ADM-(13-52) was decreased 10-fold. The present data demonstrate that ADM-(1-52) dilates the pulmonary vascular bed and suggest that the pulmonary vasodilator activity of ADM is greater on pulmonary blood vessels preconstricted through a receptor-dependent mechanism. Because meclofenamate, nitro-L-arginine methyl ester, methysergide, BW A-1433U83, U-37883A, and calcitonin gene-related peptide [CGRP-(8-37)], a CGRP-receptor antagonist, did not alter the pulmonary vasodilator response to ADM-(1-52), the present data suggest that ADM dilates the pulmonary vascular bed independently of cyclooxygenase products, endothelium-derived relaxation factor, serotoninergic receptors, adenosine1 purinoreceptors, ATP-dependent potassium channels, and CGRP receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

N omega-nitro-L-arginine attenuates endothelium-dependent pulmonary vasodilation in lambs

1991 ◽  
Vol 260 (4) ◽  
pp. H1299-H1306 ◽  
Author(s):  
J. R. Fineman ◽  
M. A. Heymann ◽  
S. J. Soifer
Keyword(s):  
Arterial Pressure ◽  
Sodium Nitroprusside ◽  
Vascular Tone ◽  
Pulmonary Arterial Pressure ◽  
Competitive Inhibitor ◽  
Pulmonary Vasodilation ◽  
Pulmonary Arterial ◽  
Spontaneously Breathing ◽  
Dose Dependent Increase

To investigate the role of endothelium-derived relaxing factor (EDRF) in the regulation of resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation, we studied the hemodynamic effects of N omega-nitro-L-arginine (a new stereospecific EDRF inhibitor) in 10 spontaneously breathing lambs and then compared the hemodynamic responses to five vasodilators during pulmonary hypertension induced by the infusion of U-46619 (a thromboxane A2 mimetic) or N omega-nitro-L-arginine. N omega-nitro-L-arginine caused a significant dose-dependent increase in pulmonary arterial pressure. Pretreatment with L-arginine blocked this increase, but pretreatment with D-arginine did not, suggesting that N omega-nitro-L-arginine is a competitive inhibitor of L-arginine for EDRF production. During U-46619 infusions, acetylcholine, ATP-MgCl2, isoproterenol, sodium nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) decreased pulmonary arterial pressure. During N omega-nitro-L-arginine infusions, the decrease in pulmonary arterial pressure caused by acetylcholine and ATP-MgCl2 (endothelium-dependent vasodilators) was significantly attenuated, but the decrease caused by isoproterenol, sodium nitroprusside, and 8-bromo-cGMP (endothelium-independent vasodilators) was unchanged. This study supports the hypothesis that EDRF in part mediates resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation. N omega-nitro-L-arginine is useful for studying EDRF inhibition in intact animals.

Flow through zone 1 lungs utilizes alveolar corner vessels

1991 ◽  
Vol 70 (4) ◽  
pp. 1518-1523 ◽  
Author(s):  
W. J. Lamm ◽  
K. R. Kirk ◽  
W. L. Hanson ◽  
W. W. Wagner ◽  
R. K. Albert
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Left Lung ◽  
Lateral Position ◽  
Double Lumen Endotracheal Tube ◽  
Mean Pulmonary Arterial Pressure ◽  
Flow Through ◽  
Pulmonary Arterial ◽  
Isolated Lungs

We have previously observed flows equivalent to 15% of the resting cardiac output of rabbits occurring through isolated lungs that were completely in zone 1. To distinguish between alveolar corner vessels and alveolar septal vessels as a possible zone 1 pathway, we made in vivo microscopic observations of the subpleural alveolar capillaries in five anesthetized dogs. Videomicroscopic recordings were made via a transparent thoracic window with the animal in the right lateral position. From recordings of the uppermost surface of the left lung, alveolar septal and corner vessels were classified depending on whether they were located within or between alveoli, respectively. Observations were made with various levels of positive end-expiratory pressure (PEEP) applied only to the left lung via a double-lumen endotracheal tube. Consistent with convention, flow through septal vessels stopped when PEEP was raised to the mean pulmonary arterial pressure (the zone 1-zone 2 border). However, flow through alveolar corner vessels continued until PEEP was 8-16 cmH2O greater than mean pulmonary arterial pressure (8-16 cm into zone 1). These direct observations support the idea that alveolar corner vessels rather than patent septal vessels provide the pathway for blood flow under zone 1 conditions.

Effect of chronic hypoxia on pulmonary vascular pressures in isolated lungs of newborn pigs

1994 ◽  
Vol 77 (6) ◽  
pp. 2853-2862 ◽  
Author(s):  
C. D. Fike ◽  
M. R. Kaplowitz
Keyword(s):  
Smooth Muscle ◽  
Arterial Pressure ◽  
Chronic Hypoxia ◽  
Pulmonary Arterial Pressure ◽  
Muscle Tone ◽  
Before And After ◽  
Alveolar Hypoxia ◽  
Pulmonary Arterial ◽  
Newborn Pigs ◽  
Isolated Lungs

Our purposes were to determine whether chronic alveolar hypoxia altered pulmonary vascular pressures in lungs of newborn pigs, evaluate the contribution of smooth muscle tone to alterations in pulmonary vascular pressures, and examine whether chronic hypoxia altered pulmonary vascular reactivity to acute hypoxia. We kept 24- to 72-h-old pigs in chambers filled with room air (control) or 11–12% O2 (chronic hypoxia) for either 3–5 (short) or 10–12 (long) days. We used isolated lungs and applied micropuncture and vascular occlusion techniques to measure pressure in 10- to 30-microns-diam venules and inflow occlusion and outflow occlusion pressures before and after the addition of the smooth muscle dilator papaverine or before and after inflation of the lungs with a hypoxic gas mixture. For pigs in both the short and long groups, pulmonary arterial pressure was the only vascular pressure that was greater in chronically hypoxic than in control lungs. Increased smooth muscle tone was the primary source of the change in pulmonary arterial pressure with short hypoxia, whereas morphometric changes contributed to the change in pulmonary arterial pressure with long hypoxia. Exposure of newborn pigs to different lengths of alveolar hypoxia is a useful model to study postnatal pulmonary hypertension in newborns and infants.

Fetal pulmonary vasodilation after exogenous platelet-activating factor

1991 ◽  
Vol 70 (2) ◽  
pp. 778-787 ◽  
Author(s):  
F. J. Accurso ◽  
S. H. Abman ◽  
R. B. Wilkening ◽  
G. S. Worthen ◽  
P. Henson
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Ductus Arteriosus ◽  
Platelet Activating Factor ◽  
Vena Cava ◽  
Arterial Blood Flow ◽  
High Dose ◽  
Pulmonary Vasodilation ◽  
Arterial Blood ◽  
Pulmonary Arterial

To determine the fetal pulmonary vascular response to platelet-activating factor (PAF), we studied the hemodynamic effects of the infusion of PAF directly into the left pulmonary artery in 21 chronically catheterized fetal lambs. Left pulmonary arterial blood flow (Q) was measured with electromagnetic flow transducers. Ten-minute infusions of low-dose PAF (10-100 ng/min) produced increases in Q from a baseline of 71 +/- 5 to 207 +/- 20 ml/min (P less than 0.001) without changes in pulmonary arterial pressure. Pulmonary vasodilation with PAF was further confirmed through increases in Q with brief (15-s) infusions and increases in the slope of the pressure-flow relationship as assessed by rapid incremental compressions of the ductus arteriosus during PAF infusion. Infusion of Lyso-PAF had no effect on Q or pulmonary arterial pressure. Treatment with CV-3988, a selective PAF receptor antagonist, but not with meclofenamate, atropine, or diphenhydramine and cimetidine blocked the response to PAF infusion and did not affect baseline tone. Systemic infusion of high-dose PAF (300 ng/min) through the fetal inferior vena cava increased pulmonary arterial pressure (46.5 +/- 1.0 to 54.8 +/- 1.9 mmHg, P less than 0.01) and aorta pressure (44.3 +/- 1.0 to 52.7 +/- 2.2 mmHg, P less than 0.01) while also increasing Q. Neither PAF nor CV-3988 changed the gradient between pulmonary arterial and aorta pressures, suggesting that PAF does not affect ductal tone. We conclude that PAF is a potent fetal pulmonary vasodilator and that the effects are not mediated through cyclooxygenase products or by cholinergic or histaminergic effects.

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.

Selective pulmonary vasodilation with ATP-MgCl2 during pulmonary hypertension in lambs

1990 ◽  
Vol 69 (5) ◽  
pp. 1836-1842 ◽  
Author(s):  
J. R. Fineman ◽  
M. R. Crowley ◽  
S. J. Soifer
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Systemic Arterial Pressure ◽  
Pulmonary Vasodilation ◽  
Potent Vasodilator ◽  
Pulmonary Arterial ◽  
Dose Dependent Decrease ◽  
High Doses ◽  
Dose Dependent

We investigated the effects of infusions of ATP-MgCl2 on the circulation in 11 spontaneously breathing newborn lambs during pulmonary hypertension induced either by the infusion of U-46619, a thromboxane A2 mimetic, or by hypoxia. During pulmonary hypertension induced by U-46619, ATP-MgCl2 (0.01-1.0 mg.kg-1.min-1) caused a significant dose-dependent decrease in pulmonary arterial pressure (12.4-40.7%, P less than 0.05), while systemic arterial pressure decreased only at the highest doses (P less than 0.05). Left atrial infusions of ATP-MgCl2 caused systemic hypotension without decreasing pulmonary arterial pressure. During hypoxia-induced pulmonary hypertension, ATP-MgCl2 caused a similar significant dose-dependent decrease in pulmonary arterial pressure (12.0-41.1%, P less than 0.05), while systemic arterial pressure decreased only at high doses (P less than 0.05). Regression analysis showed selectivity of the vasodilating effects of ATP-MgCl2 for the pulmonary circulation during pulmonary hypertension induced either by U-46619 or hypoxia. ATP-MgCl2 is a potent vasodilator with a rapid metabolism that allows for selective vasodilation of the vascular bed first encountered (pulmonary or systemic). We conclude that infusions of ATP-MgCl2 may be clinically useful in the treatment of children with pulmonary hypertension.

Pulmonary vascular response to endothelin in rats

1991 ◽  
Vol 70 (2) ◽  
pp. 567-574 ◽  
Author(s):  
B. Raffestin ◽  
S. Adnot ◽  
S. Eddahibi ◽  
I. Macquin-Mavier ◽  
P. Braquet ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Vascular Resistance ◽  
Systemic Circulation ◽  
Systemic Arterial Pressure ◽  
Vascular Response ◽  
Autonomic Blockade ◽  
Initial Drop ◽  
Pulmonary Arterial ◽  
Isolated Lungs ◽  
Dose Dependent Increase

This study investigated the pulmonary vascular response to endothelin (ET) in rats. In conscious rats, an incremental intravenous bolus of ET-1 (100-1,000 pM) caused, after an initial drop in systemic arterial pressure (Psa), a secondary dose-dependent increase of Psa concomitant with a decrease of cardiac output (CO) and heart rate (HR). Pulmonary arterial pressure (Ppa) remained unchanged, and pulmonary vascular resistance (PVR) increased significantly only after 1,000 pM (+ 40.0 +/- 10.4 at 15 min). Meclofenamate (6 mg/kg iv) did not alter hemodynamic response to ET (300 pM). After autonomic blockade with hexamethonium (6 mg/kg iv) plus atropine (0.75 mg/kg iv), bradycardia response to ET (300 pM) was blocked, but CO decreased, systemic vascular resistance increased, and PVR remained unchanged as in controls. In anesthetized ventilated rats, bolus injections of ET (10-1,000 pM) induced a transient dose-related decrease in compliance (-10.9 +/- 1.8% after 1,000 pM) but no change of conductance. In isolated lungs, Ppa increased at doses greater than 100 pM, and edema developed in response to 1,000 pM ET. The rise of Ppa in response to 300 pM was not altered by meclofenamate (3.2 x 10(-6) M) but was potentiated by inhibitors of endothelium-derived relaxing factor(s) (EDRF), methylene blue (10(-4) M), pyrogallol (3 x 10(-5) M), and NG-monomethyl-L-arginine (6 x 10(-4) M) (3.9 +/- 0.3, 4.6 +/- 0.5, and 5.9 +/- 0.3 mmHg, respectively, compared with 1.5 +/- 0.5 mmHg in control lungs). These results suggest that circulating ET is a more potent constrictor of the systemic circulation than of the pulmonary vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo attenuation of endothelium-dependent pulmonary vasodilation by methylene blue

1991 ◽  
Vol 71 (2) ◽  
pp. 735-741 ◽  
Author(s):  
J. R. Fineman ◽  
M. R. Crowley ◽  
M. A. Heymann ◽  
S. J. Soifer
Keyword(s):  
Methylene Blue ◽  
Smooth Muscle ◽  
Arterial Pressure ◽  
Guanylate Cyclase ◽  
Vascular Tone ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Vasodilation ◽  
Pulmonary Arterial

In vitro evidence suggests that resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation are mediated by changes in vascular smooth muscle concentrations of guanosine 3′,5′-cyclic monophosphate (cGMP). We investigated this hypothesis in vivo in 19 mechanically ventilated intact lambs by determining the hemodynamic effects of methylene blue (a guanylate cyclase inhibitor) and then by comparing the hemodynamic response to five vasodilators during pulmonary hypertension induced by the infusion of U-46619 (a thromboxane A2 mimic) or methylene blue. Methylene blue caused a significant time-dependent increase in pulmonary arterial pressure. During U-46619 infusions, acetylcholine, ATP-MgCl2, sodium nitroprusside, isoproterenol, and 8-bromo-cGMP decreased pulmonary arterial pressure. During methylene blue infusions, the decreases in pulmonary arterial pressure caused by acetylcholine and ATP-MgCl2 (endothelium-dependent vasodilators) and sodium nitroprusside (an endothelium-independent guanylate cyclase-dependent vasodilator) were attenuated by greater than 50%. The decreases in pulmonary arterial pressure caused by isoproterenol and 8-bromo-cGMP (endothelium-independent vasodilators) were unchanged. This study in intact lambs supports the in vitro evidence that changes in vascular smooth muscle cell concentrations of cGMP in part mediate resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation.

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