Platelet antiserum inhibits hypoxic pulmonary vasoconstriction in the dog

1976 ◽  
Vol 41 (2) ◽  
pp. 211-215 ◽  
Author(s):  
E. K. Weir ◽  
J. Mlczoch ◽  
J. Seavy ◽  
J. J. Cohen ◽  
R. F. Grover
Keyword(s):  
Platelet Count ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxic Response ◽  
Pulmonary Vasoconstriction ◽  
Vasoconstrictor Response ◽  
Hypoxic Vasoconstriction ◽  
Prior Administration ◽  
Temporary Inhibition

The literature suggests that platelets might help mediate the pulmonary vascular pressor response to hypoxia. This study evaluated the hypoxic response in dogs rendered acutely thrombocytopenic by the administration of platelet antiserum. Between 30 and 90 min after the antiserum the pulmonary vasoconstrictor response to hypoxia was virtually abolished, but subsequently returned at a time when the number of circulating platelets remained very low. The prior administration of meclofenamate completely preserved the hypoxic response, though the platelet count still fell precipitously. We conclude that circulating platelets are not necessary for hypoxic vasoconstriction. It is possible that the reaction between platelets and antiserum evokes the synthesis of a dilator prostaglandin which might be responsible for the temporary inhibition of the pressor response to hypoxia but this remains to be proven.

Does leukotriene C4 mediate hypoxic vasoconstriction in isolated ferret lungs?

1990 ◽  
Vol 68 (1) ◽  
pp. 253-259 ◽  
Author(s):  
C. M. Tseng ◽  
M. McGeady ◽  
T. Privett ◽  
A. Dunn ◽  
J. T. Sylvester
Keyword(s):  
Pulmonary Arterial Pressure ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Physiological Salt Solution ◽  
Leukotriene C4 ◽  
Prostaglandin F2 Alpha ◽  
Pulmonary Vasoconstriction ◽  
Vasoconstrictor Response ◽  
Hypoxic Vasoconstriction ◽  
Pulmonary Arterial

To evaluate leukotriene (LT) C4 as a mediator of hypoxic pulmonary vasoconstriction, we examined the effects of FPL55712, a putative LT antagonist, and indomethacin, a cyclooxygenase inhibitor, on vasopressor responses to LTC4 and hypoxia (inspired O2 tension = 25 Torr) in isolated ferret lungs perfused with a constant flow (50 ml.kg-1.min-1). Pulmonary arterial injections of LTC4 caused dose-related increases in pulmonary arterial pressure during perfusion with physiological salt solution containing Ficoll (4 g/dl). FPL55712 caused concentration-related inhibition of the pressor response to LTC4 (0.6 micrograms). Although 10 micrograms/ml FPL55712 inhibited the LTC4 pressor response by 61%, it did not alter the response to hypoxia. At 100 microgram/ml, FPL55712 inhibited the responses to LTC4 and hypoxia by 73 and 71%, respectively, but also attenuated the vasoconstrictor responses to prostaglandin F2 alpha (78% at 8 micrograms), phenylephrine (68% at 100 micrograms), and KCl (51% at 40 mM). At 0.5 microgram/ml, indomethacin significantly attenuated the pressor response to arachidonic acid but did not alter responses to LTC4 or hypoxia. These results suggest that in isolated ferret lungs 1) the vasoconstrictor response to LTC4 did not depend on release of cyclooxygenase products and 2) LTC4 did not mediate hypoxic vasoconstriction.

NO and reactive oxygen species are involved in biphasic hypoxic vasoconstriction of isolated rabbit lungs

2001 ◽  
Vol 280 (4) ◽  
pp. L638-L645 ◽  
Author(s):  
Norbert Weissmann ◽  
Stefan Winterhalder ◽  
Matthias Nollen ◽  
Robert Voswinckel ◽  
Karin Quanz ◽  
...  
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Oxidase Inhibitor ◽  
No Formation ◽  
Vasoconstrictor Response ◽  
Hypoxic Vasoconstriction ◽  
Chronic Pulmonary Hypertension ◽  
Alveolar Hypoxia ◽  
Pulmonary Arterial ◽  
Synthase Inhibitor

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventilation but may also result in chronic pulmonary hypertension. It has not been clarified whether acute HPV and the response to prolonged alveolar hypoxia are triggered by identical mechanisms. We characterized the vascular response to sustained hypoxic ventilation (3% O2for 120–180 min) in isolated rabbit lungs. Hypoxia provoked a biphasic increase in pulmonary arterial pressure (PAP). Persistent PAP elevation was observed after termination of hypoxia. Total blockage of lung nitric oxide (NO) formation by N G-monomethyl-l-arginine caused a two- to threefold amplification of acute HPV, the sustained pressor response, and the loss of posthypoxic relaxation. This amplification was only moderate when NO formation was partially blocked by the inducible NO synthase inhibitor S-methylisothiourea. The superoxide scavenger nitro blue tetrazolium and the superoxide dismutase inhibitor triethylenetetramine reduced the initial vasoconstrictor response, the prolonged PAP increase, and the loss of posthypoxic vasorelaxation to a similar extent. The NAD(P)H oxidase inhibitor diphenyleneiodonium nearly fully blocked the late vascular responses to hypoxia in a dose that effected a decrease to half of the acute HPV. In conclusion, as similarly suggested for acute HPV, lung NO synthesis and the superoxide-hydrogen peroxide axis appear to be implicated in the prolonged pressor response and the posthypoxic loss of vasorelaxation in perfused rabbit lungs undergoing 2–3 h of hypoxic ventilation.

Effects of ouabain, low K+, and aldosterone on hypoxic pressor reactivity of rat lungs

1985 ◽  
Vol 248 (1) ◽  
pp. H55-H60 ◽  
Author(s):  
J. Herget ◽  
I. F. McMurtry
Keyword(s):  
Angiotensin Ii ◽  
Energy Metabolism ◽  
Atpase Activity ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Response Curves ◽  
Hypoxic Response ◽  
Rat Lungs ◽  
Hypoxic Vasoconstriction ◽  
Low K

It can be postulated that inhibition of lung tissue Na+-K+-ATPase might potentiate hypoxic pulmonary vasoconstriction by depolarizing some excitable cell or, in contrast, that it might blunt the hypoxic response by reducing cellular metabolic rate and sensitivity to hypoxia. Thus the purpose of this study was to test in isolated rat lungs whether hypoxic pressor reactivity was related inversely or positively to Na+-K+-ATPase activity. Dose-pressor response curves to hypoxia, angiotensin II, or KCl were measured under control conditions and after exposure either to one of two inhibitors of Na+-K+-ATPase, ouabain, and low-K+ solution or to a stimulator of Na+-K+ pumping, aldosterone. Ouabain and low K+ depressed the response to hypoxia but had little effect on that to angiotensin II. The response to KCl was increased by ouabain. Aldosterone potentiated the hypoxic response. These results do not support the idea that membrane depolarization due to inhibition Na+-K+ pumping is a component of hypoxic vasoconstriction. They do suggest a positive relationship between Na+-K+-ATPase activity and hypoxic pressor reactivity and are consistent with the idea that Na+-K+-ATPase activity might influence hypoxic reactivity indirectly by altering cellular energy metabolism. It is also possible that the results were somehow due to changes in intracellular [Na+] or transmembrane Na+ gradient, rather than to changes in energy metabolism.

Prostaglandin synthetase inhibitors do not decrease hypoxic pulmonary vasoconstriction

1976 ◽  
Vol 41 (5) ◽  
pp. 714-718 ◽  
Author(s):  
E. K. Weir ◽  
I. F. McMurtry ◽  
A. Tucker ◽  
J. T. Reeves ◽  
R. F. Grover
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Prostaglandin Synthesis ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction ◽  
Before And After ◽  
Anesthetized Dogs ◽  
Prostaglandin Antagonists ◽  
The Stability

Prostaglandins are naturally occurring substances with powerful vasoactive effects that are released from tissues during hypoxia or ischemia. Several workers have suggested that a prostaglandin may help to mediate the pulmonary vascular pressor response to alveolar hypoxia. To investigate this possibility, we have measured the pressor responses to hypoxia before and after prostaglandin synthesis antagonism with meclofenamate in eight anesthetized dogs, two groups of awake calves (n=10 and =5), and nine isolated, perfused rat lungs. In addition, synthesis was inhibited by the use of indomethacin in nine additional dogs. The stability of the pulmonary vascular response to repeated hypoxic challenges was demonstrated in nine other dogs. In each species and with both prostaglandin antagonists, the pulmonary pressorresponses to hypoxia were significantly increased rather than reduced. We conclude that prostaglandins do not mediate the pulmonary vasoconstriction caused by hypoxia. The consistent increase observed suggests that hypoxic vasoconstriction stimulates prostaglandin synthesis, the net effect of which is pulmonary vasodilatation which opposes the constriction.

Inhibition of hypoxic pulmonary vasoconstriction by dipyridamole is not platelet mediated

1977 ◽  
Vol 55 (3) ◽  
pp. 448-451 ◽  
Author(s):  
Johannes Mlczoch ◽  
E. Kenneth Weir ◽  
Robert F. Grover
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Drug Treatment ◽  
Direct Effect ◽  
Platelet Function ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxic Response ◽  
Virtual Absence ◽  
Pulmonary Vasoconstriction

Dipyridamole, which is known to alter platelet function, has also been shown to reduce hypoxic pulmonary vasoconstriction. This latter effect could result from dipyridamole either acting on a platelet-mediated system, or acting directly on pulmonary vascular smooth muscle. To investigate these two possibilities, normal dogs were compared with dogs rendered thrombocytopenic by a platelet antiserum. Compared with the hypoxic pressor response before drug treatment, the hypoxic response following dipyridamole was only 32% as great in the normal dogs and only 38% as great in the thrombocytopenic dogs. Thus, dipyridamole was no less effective in reducing the hypoxic pressor response in the virtual absence of platelets. This supports a direct effect of dipyridamole on pulmonary vascular smooth muscle, which could be mediated by an increase in adenosine levels.

Effects of cyclo- and lipoxygenase inhibitors on hypoxic vasoconstriction in isolated ferret lungs

1988 ◽  
Vol 64 (3) ◽  
pp. 936-943 ◽  
Author(s):  
J. E. Gottlieb ◽  
M. McGeady ◽  
N. F. Adkinson ◽  
J. T. Sylvester
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Autologous Blood ◽  
Nordihydroguaiaretic Acid ◽  
Lipoxygenase Inhibitors ◽  
Prostaglandin F2 Alpha ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction

To evaluate the role of leukotrienes in hypoxic pulmonary vasoconstriction, we measured steady-state pressor responses to graded hypoxia in isolated ferret lungs perfused with autologous blood containing 0.001, 0.03, 1, or 3 mM nordihydroguaiaretic acid (NDGA), 1 mM BW 755C, or 0.02-0.05 mM indomethacin. Untreated lungs served as controls. Perfusate concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha, measured by radioimmunoassay, were markedly reduced in all treated lungs, indicating inhibition of cyclooxygenase. The maximum pressor response to hypoxia measured at a blood flow of 50 ml.min-1. kg-1 averaged 26.6 ± 2.4 Torr in untreated lungs and was not affected by BW 755C or 0.001-0.03 mM NDGA. Because BW 755C and NDGA inhibited cyclooxygenase at concentrations that did not affect hypoxic vasoconstriction and because both agents are thought to inhibit lipoxygenase with a potency greater than or equal to that with which they inhibit cyclooxygenase, these results do not support the possibility that hypoxic pulmonary vasoconstriction was mediated by leukotrienes. At concentrations of 1 and 3 mM, NDGA inhibited the maximum hypoxic pressor response by 57 and 95%, respectively. The mechanism of this attenuation is unknown; however, it was apparently not due to cyclooxygenase inhibition, since indomethacin enhanced the maximum hypoxic pressor response by 45%. Nor was it due to blockade of calcium entry or interference with the contractile process in pulmonary vascular smooth muscle, since 1 mM NDGA did not inhibit vasoconstrictor responses to KCl or prostaglandin F2 alpha.

Endothelin-1 is elevated in monocrotaline pulmonary hypertension

1999 ◽  
Vol 276 (2) ◽  
pp. L304-L310 ◽  
Author(s):  
H. Frederick Frasch ◽  
Carol Marshall ◽  
Bryan E. Marshall
Keyword(s):  
Pulmonary Hypertension ◽  
Ventricular Hypertrophy ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
No Production ◽  
Pulmonary Vasoconstriction ◽  
Vasoconstrictor Response ◽  
Before And After ◽  
Nos Inhibitor ◽  
Oxide Synthase

These studies document striking pulmonary vasoconstrictor response to nitric oxide synthase (NOS) inhibition in monocrotaline (MCT) pulmonary hypertension in rats. This constriction is caused by elevated endothelin (ET)-1 production acting on ETA receptors. Isolated, red blood cell plus buffer-perfused lungs from rats were studied 3 wk after MCT (60 mg/kg) or saline injection. MCT-injected rats developed pulmonary hypertension, right ventricular hypertrophy, and heightened pulmonary vasoconstriction to ANG II and the NOS inhibitor N G-monomethyl-l-arginine (l-NMMA). In MCT-injected lungs, the magnitude of the pulmonary pressor response to NOS inhibition correlated strongly with the extent of pulmonary hypertension. Pretreatment of isolated MCT-injected lungs with combined ETA (BQ-123) plus ETB (BQ-788) antagonists or ETA antagonist alone prevented thel-NMMA-induced constriction. Addition of ETA antagonist reversed establishedl-NMMA-induced constriction; ETB antagonist did not. ET-1 concentrations were elevated in MCT-injected lung perfusate compared with sham-injected lung perfusate, but ET-1 levels did not differ before and after NOS inhibition. NOS inhibition enhanced hypoxic pulmonary vasoconstriction in both sham- and MCT-injected lungs, but the enhancement was greater in MCT-injected lungs. Results suggest that in MCT pulmonary hypertension, elevated endogenous ET-1 production acting through ETA receptors causes pulmonary vasoconstriction that is normally masked by endogenous NO production.

Effects of intracellular pH on hypoxic vasoconstriction in rat lungs

1987 ◽  
Vol 63 (6) ◽  
pp. 2524-2531 ◽  
Author(s):  
B. Raffestin ◽  
I. F. McMurtry
Keyword(s):  
Intracellular Ph ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Weak Acid ◽  
Hypoxic Response ◽  
Weak Bases ◽  
Rat Lungs ◽  
Hypoxic Vasoconstriction ◽  
Ethanesulfonic Acid ◽  
Vasoactive Mediator ◽  
Isolated Rat

Isolated rat lungs perfused with physiological salt-Ficoll solutions were studied to test whether hypoxic pulmonary vasoconstriction was potentiated by increases in intracellular pH (pHi) and blunted by decreases in pHi. Whereas addition to perfusate of 5 nM phorbol myristate acetate (PMA), a stimulator of exchange of intracellular H+ for extracellular Na+, potentiated hypoxic vasoconstriction, 1 mM amiloride, an inhibitor of Na+-H+ exchange, blunted the hypoxic response. Hypoxic vasoconstriction was also potentiated by the weak bases NH4Cl (20 mM), methylamine (10 mM), and imidazole (5 mM) and was inhibited by the weak acid sodium acetate (40 mM). NH4Cl, imidazole, and acetate had the same effects on KCl-induced vasoconstriction and on the hypoxic response. Hypoxic vasoconstriction was greater in lungs perfused with N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES)-buffered solution than in those perfused with CO2/HCO3--buffered solution. Similarly, lungs perfused with CO2/HCO3--buffered solution containing 1.8 mM Cl- (NaNO3 and KNO3 substituted for NaCl and KCl) had larger hypoxic and angiotensin II pressor responses than those perfused with 122.5 mM Cl-. Because PMA, NH4Cl, methylamine, imidazole, HEPES-buffered solutions, and low-Cl- solutions can cause increases in pHi and amiloride and acetate can cause decreases in pHi, these results suggest that intracellular alkalosis and acidosis, respectively, potentiate and blunt vasoconstrictor responses to hypoxia and other stimuli in isolated rat lungs. These effects could be related to pHi-dependent changes in either the sensitivity of the arterial smooth muscle contractile machinery to Ca2+ or the release of a vasoactive mediator or modulator by some other lung cell.

scholarly journals Evidence for a role of protein kinase C in hypoxic pulmonary vasoconstriction

1999 ◽  
Vol 276 (1) ◽  
pp. L90-L95 ◽  
Author(s):  
Norbert Weissmann ◽  
Robert Voswinckel ◽  
Thorsten Hardebusch ◽  
Simone Rosseau ◽  
Hossein Ardeschir Ghofrani ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nadph Oxidase ◽  
Superoxide Anion ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Ang Ii ◽  
Pkc Inhibitor ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation, thus optimizing gas exchange. NADPH oxidase-related superoxide anion generation has been suggested as part of the signaling response to hypoxia. Because protein kinase (PK) C activation can occur during hypoxia and PKC activation is known to be critical for NADPH oxidase stimulation in different cell types, we probed the role of PKC in hypoxic vasoconstriction in intact rabbit lungs. Control vasoconstrictor responses were elicited by angiotensin II (ANG II) and the stable thromboxane analog U-46619. Portions of the experiments were performed while NO synthesis and prostanoid generation were blocked with N G-monomethyl-l-arginine and acetylsalicylic acid to avoid confounding effects due to interference with these vasoactive mediators. The PKC inhibitor H-7 (10–50 μM) caused dose-dependent inhibition of HPV, but this agent lacked specificity because ANG II- and U-46619-induced vasoconstrictions were correspondingly suppressed. In contrast, low concentrations of the specific PKC inhibitor bisindolylmaleimide I (BIM; 1–15 μM) strongly inhibited the hypoxic vasoconstriction without any interference with the responses to the pharmacological agents. Superimposable dose-inhibition curves were also obtained for BIM when lung NO synthesis and prostanoid generation were blocked throughout the experiments. Under either condition, BIM did not affect normoxic vascular tone. The PKC activator farnesylthiotriazole (FTT), ascertained to stimulate rabbit NADPH oxidase by provocation of alveolar macrophage superoxide anion generation in vitro, caused rapid-onset, transient pressor responses in normoxic lungs. After FTT, the hypoxic vasoconstrictor response was totally suppressed, in contrast to the largely maintained pressor responses to ANG II and U-46619. The lungs became refractory even to delayed hypoxic challenges after FTT application. In conclusion, these data support the concept that activation of PKC is involved in the transduction pathway forwarding pulmonary vasoconstriction in response to alveolar hypoxia.

Loss of hypoxic pulmonary vasoconstriction in chronic pneumonia is not mediated by nitric oxide

1993 ◽  
Vol 265 (5) ◽  
pp. H1523-H1528 ◽  
Author(s):  
D. G. McCormack ◽  
N. A. Paterson
Keyword(s):  
Nitric Oxide ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Sprague Dawley ◽  
Absolute Increase ◽  
Pulmonary Vasoconstriction ◽  
Sprague Dawley Rats ◽  
Before And After ◽  
Inflammatory Processes ◽  
The Difference

In pulmonary inflammatory processes such as pneumonia there is diminished hypoxic pulmonary vasoconstriction (HPV). We investigated whether the attenuated HPV in pneumonia is a due to excess nitric oxide (NO) release. Sprague-Dawley rats were anesthetized, and a slurry (0.06 ml) of infected agar beads (containing 6 x 10(5) Pseudomonas aeruginosa organisms) or control (sterile) beads was then injected into a distal bronchus through a tracheotomy. After the establishment of a chronic P. aeruginosa pneumonia (7-10 days later) animals were instrumented for hemodynamic monitoring, and the response to exposure to hypoxic gas (fraction of inspired O2 = 0.08) was recorded before and after the administration of NG-monomethyl-L-arginine (L-NMMA; 50 mg/kg), an inhibitor of NO synthesis. The hypoxic pressor response, as assessed by the absolute increase in pulmonary arterial pressure (PAP) and total pulmonary resistance (TPR), was reduced in infected animals compared with control animals. The change in PAP and TPR was 8.5 +/- 0.7 and 0.053 +/- 0.007, respectively, in control animals compared with 5.9 +/- 0.5 and 0.041 +/- 0.011 in infected animals. After L-NMMA the increase in PAP and TPR during hypoxia was greater in both control and infected animals. However, treatment with L-NMMA did not affect the difference between control and infected animals. We conclude that excess release of NO does not account for the attenuated hypoxic pressor response in pneumonia.

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