Pulmonary vascular reactivity: effect of PAF and PAF antagonists

1992 ◽  
Vol 73 (5) ◽  
pp. 1762-1769 ◽  
Author(s):  
C. R. Chen ◽  
N. F. Voelkel ◽  
S. W. Chang
Keyword(s):  
Angiotensin Ii ◽  
Vascular Reactivity ◽  
Platelet Activating Factor ◽  
Lung Edema ◽  
Physiological Salt Solution ◽  
Similar Response ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasoconstriction ◽  
Paf Antagonists ◽  
Web 2086

We investigated the effects of two different platelet-activating factor (PAF) antagonists, SRI 63–441 and WEB 2086, on PAF-, angiotensin II-, and hypoxia-induced vasoconstrictions in isolated rat lungs perfused with a physiological salt solution. Bolus injection of PAF (0.5 micrograms) increased pulmonary arterial and microvascular pressures and caused lung edema. Both SRI 63–441, a PAF-analogue antagonist, and WEB 2086, a thienotriazolodiazepine structurally unrelated to PAF, completely blocked PAF-induced vasoconstriction and lung edema at 10(-5) M. At a lower concentration (10(-6) M), WEB 2086 was more effective than SRI 63–441. WEB 2086 also blocked the pulmonary vasodilation induced by low-dose PAF (15 ng) in blood-perfused lungs preconstricted with hypoxia. SRI 63–441 and CV 3988 (another PAF analogue antagonist), but not WEB 2086, caused acute pulmonary vasoconstriction at 10(-5) M and severe lung edema at a higher concentration (10(-4) M). PAF-induced but not SRI- or CV-induced pulmonary vasoconstriction and edema were inhibited by WEB 2086. In addition, SRI 63–441 potentiated angiotensin II- and hypoxia-induced vasoconstrictions. This effect of SRI 63-441 is not due to PAF receptor blockade because 1) addition of PAF (1.6 nM) to the perfusate likewise potentiated angiotensin II-induced vasoconstriction and 2) WEB 2086 did not cause a similar response. We conclude that both SRI 63–441 and WEB 2086 are effective inhibitors of PAF actions in the rat pulmonary circulation. However, antagonists with structures analogous to PAF (SRI 63–441 and CV 3988) can have significant pulmonary vasoactive side effects.

Bleomycin-induced lung injury in rats selectively abolishes hypoxic pulmonary vasoconstriction: Evidence against a role for platelet-activating factor

1992 ◽  
Vol 82 (3) ◽  
pp. 259-264 ◽  
Author(s):  
David G. McCormack ◽  
David E. Crawley ◽  
Peter J. Barnes ◽  
Timothy W. Evans
Keyword(s):  
Angiotensin Ii ◽  
Lung Injury ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Platelet Activating Factor ◽  
Saline Control ◽  
Lung Weight ◽  
Intratracheal Administration ◽  
Pulmonary Vasoconstriction ◽  
Web 2086

1. The role of platelet-activating factor in the attenuated hypoxic pulmonary vasoconstriction associated with lung injury was evaluated using specific platelet-activating factor antagonists and an isolated perfused lung preparation. 2. Intratracheal bleomycin was administered to rats to produce acute lung injury. Animals received intratracheal saline (control), intratracheal bleomycin or the platelet-activating factor anatagonists BN 52021, WEB 2170 or WEB 2086 before and after bleomycin treatment. Forty-eight hours after intratracheal administration of bleomycin or saline the animals were killed. 3. The increases in pulmonary artery pressure during two periods of hypoxic ventilation and in response to 0.2 μg of angiotensin II were measured. Acetylcholine-induced vasodilatation after pre-constriction with prostaglandin F2α was also measured. To quantify lung injury, the wet/ dry ratio of lung weight was determined. 4. Bleomycin treatment attenuated the first and second hypoxic pressor responses by 93% and 77%, respectively, but not the pressor response to angiotensin II nor the vasodilator response to acetylcholine. BN 52021 plus bleomycin augmented the first hypoxic pressor response compared with bleomycin treatment alone, but the structurally unrelated platelet-activating factor antagonists WEB 2170 and WEB 2086 had no significant effect on the bleomycin-induced attenuation of hypoxic pulmonary vasoconstriction. None of the platelet-activating factor antagonists blocked the increase in the wet/dry lung weight ratio induced by bleomycin. 5. Bleomycin-induced lung injury selectively attenuates hypoxic pulmonary vasoconstriction, an effect that does not appear to be mediated by platelet-activating factor. The mechanism remains to be elucidated, but may involve destruction of the hypoxic ‘sensor’ within the respiratory tract.

TNF potentiates PAF-induced pulmonary vasoconstriction in the rat: role of neutrophils and thromboxane A2

1994 ◽  
Vol 77 (6) ◽  
pp. 2817-2826 ◽  
Author(s):  
S. W. Chang
Keyword(s):  
Angiotensin Ii ◽  
Ex Vivo ◽  
Platelet Activating Factor ◽  
Physiological Salt Solution ◽  
Myeloperoxidase Activity ◽  
Lung Isolation ◽  
Pulmonary Vasoconstriction ◽  
Pressor Responses ◽  
Synthase Inhibitor

Both tumor necrosis factor (TNF) and platelet-activating factor (PAF) are released during sepsis and are important mediators of septic lung injury. I investigated the interactions of TNF and PAF on vasoactive responses in the pulmonary circulation. In isolated rat lungs perfused with a cell- and plasma-free physiological salt solution, PAF (0.01- and 0.1-micrograms boluses) caused transient dose-dependent pulmonary arterial and venous constrictions. In vivo pretreatment of the rats with TNF (0.02 or 0.2 mg/kg i.v.) 1 h before lung isolation increased lung myeloperoxidase activity and markedly enhanced PAF-induced pulmonary vasoconstriction without affecting the pressor responses to angiotensin II or hypoxia. In contrast, pretreatment with lipopolysaccharide (10 mg/kg), which increased lung myeloperoxidase to the same extent as TNF, caused only a modest enhancement of PAF-induced vasoconstriction associated with reduced pressor responses to angiotensin II and hypoxia. Ex vivo perfusion of isolated lungs with TNF for 1 h did not affect PAF vasoconstriction. The TNF-induced potentiation of PAF vasoconstriction was not altered by depletion of circulating neutrophils with vinblastine but was blocked by Dazmegrel, a thromboxane synthase inhibitor. Thus, TNF potentiates PAF-induced pulmonary vasoconstriction by an in vivo mechanism that is neutrophil independent but thromboxane dependent. This TNF-PAF interaction likely contributes to the development of pulmonary hypertension during sepsis.

Platelet-activating factor-antagonists reduce implantation in mice at low doses only

1995 ◽  
Vol 7 (1) ◽  
pp. 51 ◽  
Author(s):  
C O'Neill
Keyword(s):  
Early Pregnancy ◽  
Embryo Implantation ◽  
Platelet Activating Factor ◽  
Implantation Rate ◽  
Corpora Lutea ◽  
Detailed Knowledge ◽  
Low Doses ◽  
Paf Antagonists ◽  
Implantation Sites ◽  
Web 2086

The effects of a number of platelet-activating factor (PAF)-antagonists on embryo implantation were investigated. Mice were treated from Day 1 to Day 4 of pregnancy with three defined PAF-antagonists: SRI 63 441, BN 52021, and WEB 2086. Necroscopies were performed on Day 8 and the number of implantation sites, the implantation rate (number of implanted embryos compared with the number of corpora lutea) and the proportion of animals pregnant were determined. Each agent caused a reduction in the number of implantation sites at relatively low doses. The dose that had a maximum contragestational effect was 40 micrograms, 10 micrograms and 10 micrograms (per 30 g bodyweight per day) for SRI 63 441, WEB 2086 and BN 52021 respectively. This contragestational effect was completely lost at twice (SRI 63 441), five times (WEB 2086) and ten times (BN 52021) the most effective dose. Treatment with WEB 2086 on the day of implantation (Day 4) by intraperitoneal injection or instillation into the uterus only did not significantly reduce the implantation rate and neither did treatment after implantation (Days 5-8). The results show that the pharmacology of PAF-antagonists in early pregnancy is not simple. An understanding of the actions of these agents in early pregnancy will require a detailed knowledge of their pharmacokinetics, pharmacodynamics and targets of action in early pregnancy.

PAF antagonists inhibit monocrotaline-induced lung injury and pulmonary hypertension

1991 ◽  
Vol 71 (6) ◽  
pp. 2483-2492 ◽  
Author(s):  
S. Ono ◽  
N. F. Voelkel
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Injury ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Platelet Activating Factor ◽  
Lipid Mediators ◽  
Right Ventricular Hypertrophy ◽  
Vascular Leak ◽  
Paf Antagonists ◽  
Web 2086

Lung platelet-activating factor (PAF) levels increased in some rats at 1–3 wk after subcutaneous injection of monocrotaline (MCT). We tested the effect of specific PAF antagonists, WEB 2086 and WEB 2170, on MCT-induced lung injury and subsequent pulmonary hypertension and right ventricular hypertrophy. Treatment with either agent decreased MCT-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk after injection. Treatment with WEB 2170 reduced MCT-induced pulmonary vascular leak at 1 wk after injection, and WEB 2086-treatment exclusively during the early leak phase also decreased MCT-induced right ventricular hypertrophy at 3 wk. Treatment with WEB 2170 between the 3rd and 4th wk after MCT injection inhibited the progression of right ventricular hypertrophy at 4 wk. These results suggest that PAF contributes to the early pulmonary vascular leak, and this leak phase is important for the development of pulmonary hypertension and right ventricular hypertrophy in MCT-treated rats. Furthermore, it appears that PAF action contributes to the maintenance of a chronic inflammatory process that involves the synthesis of other lipid mediators (prostaglandins and leukotrienes) and leads to pulmonary hypertension. We conclude that PAF has a role in the MCT-induced inflammatory lung injury and pulmonary hypertension.

Simultaneous measurement of O2 radicals and pulmonary vascular reactivity in rat lung

1989 ◽  
Vol 67 (5) ◽  
pp. 1903-1911 ◽  
Author(s):  
S. L. Archer ◽  
D. P. Nelson ◽  
E. K. Weir
Keyword(s):  
Superoxide Dismutase ◽  
Angiotensin Ii ◽  
Simultaneous Measurement ◽  
Vascular Tone ◽  
Vascular Reactivity ◽  
Pressor Response ◽  
Related Substance ◽  
Enhanced Chemiluminescence ◽  
Pulmonary Vasoconstriction ◽  
Alveolar Hypoxia

The role of endogenous radicals in the regulation of pulmonary vascular tone was evaluated by simultaneous measurement of pulmonary artery pressure and lung radical levels during exposure of isolated rat lungs to varying inspired O2 concentrations (0-95%) and angiotensin II. Lung radical levels, measured “on-line” using luminol and lucigenin-enhanced chemiluminescence, decreased in proportion to the degree of alveolar hypoxia. Radical levels fell during hypoxia before the onset of pulmonary vasoconstriction and promptly returned to basal levels with restoration of normoxic ventilation. Mild alveolar hypoxia (10% O2), which failed to decrease chemiluminescence, did not trigger pulmonary vasoconstriction. Although chemiluminescence tended to decrease more as the hypoxic response strengthened, there was not a simple correlation between the magnitude of the change in chemiluminescence induced by hypoxia and the strength of the hypoxic pressor response. Normoxic chemiluminescence was largely inhibited by superoxide dismutase but not catalase. Superoxide dismutase also increased normoxic pulmonary vascular tone and the strength of the pressor response to hypoxia and angiotensin II. Thus the predominant activated O2 species in the lung, during normoxia, was the superoxide anion or a closely related substance. Alteration of endogenous radical levels can result in changes in vascular tone. It remains uncertain whether the decrease in lung radical production during hypoxia caused pulmonary vasoconstriction or was merely associated with hypoxic ventilation.

Angiotensin is not required for hypoxic constriction in salt solution-perfused rat lungs

1984 ◽  
Vol 56 (2) ◽  
pp. 375-380 ◽  
Author(s):  
I. F. McMurtry
Keyword(s):  
Angiotensin Ii ◽  
Salt Solution ◽  
Vascular Reactivity ◽  
Saline Control ◽  
Physiological Salt Solution ◽  
Rat Lungs ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction ◽  
Integral Role ◽  
Vascular Hyporeactivity

It has been reported that angiotensin II is specifically required for hypoxic vasoconstriction in rat lungs perfused with physiological salt solution. However, studies with other preparations indicate that angiotensin II does not play a necessary role in the mechanism of hypoxic vasoconstriction. In an attempt to resolve this disagreement I investigated in salt solution-perfused rat lungs whether vasoactive agents other than angiotensin II would induce hypoxic vasoconstriction, and, if so, whether the effect was due to selective action on the hypoxic mechanism or to a nonspecific increase in vascular reactivity. The results showed the development of hypoxic pressor responses after addition to perfusate of plasma, angiotensin II, KCl, vanadate, 4-aminopyridine, or norepinephrine plus propranolol. In contrast, addition of saline (control), ouabain, or tetraethylammonium chloride did not induce hypoxic vasoconstriction. Saralasin inhibited the effect of angiotensin II, but not that of plasma. Induction of responsiveness to hypoxia was associated with an increase in normoxic perfusion pressure and with potentiation of pressor responses to KCl. These results suggest that angiotensin II does not play a unique, integral role in the hypoxic mechanism, but instead is only one of many substances that will induce hypoxic pressor reactivity by reversing the vascular hyporeactivity of salt solution-perfused rat lungs.

Intact lung cytochrome P-450 is not required for hypoxic pulmonary vasoconstriction

1992 ◽  
Vol 263 (4) ◽  
pp. L446-L453 ◽  
Author(s):  
S. W. Chang ◽  
D. Dutton ◽  
H. L. Wang ◽  
L. S. He ◽  
R. Stearns ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Vascular Reactivity ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Organ Bath ◽  
Pulmonary Vasoconstriction ◽  
Rat Lungs ◽  
Persistent Depression ◽  
Pulmonary Arterial ◽  
Suicide Substrate ◽  
Cytochrome P 450

Lung cytochrome P-450 has been suggested to play a role in hypoxic pulmonary vasoconstriction. We reexamined this hypothesis using specific suicide substrate inhibitors of cytochrome P-450, 1-aminobenzotriazole (1-ABT), and chloramphenicol. In isolated, blood-perfused rat lungs, 1-ABT (0.5 mg/ml) and chloramphenicol (1 mg/ml) inhibited lung microsomal cytochrome P-450 (ethoxycoumarin O-deethylase) activity to 24 and 44% of control, respectively, and blunted hypoxia and angiotensin II-induced vasoconstriction. The depression of vascular contraction by 1-ABT was not due to an effect on calcium channels, since similar concentrations of 1-ABT had no inhibitory activity on electrical field-stimulated contractile response in rabbit papillary muscle strips. However, when 1-ABT was washed out of the lung after preincubation, the vascular reactivity to hypoxia and angiotensin II was restored despite persistent depression of lung cytochrome P-450 activity to 26% of control values. In isolated rat aortic and pulmonary arterial rings, addition of 1-ABT or metyrapone to the organ bath acutely reversed norepinephrine-induced contraction but preincubation with 1-ABT, metyrapone, or chloramphenicol had no effect on subsequent norepinephrine contractions. We conclude that 1-ABT inhibited lung vascular reactivity by a mechanism independent of cytochrome P-450 inhibition or calcium channel blockade and that an intact lung cytochrome P-450 system is not required for hypoxic pulmonary vasoconstriction in rat lungs.

BAY K 8644 potentiates and A23187 inhibits hypoxic vasoconstriction in rat lungs

1985 ◽  
Vol 249 (4) ◽  
pp. H741-H746 ◽  
Author(s):  
I. F. McMurtry
Keyword(s):  
Angiotensin Ii ◽  
Vascular Tone ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Bay K 8644 ◽  
Physiological Salt Solution ◽  
Pulmonary Vasoconstriction ◽  
Rat Lungs ◽  
Hypoxic Vasoconstriction ◽  
Voltage Dependent ◽  
Ca2 Channels

The susceptibility of hypoxic pulmonary vasoconstriction to inhibition by Ca2+ channel antagonists suggests that membrane depolarization and Ca2+ influx are components of the hypoxic mechanism. Recent characterization of BAY K 8644 as a 1,4-dihydropyridine that facilitates Ca2+ influx through partially activated voltage-dependent Ca2+ channels provides a new pharmacological tool to further test this idea. Effects of BAY K 8644 on normoxic vascular tone and on hypoxic and angiotensin II-induced vasoconstriction were examined in isolated rat lungs perfused with either blood or physiological salt solution (PSS) containing meclofenamate. Parallel experiments were performed with the Ca2+ ionophore A23187 for comparison with a Ca2+-active agent that does not act selectively on the voltage-dependent Ca2+ channel. Addition of BAY K 8644 (10(-7) to 10(-5) M) to the perfusate did not alter base-line vascular tone of the normoxic lung, but it potentiated hypoxic and angiotensin II pressor responses. For example, addition of 10(-7) M BAY K 8644 to five PSS-perfused lungs increased the hypoxic (5% O2) pressor response from 8.7 +/- 2.1 to 19.5 +/- 4.2 Torr and the angiotensin II (0.1 micrograms) response from 2.1 +/- 0.4 to 6.5 +/- 2.0 Torr. In contrast, addition of A23187 (10(-7) to 10(-6) M) to the perfusate increased normoxic perfusion pressure and inhibited hypoxic vasoconstriction. The respective effects of BAY K 8644 and A23187 were essentially the same in both blood- and PSS-perfused lungs. These results indicate that a Ca2+ channel facilitator and a Ca2+ ionophore have diametric effects on pulmonary vasoreactivity. The marked potentiation of hypoxic vasoconstriction by BAY K 8644 supports the idea that activation of voltage-dependent Ca2+ channels is an important component of the mechanism of hypoxic pulmonary vasoconstriction.

Evidence against a Role for Platelet-Activating Factor in Hypoxic Pulmonary Vasoconstriction in the Rat

1989 ◽  
Vol 77 (4) ◽  
pp. 439-443 ◽  
Author(s):  
D. G. McCormack ◽  
P. J. Barnes ◽  
T. W. Evans
Keyword(s):  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Platelet Activating Factor ◽  
Pulmonary Vasoconstriction ◽  
Paf Receptor ◽  
Pre Treatment ◽  
Dose Dependent ◽  
Higher Doses ◽  
Lung Preparation ◽  
Web 2086

1. The effect of two structurally different platelet-activating factor (PAF) receptor antagonists, WEB 2086({3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-[1,2,4]-treazolo-[4,3-a][1,4]-diazepine-2-yl]-1-(morpholinyl)-1-propanone}) and BN 52021, on hypoxic pulmonary vasoconstriction (HPV) was studied using an isolated rat lung preparation perfused with blood. 2. In lungs treated with WEB 2086 there was a dose-dependent attenuation of HPV, with complete abolition of HPV at the maximum dose. 3. Low doses of WEB 2086 caused only slight diminution of the pressor response to angiotensin II, although higher doses caused increasing attenuation of the angiotensin pressor response. 4. BN 52021 did not affect HPV. 5. Injection of PAF caused an increase in pulmonary artery pressure of 145%, a response abolished by pre-treatment of the lungs with either WEB 2086 or BN 52021. 6. These results suggest that PAF does not mediate HPV in the rat.

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