Role of eicosanoids in PAF-induced increases of the vascular permeability in rat airways.

1. Platelet activating factor (PAF; 1.0 and 5.0 micrograms kg-1) injected in the tail vein of unanaesthetized rats dose-dependently increased the vascular permeability of the trachea, upper and lower bronchi (up to 400%) as measured by the extravasation of Evans blue dye. The permeability of the parenchyma was not affected by PAF treatment. 2. Pretreatment of the animals with an intravenous injection of the PAF antagonist BN-52021 (10 mg kg-1) abolished almost totally the vascular permeability changes elicited by PAF injection (5.0 micrograms kg-1). 3. Pretreatment of the animals with intravenous injections of inhibitors of thromboxane formation, indomethacin (10 mg kg-1) and compound OKY-046 (10 mg kg-1), and thromboxane antagonist, compound L-655,240 (5 mg kg-1), partially reduced PAF effects in the airways (from 28 to 69%). The thromboxane mimic U-44069 (5.0 micrograms kg-1) did not modify the vascular permeability of rat airways. The effect of a low dose of PAF (0.1 microgram kg-1) on the vascular permeability of the trachea and bronchi (but not of the parenchyma) was potentiated by compound U-44069 (5.0 micrograms kg-1) or noradrenaline (400 ng kg-1) whereas the effect of a high dose of PAF (5.0 micrograms kg-1) was not affected. 4. Neither the peptidoleukotriene antagonist MK-571 (10 mg kg-1) nor the 5-lipoxygenase inhibitor, L-663,536 (10 mg kg-1) given before the injection of PAF (5.0 micrograms kg-1) affected the protein extravasation in rat lung tissues.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increase in vascular permeability produced in rat airways by PAF: potentiation by adrenalectomy.

1. The effect of bilateral adrenalectomy on the sensitivity of blood vessels in rat airways to mediators that increase vascular permeability was examined. 2. An increase in vascular permeability was induced by intravenous platelet activating factor (PAF, 50, 100, 500, 1000 ng kg-1) and measured by quantifying the extravasation of Evans blue dye. 3. PAF consistently increased the amount of Evans blue extravasation in the larynx, trachea, main bronchi and intrapulmonary airways in sham-operated rats. 4. The magnitude of this extravasation was significantly greater in the larynx (P less than 0.05), trachea (P less than 0.05) and main bronchi (P less than 0.05) of the adrenalectomized rats than it was in these tissues of the sham-operated rats. 5. When adrenalectomized rats were given subcutaneous dexamethasone (0.2 mg kg-1 4 h before PAF) the amount of plasma extravasation produced by PAF was decreased to the level of the sham-operated rats. 6. We conclude that adrenalectomy potentiates the increase in airway vascular permeability induced by PAF in rats and that this effect may be due to the depletion of endogenous corticosteroids.     

Effect of PAF on rat lung vascular permeability: role of platelets and polymorphonuclear leucocytes.

1. The objectives of the present experiments were to assess the contribution of polymorphonuclear leucocytes (PMNLs), platelets and their products such as thromboxane A2 (TxA2), histamine and 5-hydroxytryptamine to platelet activating factor (PAF)-mediated protein extravasation in rat lungs. 2. Intravenous injection of PAF (1.0 and 5.0 micrograms kg-1) increased dose-dependently (up to 7.5 fold) the vascular permeability of the trachea, upper and lower bronchi to Evans blue dye (EB), a marker of albumin extravasation. The permeability of the pulmonary parenchyma was not affected significantly by PAF. 3. Thrombocytopenia induced by administration of the IgG fraction of goat anti-rat platelet serum (APS; 15 mg 100 g-1, i.p., 16-18 h) reduced by 55, 58 and 40% the effects of the lower dose of PAF (1.0 microgram kg-1) and by 31, 23 and 15% the effects of the higher dose of PAF (5.0 micrograms kg-1) on the permeability of the trachea, upper and lower bronchi respectively to albumin. 4. PMNL depletion induced by administration of rabbit anti-rat polymorphonuclear serum (ANS; 2 mg kg-1, i.v., 24 h) did not reduce significantly the effects of the lower dose of PAF (1.0 microgram kg-1) on the airways, however the effects of the higher dose of PAF (5.0 micrograms kg-1) on the permeability of the trachea, upper and lower bronchi to albumin were reduced by 43, 25 and 23% respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bradykinin-induced plasma exudation in guinea-pig airways: involvement of platelet activating factor.

1. We studied the effect of bradykinin on plasma exudation in the airways of the anaesthetized guinea-pig in vivo. Tissue content of extravasated Evans blue dye was used as an index of protein exudation in the larynx, trachea, main bronchi and intrapulmonary airways (i.p.a.). 2. Bradykinin increased the content of Evans blue in all tissues studied in a dose-related manner. The response was greatest in the main bronchi and i.p.a., less in the trachea and least in the larynx. A dose of 47 nmol kg-1 was the lowest tested which caused significant (P less than 0.001) plasma exudation with increases in leakage above control values of 256% in the larynx, 405% in the trachea, 394% in the main bronchi and 485% in intrapulmonary airways. 3. Leakage was significantly (P less than 0.05) increased above control values by 1 min after bradykinin (47 nmol kg-1) in the main bronchi and intrapulmonary airways and was maximal in all airways 5 min after bradykinin. Although reduced by 15 min, the tissue content of dye was still significantly (P less than 0.05) increased 2 h after bradykinin. 4. The prolonged tissue dye retention was due to a later phase of slow and maintained exudation preventing full clearance of dye after the initial response. 5. The initial phase of leakage was partially attenuated by the platelet activating factor (PAF) receptor antagonists WEB 2086 or BN 52021, by indomethacin or by inhibiting sensory nerve activation by opioid anaesthesia: it was not affected by mepyramine and cimetidine nor by the sulphidopeptide leukotriene receptor antagonists FPL 55712 or ICI 198,615.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ruthenium red, but not capsazepine reduces plasma extravasation by cigarette smoke in rat airways.

1. Cigarette smoke increases vascular permeability in rat airways by activating release of tachykinin from capsaicin-sensitive sensory nerves. However, the mechanism by which cigarette smoke induces secretion of sensory neuropeptides is unknown. Here we hypothesized that cigarette smoke activates sensory nerve endings via a mechanism similar to that of capsaicin. 2. We studied the effects of ruthenium red, an inorganic dye which blocks the cation influx promoted by capsaicin and of the capsaicin antagonist capsazepine on the increase in vascular permeability produced by cigarette smoke, capsaicin, hypertonic saline and substance P in the trachea of pentobarbitone anaesthetized rats. We also investigated the ability of cigarette smoke to desensitize sensory nerve fibres. 3. Ruthenium red (10 mM) by aerosol blocked the increase in vascular permeability induced by capsaicin (0.5 microM) and reduced the response to cigarette smoke (5 puffs) but did not affect responses evoked by hypertonic saline (7.2%) or by substance P (10 microM) (all given by aerosol). Aerosols of capsazepine (0.1 mM) prevented extravasation by capsaicin, but did not inhibit response to cigarette smoke, hypertonic saline or substance P. Finally, pre-exposure to a high dose of cigarette smoke (10 puffs) prevented the extravasation caused by cigarette smoke (5 puffs) itself and by intravenous capsaicin (150 micrograms kg-1), but not that by intravenous substance P (10 nmol kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Phosphoramidon blocks big-endothelin-1 but not endothelin-1 enhancement of vascular permeability in the rat.

1. Changes in vascular permeability following intravenous injections of human big-endothelin-1 (big-ET-1) and endothelin-1 (ET-1) were measured by extravasation of Evans blue dye (EB, 20 mg kg-1) in selected tissues. 2. A low dose of big-ET-1 (40 pmol kg-1) failed to alter vascular permeability but a dose of 400 pmol kg-1 increased EB extravasation in the trachea, upper and lower bronchi, and lung parenchyma by 55 to 69% (P < 0.05). Vascular permeability was also enhanced in the liver, spleen, kidney, heart, and diaphragm by 20, 14, 41, 25, and 67%, respectively (P < 0.05). 3. Upon injection of ET-1 (400 pmol kg-1), EB extravasation increased in the upper and lower bronchi, lung parenchyma, liver, pancreas, kidney, heart, and diaphragm. 4. Administration of ET-1 and big-ET-1 was not associated with significant systemic responses. 5. Pretreatment with phosphoramidon (PA) blocked the response to big-ET-1 in all tissues examined but this inhibitor failed to alter the response to ET-1. 6. We conclude from these results that the dose-dependent increase in vascular permeability induced by big-ET-1 in various tissues follows its conversion to ET-1 by the endothelin converting enzyme, a PA-sensitive process.     

白细胞三烯拮抗剂ONO-1078对豚鼠迷走神经电刺激引起气道痉挛及微血管渗漏作用

阿托品预先处理的豚鼠,电刺激迷走神经(10Hz,5ms,2V或10V,90s)引起气道阻力增高,气管、主支气管和肺内气道的依文思蓝渗出量增加,并随刺激强度加大而增强。白细胞三烯拮抗剂ONO-1078(0.03,0.1mg·kg^-1,iv)对气道阻力的增高无明显影响;但显著抑制微血管渗漏,在刺激强度低(2V)时更明显。结果提示白细胞三烯类参与神经原性炎症时的气道微血管渗漏反应。     

Effects and interactions of sensory neuropeptides on airway microvascular leakage in guinea-pigs.

1. We have studied the effect of the sensory neuropeptides substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and calcitonin gene-related peptide (CGRP) on microvascular permeability in guinea-pig airways in vivo and investigated whether CGRP would potentiate the effect of SP. We used the extravasation of intravenously-injected Evans blue dye as an index of permeability. 2. The tachykinins SP, NKA and NKB (0.025-5.0 nmol kg-1, i.v.) significantly (P less than 0.05) increased extravasation of dye in a dose-related manner and with a similar pattern of distribution; they were most potent in the trachea and main bronchi, less potent in the larynx and intrapulmonary airways, and had little significant effect in the bladder. 3. SP was significantly more potent in causing extravasation of dye than NKA or NKB with ED50 values (nmol kg-1) in the range 0.04-0.1, depending on the airway level, compared with values in the range 0.3-0.7 for the neurokinins. 4. CGRP (0.0025-2.5 nmol kg-1, i.v.) had no significant effect on microvascular permeability and did not potentiate SP-induced extravasation of dye. 5. Each neuropeptide decreased mean arterial blood pressure, indicating vasodilatation, in a dose-related manner. Co-injection of CGRP and SP produced additive decreases in arterial pressure. 6. We conclude that, in guinea-pig airways, tachykinins increase microvascular permeability via tachykinin receptors of the NK-1 sub-type (indicated by an order of potency of SP greater than NKA = NKB) on endothelial cells. The response appears to be related to mechanisms in addition to vasodilatation. The relevance of the responses to the tachykinins in asthma is discussed.     

Formoterol and salbutamol inhibit bradykinin- and histamine-induced airway microvascular leakage in guinea-pig.

1. The effects of the beta 2-adrenoceptor agonists, salbutamol and formoterol, on the increase of microvascular permeability induced by histamine or bradykinin in guinea-pig airways have been studied in vivo. Extravasation of intravenously injected Evans blue dye was used as an index of permeability. The effects of salbutamol and formoterol on the increase in pulmonary airway resistance induced by histamine or bradykinin have also been studied. 2. The increase in pulmonary airway resistance induced by histamine or bradykinin was totally inhibited by salbutamol and formoterol. The ED50 of the two mediators were 0.59 +/- 0.21 (n = 5) and 0.20 +/- 0.14 (n = 5) micrograms kg-1 respectively for salbutamol, and 0.13 +/- 0.12 (n = 6) and 0.02 +/- 0.01 (n = 6) micrograms kg-1 respectively for formoterol. 3. Salbutamol (10 and 30 micrograms kg-1) and formoterol (1 and 10 micrograms kg-1) inhibited the increase of microvascular permeability induced by histamine (30 micrograms kg-1) in the guinea-pig airways. The inhibitory effect was predominant in the trachea and the main bronchi, with a maximum inhibition of 20 to 50%. The two drugs had little or no inhibitory effect on the other structures studied, viz. nasal mucosa, larynx, proximal and distal intrapulmonary airways. 4. Salbutamol and formoterol (1 and 10 micrograms kg-1) abolished the increase in microvascular permeability induced by bradykinin (0.3 micrograms kg-1). This inhibitory effect of two beta-adrenoceptor stimulants was predominant in the trachea and the nasal mucosa where it was observed with 1 microgram kg-1 of the beta-adrenoceptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of endothelin-1 on vascular permeability in the conscious rat: interactions with platelet-activating factor.

1. The objectives of the present experiments were to assess the effects of endothelin-1 on the macrovascular permeability in selected vascular beds, to study the involvement of platelet-activating factor (PAF) in vascular responses to endothelin-1 and to examine the vascular effects of combined administration of endothelin-1 and PAF in conscious rats. 2. Intravenous bolus injection of endothelin-1 (0.1-2 nmol kg-1) resulted in a dose-dependent biphasic change in mean arterial blood pressure (MABP) with initial transient hypotension followed by a prolonged pressor action. These changes were accompanied by a dose-dependent increase in haematocrit values. 3. Endothelin-1 (0.1 and 1 nmol kg-1) increased dose-dependently the vascular permeability of the trachea, upper and lower bronchi, stomach, duodenum, spleen and kidney (up to 240%) as measured by the extravasation of Evans blue dye. The permeability of pulmonary parenchyma, liver and pancreas was not affected significantly by endothelin-1 treatment. 4. Pretreatment of animals with the specific PAF receptor antagonist, WEB 2086 (1 mg kg-1, i.v.) or BN 52021 (10 mg kg-1, i.v.) reduced the endothelin-1 (1 nmol kg-1)-induced rise in haematocrit by about 50 and 30%, respectively. Both antagonists were highly effective at inhibiting protein extravasation in the stomach, duodenum and kidney. On the other hand, BN 52021, but not WEB 2086, significantly attenuated the effect of endothelin-1 on permeability in the lower bronchi and spleen. Neither WEB 2086 nor BN 52021 modified the changes in MABP evoked by endothelin-1.(ABSTRACT TRUNCATED AT 250 WORDS)