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PubMed1994

Analysis of responses to bradykinin and influence of HOE 140 in the isolated perfused rat lung.

The inhibitory effects of HOE 140, a novel bradykinin B2 receptor antagonist, on pulmonary vascular and airway responses to bradykinin (BK) were investigated under conditions of controlled pulmonary blood flow and ventilation and constant left atrial pressure in the isolated blood-perfused rat lung. Under baseline conditions, BK produced dose-related increases in pulmonary arterial perfusion pressure without changing airway pressure. However, when pulmonary arterial pressure was raised to a high steady level, increases in pulmonary arterial pressure in response to BK were enhanced and BK then produced dose-related increases in airway pressure. Responses to BK were reproducible with respect to time and were not different when the inspired fraction of O2 was 0.21 or 0.95 and HOE 140 was 0.8 nM/ml (50 micrograms/kg) and decreased both pulmonary vascular and airway responses to the peptide. HOE 140 had no significant effect on pulmonary vascular responses to angiotensin II, serotonin, nitric oxide, sodium nitroprusside, albuterol, or pinacidil. Additionally, in these experiments, HOE 140 had no effect on the pulmonary arterial pressor response to ventilatory hypoxia. These results suggest BK has significant vasoconstrictor and bronchoconstrictor effects that are mediated by B2 receptors and are dependent on the baseline level of tone in the airways and in the pulmonary vascular bed. The present results suggest that HOE 140 is a highly selective, BK B2 receptor antagonist in the pulmonary vascular bed of the rat. These data also suggest that HOE 140 may be a useful probe for studying the role of BK in the pulmonary vascular bed in physiological and pathophysiological conditions.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1984

Analysis of responses to leukotriene D4 in the pulmonary vascular bed.

Pulmonary vascular responses to leukotriene D4 were investigated in the intact-chest animal under conditions of controlled pulmonary blood flow. Intralobar injections of leukotriene D4 in the sheep caused dose-dependent increases in lobar arterial and small vein pressures without influencing left atrial or systemic arterial pressure. Leukotriene D4 was very potent in increasing pulmonary vascular resistance in the sheep, with activity similar to that of U-46619, a thromboxane A2 mimic. Pulmonary vascular responses to leukotriene D4 in the sheep were similar when the lung was ventilated and when lobar ventilation was arrested. Responses to leukotriene D4 were similar when the lung was perfused with blood or with dextran. Pulmonary vascular responses to leukotriene D4 but not U-46619 in the sheep were reduced by inhibitors of cyclooxygenase and thromboxane synthesis. In contrast, leukotriene D4 had modest pressor activity in the pulmonary vascular bed of the cat whereas U-46619 had marked activity in this species. Responses to leukotriene D4 in the cat were not altered by cyclooxygenase inhibitors. It is concluded that leukotriene D4 has marked pulmonary vasoconstrictor activity in the sheep, increasing pulmonary vascular resistance by constricting intrapulmonary veins and upstream segments. In this species, responses to leukotriene D4 were independent of changes in ventilation or interaction with formed elements but were dependent on the formation of cyclooxygenase products including thromboxane A2. However, in the cat, leukotriene D4 had very modest pressor activity, and this activity was not dependent on the integrity of the cyclooxygenase pathway. These data suggest considerable species difference in responses to leukotriene D4, a major component of the slow-reacting substance of anaphylaxis, in the pulmonary vascular bed.

Animals↗
PubMed1980

The action of non-steroidal antiinflammatory agents on platelet aggregation and vessel tone in relation to inhibition of PGI2- and thromboxane-release. With particular reference to 5-benzoyl-alpha-methyl-2-thiophene acetic acid (tiaprofenic acid).

The actions of 5-benzoyl-alpha-methyl-2-thiophene acetic acid (tiaprofenic acid) on platelet aggregation, coronary vascular tone and myocardial oxygen consumption were studied in vitro and compared to those of diclofenac sodium, indometacin and meclofenamate. Tiaprofenic acid dose-dependently and reversibly inhibited collagen- and arachidonic acid-induced aggregation of rabbit platelet-rich plasma (IC50 2--5 micromol/l) and was as effective in this system as the reference compounds. Tiaprofenic acid did not alter the myocardial oxygen consumption up to 120 micromol/l but produced reversible and dose-dependent increases in the coronary vascular tone of both guinea pig hearts and isolated bovine coronary arteries at 0.1--10 micromol/l concentrations. This coronary vasomotor activity of tiaprofenic acid could be correlated to its ability to inhibit the vascular PGI2 production whereas the inhibition of platelet aggregation by all of the substances studied does not seem to be tightly correlated to their inhibitory effect on the thromboxane formation of blood platelets.

Animals↗
PubMed1989

Allergen-stimulated release of mediators into sheep bronchoalveolar lavage fluid. Effect of cyclooxygenase inhibition.

Products of arachidonic acid have been implicated as potential mediators of allergic airway responses in sheep and in humans. We therefore measured the release of arachidonate metabolites into sheep bronchoalveolar lavage fluid (BALF) after local instillation of Ascaris antigen, using a highly specific and sensitive approach, gas chromatography-negative ion-chemical ionization mass spectrometry. Allergen instillation caused increases in the levels of the potent bronchoconstrictors prostaglandin (PG) D2 and thromboxane (TX) A2 (as reflected by levels of TXB2) and of their enzymatic metabolites, 9 alpha, 11 beta-PGF2 and 11-dehydro-TXB2, respectively. Potential bronchodilators, PGI2 and PGE2, were also formed in increased amounts. Levels of the 5-lipoxygenase products, leukotriene (LT) B4 and C4, were not significantly increased. Pretreatment of sheep with cyclooxygenase inhibitors was associated with a decrease in the release of cyclooxygenase products and a concomitant increase in the allergen-stimulated release of LTB4 and LTC4. Eicosanoids are formed promptly in vivo in sheep after allergen instillation: inhibition of cyclooxygenase results in augmented generation of leukotrienes in the airways of sensitive sheep in response to antigen challenge.

Allergens↗
PubMed1991

Paradoxical constriction to platelets by arteries from rats with pulmonary hypertension.

We recently described the early appearance of pulmonary hypertension in the fawn-hooded rat (FHR), an animal with platelet storage pool disease also known to develop systemic hypertension at later ages. Since mediators released from aggregating platelets influence vascular tone, we hypothesized that platelet-mediated pulmonary vascular responses in FHR may be abnormal and potentially linked to the mechanism of pulmonary hypertension. To test this we examined reactivity of isolated pulmonary arteries (PA) and thoracic aortas (Ao) from young FHR with moderately severe pulmonary hypertension but normal systemic pressures. These vessels were compared with PA and Ao from control Sprague-Dawley rat (SDR). Aggregating platelets (1,000-40,000 platelets/mm3) from FHR caused dilation of SDR PA and Ao but constriction of FHR PA and Ao. Qualitatively similar responses were also observed with platelets isolated from SDR implying that abnormal responses were not simply due to the storage pool deficiency in FHR. Response to the platelet-derived endothelium-dependent vasodilator ADP was markedly impaired in FHR PA and mildly impaired in FHR Ao. Endothelium-dependent dilation to acetylcholine, but not to A23187, was mildly impaired in FHR PA while responses to both dilators were normal in FHR Ao. Endothelium-independent dilation to sodium nitroprusside was normal in both FHR PA and Ao. Constrictor sensitivity to serotonin, but not to the thromboxane A2 mimetic U-46619, was increased in FHR PA while responses to both constrictors were normal in FHR Ao. In summary, PAs from FHR with spontaneous pulmonary hypertension exhibit paradoxical constriction to both normal and storage pool deficient platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1988

Arachidonic acid evokes epithelium-dependent relaxations in canine airways.

Responses to arachidonate were examined in rings with and without epithelium of lobar, segmental, and subsegmental canine bronchi. Arachidonate evoked epithelium-dependent relaxations, which were less pronounced in subsegmental bronchi and abolished by indomethacin and meclofenamate. Nordihydroguairetic acid (NDGA) and nafazatrom reduced epithelium-dependent relaxations only in lobar but unmasked epithelium-independent relaxations to arachidonate in all bronchi. Prostaglandin E2 and prostacyclin relaxed all tissues similarly. In lobar bronchi without epithelium, basal release of prostaglandin E2 was reduced by indomethacin but unaffected by NDGA. Arachidonate augmented prostaglandin E2 release more in subsegmental than in lobar bronchi with epithelium; in bronchi without epithelium the rise was absent (lobar) or attenuated (subsegmental). Arachidonate augmented the release of 6-ketoprostaglandin F1 alpha more in lobar bronchi with than without epithelium; this was inhibited by indomethacin, but not NDGA. Thus arachidonate releases prostaglandin E2 (possibly produced by cyclooxygenase inaccessible to inhibitors and activated by lipoxygenase products) but not prostacyclin from the epithelium. Heterogeneity in response to arachidonate is not due to different sensitivity to, or production of, prostaglandins.

Animals↗
PubMed1981

Lymphokine-mediated suppression of chondrocyte glycosaminoglycan and protein synthesis.

Spontaneously released and T cell mitogen augmented lymphokine produced by human mononuclear cells has been shown to induce a concentration dependent reversible suppression of chondrocyte glycosaminoglycan and protein synthesis without significantly enhancing chondrocyte catabolic activity. The modulatory factor(s) is of T cell origin and is trypsin, pronase, and heat sensitive. Prostaglandin inhibitors failed to influence factor formation or activity. Although eluting from Sephadex G-100 over a wide range, peak activity had an approximate molecular weight of 53,000 and appeared distinct from recognized forms of lymphotoxin.

Amino Acids↗
PubMed1993

Indomethacin reduces acute baroreceptor resetting in the dog.

1. The influence of local perfusion of the carotid sinus with the cyclo-oxygenase blocker indomethacin on acute baroreceptor resetting was investigated in anaesthetized dogs. 2. The carotid sinus was isolated and perfused with oxygenated Krebs-Henseleit solution. Single units from the carotid sinus nerve were recorded. The carotid sinus was conditioned with static pressures of 50, 100 and 150 mmHg for 15 min. Following the conditioning period a carotid sinus pressure (CSP)-discharge curve was constructed using static stepwise increases in CSP. 3. Perfusion of the carotid sinus with indomethacin (20 microM) caused an elevation in the threshold at every conditioning pressure (96.8 +/- 4.8 vs. 83.8 +/- 4.1 mmHg for 100 mmHg, P < 0.01; 91.9 +/- 4.7 vs. 70.3 +/- 4.4 mmHg for 50 mmHg, P < 0.01; and 103.5 +/- 4.4 vs. 96.4 +/- 4.1 mmHg for 150 mmHg, P = 0.06, respectively) and a significant reduction in the peak discharge rate at each conditioning pressure (32.0 +/- 4.4 vs. 48.2 +/- 5.5 spikes/s for 100 mmHg, P < 0.01; 32.2 +/- 5.8 vs. 45.8 +/- 5.1 spikes/s for 50 mmHg, P < 0.01; 32.0 +/- 3.7 vs. 51.1 +/- 8.1 spikes/s for 150 mmHg, P < 0.01). The resetting ratio (change in threshold/change in conditioning CSP) for both downward resetting (conditioning CSP from 100 to 50 mmHg) and upward resetting (conditioning CSP from 100 to 150 mmHg) was significantly decreased after indomethacin (0.10 +/- 0.02 vs. 0.27 +/- 0.02 for downward resetting, P < 0.01 and 0.14 +/- 0.03 vs. 0.25 +/- 0.01 for upward resetting, P < 0.01, respectively). 4. Conversely, perfusion of the carotid sinus with arachidonic acid (20 microM) significantly decreased the threshold at each conditioning CSP and increased the peak discharge rate at each conditioning CSP. The resetting ratio was significantly increased after arachidonic acid. 5. There was no change in resting carotid diameter or in the carotid sinus pressure-carotid diameter relationship after indomethacin or arachidonic acid. 6. Removal of the endothelial cells in the carotid area with saponin did not prevent the effects of indomethacin on baroreceptor resetting. 7. These results suggest that prostaglandins have a tonic effect on the activity of the carotid sinus baroreceptor and may play a role in acute baroreceptor resetting.

Anesthesia↗
PubMed1995

Analysis of responses to angiotensin peptides in the hindquarters vascular bed of the cat.

Responses to angiotensin I, II, III, and IV, des-Asp1-angiotensin I, and (p-amino-Phe6)-angiotensin II were compared in the hindquarters vascular bed of the cat. The peptides produced dose-related increases in perfusion pressure, and dose-response curves to all six peptides were parallel. Des-Asp1-angiotensin I, angiotensin I, II, and III produced similar increases in perfusion pressure and were approximately 300-fold more potent than (p-amino-Phe6)-angiotensin II, 100-fold more potent than angiotensin IV, 30-fold more potent than norepinephrine, and 10-fold more potent than U-46619. The time courses of the response to des-Asp1-angiotensin I, angiotensin I, II, and III were similar, and responses were not altered by a time-delay coil. DuP-532, an AT1 receptor antagonist, reduced responses to the six angiotensin peptides. PD-123,319 did not alter responses to the angiotensin peptides. The angiotensin-converting enzyme inhibitor captopril reduced responses to angiotensin I and des-Asp1-angiotensin I. These results show that des-Asp1-angiotensin I as well as angiotensin I, II, III, and IV have similar efficacy and that responses to the peptides and (p-amino-Phe6)-angiotensin II are mediated by AT1 receptors. These results suggest that AT2 receptors have little role in modulating responses and that angiotensin IV has a lower affinity for the AT1 receptor than does angiotensin II or III. The results also indicate that complete rapid local conversion of the substrates into active peptides occurs near the site of action within the hindquarters vascular bed.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1994

Effects of non-steroidal anti-inflammatory drugs on polymorphonuclear leukocyte functions in vitro: focus on fenamates.

Prostanoid-independent anti-rheumatic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are a matter of debate. The aim of the present study was to compare the effects of chemically different NSAIDs (diclofenac, indomethacin, ketoprofen, paracetamol, piroxicam and four fenamates: flufenamic, meclofenamic, mefenamic and tolfenamic acids) on human polymorphonuclear leukocyte (PMN) functions, i.e. calcium ionophore A23187-triggered degranulation, leukotriene B4 (LTB4) release, platelet-activating factor (PAF) production and migration towards LTB4. The four fenamates caused a dose-dependent inhibition of each of the PMN functions tested. Flufenamic, meclofenamic and tolfenamic acids were about equipotent to inhibit PMN degranulation (IC50S 21-32 microM) and LTB4 release (IC50s 21-25 microM) whereas mefenamic acid achieved similar effects at somewhat higher drug concentrations. Tolfenamic and meclofenamic acids were the most potent fenamates to inhibit PAF synthesis (IC50s 37 and 51 microM) as well as migration towards LTB4 (IC50s 61 and 92 microM). Out of the other NSAIDs, diclofenac (which is chemically related to fenamates) suppressed degranulation as well as LTB4 and PAF production. Indomethacin inhibited LTB4 and PAF synthesis whereas ketoprofen reduced degranulation. The inhibitory effects of the non-fenamate NSAIDs occurred only at drug concentrations far higher than those achieved clinically. Paracetamol and piroxicam (up to 300 microM) did not influence the PMN functions tested. We conclude that NSAIDs with a fenamate structure differ from other NSAIDs by inhibiting PMN functions induced either by receptor-mediated stimulus (LTB4) or calcium ionophore (A23187) at micromolar drug concentrations.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1986

Prostaglandins may mediate chloride concentration gradient across domes formed by MDCK1 cells.

The MDCK1 and LLC-PK1 cell lines have been used to characterize transepithelial transport in isolated culture. Both can be maintained in continuous culture and form domes that represent fluid actively transported from luminal to contraluminal surface. Fluid in domes from LLC-PK1 cells was isotonic with the culture medium and no Cl gradient between domes and medium was present. Fluid from domes formed by MDCK1 cells was also isotonic with respect to Na and K but there was a persistent Cl concentration gradient. To evaluate prostaglandin (PG) production by these cell lines, the culture medium was analyzed for PGE. LLC-PK1 cells released no measurable PGE; MDCK1 cells regularly released PGE both during basal conditions and after augmentation of PG synthesis by a high Ca concentration in the medium. Qualitatively similar results had previously been found with these cell lines when PG synthesis was augmented with addition of arachidonic acid or Ca ionophore A23187, and PGE or 6-keto-prostaglandin F1 alpha was measured in the medium. To evaluate whether PGs might be responsible for the Cl gradient across MDCK1 cells, indomethacin or meclofenamate was added. There was a marked decrease in the Cl gradient with either agent at 5 h. To evaluate the possibility that PGE2 or PGI2 plays a role in maintaining this Cl gradient, further studies were done in which indomethacin was added to the culture medium to block endogenous PG synthesis, and exogenous PGE2 or PGI2 was added. Although addition of PGE2 was without effect, addition of PGI2 to indomethacin-treated cells maintained the Cl gradient for at least 5 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Relation between arachidonic acid metabolism and development of thymocytes in fetal thymic organ cultures.

Because products of arachidonic acid metabolism, particularly the PG, have been implicated as modulators of growth and differentiation of adult thymocytes, we investigated relations between metabolism of arachidonic acid and growth, as well as differentiation, of thymocytes during fetal thymic organ culture. Fetal thymic cells synthesized immunoreactive PGE2 during organ culture and were found to be capable of metabolizing exogenous arachidonic acid to products that cochromatographed with authentic 6-keto-PGF1 alpha, PGE2, PGF2 alpha. Synthesis of these products and growth and expression of Thy-1 and Lyt-1 Ag were inhibited by culture of fetal thymic lobes with indomethacin, a cyclooxygenase inhibitor, as well as meclofenamate and eicosatetraynoic acid, inhibitors of cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism. Only indomethacin inhibited expression of Lyt-2. Culture with eicosatetraynoic acid also inhibited the capacity of thymic lobes to synthesize 15-hydroxyeicosatetraenoic acid-like products. The inhibitory effects of indomethacin on growth and expression of Thy-1 were partially reversed by simultaneous addition of arachidonic acid. Thus, fetal thymic cells appear to require an intact cyclooxygenase, and possibly lipoxygenase, pathway of arachidonic acid metabolism for growth and differentiation. These data also provide evidence that Lyt-1 and Lyt-2 may be regulated by different requirements with respect to arachidonic acid metabolism.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1990

Solid-phase extraction, identification, and quantitation of 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid.

A procedure has been developed to extract and recover minute amounts of delta-9-carboxytetrahydrocannabinol (THC-COOH) from urine. A new non-isotopic internal standard is introduced to permit a chromatographic assay of the metabolite. The method affords a 91% recovery of 20 ng/mL of the THC-COOH acid from spiked urine with the assurance of a 3.8% coefficient of variation.

Chromatography, Gas↗
PubMed1988

Salicylic acid causes a diuresis and natriuresis in normal and common bile-duct-ligated cirrhotic miniature swine.

In patients with liver disease, or in normal subjects who are sodium-depleted, the administration of either a nonsteroidal anti-inflammatory drug or acetylsalicylate (aspirin) has a detrimental effect on the kidney; profound renal vasoconstriction and the retention of sodium and water may occur. We observed recently that salicylate (SA), in contrast to meclofenamate (MECLO) or aspirin, caused a diuresis and natriuresis in the sodium-depleted dog. To determine if SA would similarly affect the kidneys in a cirrhotic subject, the effects of SA (40 mg/kg) and subsequent MECLO treatment (2 mg/kg) were evaluated in five normal and six common bile-duct-ligated (CBDL) miniature swine. All six CBDL animals showed signs of biliary cirrhosis and four of the six were ascitic at the time of study. SA did not significantly alter renal blood flow or glomerular filtration rate in either the normal or CBDL animals. In both groups, SA caused a significant diuresis and natriuresis. MECLO, given after SA, caused a reduction in renal blood flow in the normal but not in the CBDL animals, but did not alter glomerular filtration rate in either group. In the CBDL animals, when MECLO was given alone a significant decrease in renal blood flow occurred. MECLO abolished the SA-induced diuresis and natriuresis in the normal swine but only affected the SA-mediated natriuresis in the CBDL animals. SA significantly reduced renal prostaglandin E2 excretion in both groups. With MECLO, prostaglandin E2 excretion was reduced further in the normals but not in the CBDL animals. These data demonstrate that SA does not produce detectable renal vasoconstriction in the cirrhotic pig.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Mechanisms of ANG II-induced mitogenic responses: role of 12-lipoxygenase and biphasic MAP kinase.

The potential mechanisms of angiotensin II (ANG II)-induced mitogenesis were studied in a Chinese hamster ovary fibroblast cell line overexpressing the rat vascular type 1a ANG II receptor (CHO-AT1a). ANG II had potent mitogenic effects in these CHO-AT1a cells, leading to a sustained increase in cell number as well as a dose-dependent increase in DNA synthesis. ANG II treatment also induced a biphasic elevation of mitogen-activated protein (MAP) kinase activity of both p42MAPK and p44MAPK with a rapid early peak at 5 min (2- to 6-fold) followed by a second sustained increase that reached a peak at 3 h (1.5- to 3-fold). We have previously shown that the 12-lipoxygenase (12-LO) pathway of arachidonate metabolism plays a key role in ANG II-induced growth of vascular smooth muscle and adrenal cells. In the present study, ANG II (10(-7) M) increased the formation of the 12-LO product, 12-hydroxyeicosatetraenoic acid (12-HETE). ANG II-induced DNA synthesis was inhibited by a specific LO inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC, 10 microM). In contrast, a cyclooxygenase blocker of arachidonate metabolism such as ibuprofen had no effect on ANG II-induced DNA synthesis. ANG II-induced DNA synthesis was also partially (32%) blocked by pertussis toxin (PTX). CDC and PTX also selectively blocked only the late (3 h) peak of ANG II-induced MAP kinase activity, suggesting that the late sustained peak of MAP kinase activity may be linked to the mitogenic effect of ANG II. Direct addition of 12-HETE (10(-7) M) led to a sustained increase in cell number similar to the effect of ANG II. 12-HETE also caused an increase in MAP kinase activity, and 12-HETE effects were blocked by PTX. These results suggest that ANG II-induced mitogenic response is associated with sustained MAP kinase activation and that LO activation may play a key role in this process.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗