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Biomedical subjects

B M Weichman

Publications and source records attributed to B M Weichman.

At least 55 records · Page 3Linked to original sources
PubMed1984

Propranolol potentiates leukotriene D4-induced bronchoconstriction and enhances antagonism by FPL 55712.

Aerosol LTD4-induced bronchoconstriction in anesthetized, spontaneously breathing guinea pigs was potentiated by either pretreatment with propranolol or bilateral adrenalectomy, whereas bilateral vagotomy did not affect the LTD4 response. The dose-response curve describing LTD4-induced changes in dynamic lung compliance (CDYN) and pulmonary resistance (RL) [as reflective indices of bronchoconstriction] was shifted to the left by approximately 20-fold by propranolol. Against an equal degree of LTD4-induced bronchoconstriction, the leukotriene antagonist, FPL 55712, had an apparent 20-fold greater potency in propranolol-pretreated animals vis a vis saline-treated controls. The duration of action of aerosol FPL 55712 was similar in both propranolol-treated and saline-treated animals. These results demonstrate that aerosol LTD4-induced bronchoconstriction is modulated by an adrenergic compensatory bronchodilator mechanism that is apparently dependent upon the adrenals and independent of vagal influences. Inhibition of the effect of this reflex with propranolol also enhances the apparent potency of an aerosol leukotriene antagonist, FPL 55712, presumably reflecting a constant LTD4 to antagonist ratio in the saline-treated and propranolol-pretreated guinea pigs.

Adrenalectomy↗
PubMed1984

Analysis of the antagonist profile of SK&F 88046 on guinea pig trachea.

SK&F 88046 preferentially antagonized the contractions elicited by the functional thromboxane (Tx) A2 mimics and structural endoperoxide analogs, U-44069 and U-46619, on the guinea pig trachea. This concentration-dependent antagonism was described by pA2 values of 7.03 against U-46619 and 6.97 against U-44069; the slopes of both Schild plots were 0.9. Whereas SK&F 88046 did not antagonize the tracheal contractions elicited by leukotriene (LT) C4 or D4, carbachol or histamine, this agent did antagonize the contractions induced by carbocyclic thromboxane A2 (CTA2) and prostaglandin (PG) F2 alpha and D2. At 1 X 10(-5)M SK&F 88046, the antagonism was described by -log KB values of 5.9 for CTA2, 5.5 for PGF2 alpha, and 6.4 for PGD2. Thus, SK&F 88046 was 3 to 20-fold more potent an antagonist of U-44069 and U-46619, suggesting that SK&F 88046 may function primarily as a thromboxane/endoperoxide antagonist on the guinea pig trachea.

Animals↗
PubMed1984

SK&F 88046: a unique pharmacologic antagonist of bronchoconstriction induced by leukotriene D4, thromboxane and prostaglandins F2 alpha and D2 in vitro.

SK&F 88046, an imidodisulfamide initially reported as an end organ leukotriene (LT)D4 antagonist on guinea-pig lung parenchyma (Gleason et al., 1982), was studied further in order to elucidate its mechanism of action. The LTD4-induced contraction of the guinea-pig lung parenchyma, which occurs via both a direct action and an indirect, thromboxane (Tx)-dependent pathway (Weichman et al., 1982), was antagonized by SK&F 88046 and FPL 55712. SK&F 88046 was not acting on the lung parenchyma as a result of antagonism of cyclooxygenase or Tx synthetase, as SK&F 88046 did not block the LTD4-induced generation of TxB2 from the parenchyma. In contrast, the LTD4-induced contraction of the guinea-pig trachea, which is only directly mediated, was antagonized by FPL 55712 but not by SK&F 88046. However, SK&F 88046 did antagonize the contractions elicited by carbocyclic TxA2, a stable Tx analog, as well as those elicited by prostaglandins F2 alpha and D2, but not those elicited by histamine, carbachol or KCI. FPL 55712 weakly antagonized the actions of carbocyclic TxA2, but not the contractions induced by the other agonists. These results demonstrate that SK&F 88046 is an antagonist of the indirect, Tx-dependent component of LTD4 action in the guinea pig, presumably via antagonism of Tx on the end organ. These results provide additional evidence that LTD4 can exert its bronchoconstrictive actions via two mechanisms, a direct pathway and an indirect, Tx-dependent pathway.

Airway Resistance↗
PubMed1983

2-nor-leukotriene analogs: antagonists of the airway and vascular smooth muscle effects of leukotriene C4, D4 and E4.

A structural analog of LTD4, 4R-hydroxy-5S-cysteinylglycyl-6Z-nonadecenoic acid (4R, 5S, 6Z-2-nor-LTD1) has been synthesized and pharmacologically characterized. It significantly antagonized the contractile action of LTD4, LTC4 and LTE4 in guinea pig airways. In addition, this compound antagonized the in vitro vasoconstrictive effects of LTD4 in the guinea pig pulmonary artery. The study of a series of structural analogs of 4R, 5S, 6Z-2-nor-LTD1 suggests that the spatial separation of the C-1 (eicosanoid) carboxyl relative to the hydroxyl is a critical determinant in LTD4 agonist/antagonist activity.

Airway Resistance↗
PubMed1983

Investigation of leukotriene involvement in the vasopermeability response associated with guinea pig tracheal anaphylaxis: comparison with cutaneous anaphylaxis.

A direct comparison of the role of leukotrienes in mediating the increase in microvascular permeability associated with guinea pig tracheal and cutaneous anaphylaxis was obtained by simultaneous administration of inflammatory stimuli to both trachea and ear. The SRS-A antagonist, FPL 55712, reduced the increase in tracheal extravascular albumin content evoked by LTC4, LTD4, and LTE4 but failed to significantly reduce the tracheal microvascular permeability response associated with local anaphylaxis. Moreover, the inhibitory effect of the histamine H1-receptor antagonist, mepyramine, was not augmented by the additional presence of FPL 55712. In contrast to tracheal anaphylaxis, a distinct leukotriene component was indicated in cutaneous anaphylaxis since the mepyramine-FPL 55712 combination produced a greater inhibition than mepyramine alone. These results suggest that the degree of leukotriene involvement in anaphylaxis may vary between tissues.

Anaphylaxis↗
PubMed1983

Effect of inhibition of thromboxane production on the leukotriene D4-mediated bronchoconstriction in the guinea pig.

Leukotriene D4 (LTD4) administered intravenously to anesthetized, spontaneously breathing guinea pigs elicited decreases in dynamic lung compliance (Cdyn) and airway conductance (GAW) with a maximal response achieved at 0.5 min. Simultaneously, plasma levels of the thromboxane metabolite, TxB2, and the prostacyclin metabolite, 6-keto-PGF1 alpha, increased 10-fold over pre-LTD4 levels. Pretreatment of the guinea pigs with meclofenamic acid delayed the onset of the LTD4-induced bronchoconstriction, antagonized the magnitude of the decreases in Cdyn and GAW, and blocked the increase in plasma TxB2 and 6-keto-PGF1 alpha levels. The thromboxane synthetase inhibitor, UK 37,248, suppressed the LTD4-induced bronchoconstriction, while it completely blocked TxB2 production without significantly affecting 6-keto-PGF1 alpha. The SRS-A end organ antagonist, FPL 55712, blocked both the LTD4-induced bronchoconstriction and the production of the arachidonic acid metabolites. These results suggest that thromboxane A2 plays an important role in mediating part of the bronchoconstriction elicited by intravenously administered LTD4 in the guinea pig.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

The effect of synthetic leukotrienes on tracheal microvascular permeability.

The effect of synthetic leukotrienes (LT) C4, D4 and E4 on the permeability of the airway microvasculature to plasma albumin was quantitatively evaluated using an in situ guinea pig tracheal model. Vascular permeability was measured as extravascular albumin content by employing 125I-bovine serum albumin and, in order to correct for blood volume, 51Cr-erythrocytes were used. Intratracheal injection of synthetic LTC4, LTD4 and LTE4 (0.1-1000 ng) produced dose-dependent increases in tracheal extravascular albumin content. The leukotrienes were approximately 100-1000 fold more potent than histamine, although histamine did produce a greater maximal increase in extravascular albumin than the leukotrienes. Methacholine did not increase extravascular albumin content. The microvascular permeability effect of LTD4 was antagonized by FPL 55712 but not by mepyramine; conversely, the effect of histamine was antagonized by mepyramine and not by FPL 55712. Additionally, indomethacin did not alter the LTD4-induced increases in tracheal vascular permeability. These results suggest that the effect of LTD4 on tracheal microvascular permeability is directly mediated and is not the indirect result of cholinergic stimulation, histamine release or de novo synthesis of cyclooxygenase products.

Animals↗
PubMed1983

Antagonism of the pulmonary effects of the peptidoleukotrienes by a leukotriene D4 analog.

4R-hydroxy-5S-cysteinylglycine-6-Z-nonadecenoic acid (4R,5S, 6Z-2-nor-LTD1), a structural analog of leukotriene (LT) D4 (LTD4), significantly antagonized the pulmonary actions of LTD4 in several guinea pig models of LT-mediated bronchoconstriction and edema formation. In vitro, 4R,5S,6Z-2-nor-LTD1 (10(-5) and 10(-4) M) antagonized the LTD4-induced contraction of tracheal spirals and lung parenchymal strips. This antagonist action of 4R,5S,6Z-2-nor-LTD1 was specific for the LTs, in that LTC4- and LTE4-induced contractions of the trachea were also antagonized, whereas the contractions elicited by other spasmogens, e.g., histamine, carbachol, prostaglandin F2 alpha and KCl, were not antagonized. In vivo, the LTD4-induced bronchoconstriction in anesthetized, spontaneously breathing guinea pigs as reflected by decreases in dynamic lung compliance and airway conductance were attenuated significantly by a 1-min pretreatment with 4R,5S,6Z-2-nor-LTD1 at 5 mg/kg i.v. Similarly, the LTD4-induced increase in tracheal microvascular permeability, as assessed by extravasation of [125I]bovine serum albumin, was blocked by pretreatment with 4R,5S,6Z-2-nor-LTD1. These results provide the first demonstration that a structural analog of the peptidoleukotrienes can pharmacologically antagonize the potent actions of these LTs.

Animals↗
PubMed1983

Effect of calcium antagonists on leukotriene D4-induced contractions of the guinea-pig trachea and lung parenchyma.

The directly mediated contractile activity of leukotriene (LT) D4 on isolated guinea-pig trachea and lung parenchyma was dependent upon the presence of calcium in the bathing buffer. Whereas 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8), a calcium antagonist believed to act intracellularly, completely antagonized the LTD4-induced contraction, the calcium channel entry blockers, nifedipine and verapamil, only partially inhibited LTD4 contractile activity; diltiazem was inactive. TMB-8, nifedipine and verapamil were more effective in blocking the contraction of the trachea elicited by KCl-induced membrane depolarization than the contraction induced by LTD4. Of the channel entry blockers, only nifedipine appeared capable of partially relaxing an established LTD4-contracted trachea, whereas TMB-8 almost completely reversed the LTD4 contraction. On the lung parenchyma, the LTD4-induced contraction was suppressed, but not abolished in Ca++-free buffer; this contraction was antagonized by meclofenamic acid, thus suggesting it could be due in part to the indirect thromboxane (Tx) A2-mediated pathway of LT action. In Ca++-free buffer, LTD4 was still capable of generating TxB2, although lower amounts were found when compared to Ca++-containing buffer. Incremental addition of calcium to the parenchyma in Ca++-free buffer containing LTD4 elicited greater than control LTD4-induced contraction and TxB2 generation. Neither the contraction of the parenchyma nor the generation of TxB2 was antagonized by nifedipine; conversely, TMB-8 blocked both completely. Thus, based upon the use of pharmacological antagonists of calcium, these results suggest that LTD4 contractile activity in the respiratory system is dependent upon calcium, with calcium of intracellular origin potentially of significance.

Animals↗
PubMed1982

Contraction of guinea pig uterus by synthetic leukotrienes.

Synthetic leukotrienes (LT) C4 and D4 elicited concentration-dependent contractions of the guinea pig uterus between 10(-8)-10(-6)M, whereas LTE4 appeared 1000-fold weaker. The potencies of LTC4 and LTD4 were similar to that of acetylcholine and PGF2 alpha but weaker than that of PGE2. The maximal contractions elicited by LTC4 and LTD4 were 66.0 +/- 2.1% and 63.8 +/- 4.6% that elicited by acetylcholine. FPL 55712 (10(-5)M) antagonized the uterine contractile activity of LTD4, while meclofenamic acid at 10(-5)M but not at 10(-6)M also antagonized the LTD4-induced contraction. Radioimmunoassay of the uterine tissue bathing fluid following LTD4 indicated the variable presence of low concentrations of PGE2, PGF2 alpha and TxB2. These results demonstrate that LTC4 and LTD4 possess significant uterine contractile activity, which may only partially be mediated indirectly via prostaglandin products.

Acetylcholine↗
PubMed1982

Ligand binding properties of the basophilic IgE receptor of normal and allergic individuals.

The interaction of [125I]-human myeloma IgE with the human basophilic IgE receptor of normal and allergic individuals was quantitated by direct ligand binding analysis after removal of endogenous IgE. Using a mixed leucocyte preparation containing 2 to 5% basophils, the [125I]-IgE binding was specific for human IgE, paralleled the presence of basophils in the cell preparation, and was described by a time course similar to that reported for passive sensitization experiments. The Kd values were 4.0 to 13.2 nM for the normal individuals with 1.5 to 8.4 x 10(5) receptors per basophil, while the IgE receptor of allergic individuals was described by Kd values of 4.2 to 11.7 nM and 3.0 to 4.7 x 10(5) sites per basophil. Based upon the eleven individuals studied, these results suggest that the binding properties of the IgE receptor of normal and allergic individuals are similar.

Antibody Specificity↗
PubMed1982

Regulation of the synthesis and release of slow-reacting substance of anaphylaxis from sensitized monkey lung.

Immunological challenge of sensitized fragmented cynomolgus monkey lung with anti-human IgE (immunoglobulin E) induced the appearance of slow reacting substance of anaphylaxis (SRS-A) in the tissue and evoked the release of SRS-A into the Tyrode's supernatant. The elevation of tissue or residual SRS-A levels was maximal 2 min after anti-IgE challenge and remained at that plateau for at least 60 min. The released SRS-A, first detectable 3 to 5 min after challenge, achieved a plateau by 10 min. Both the released and residual SRS-A were similarly inactivated by soybean lipoxidase and were antagonized by FPL 55712 on the guinea-pig ileum. Isoproterenol, 5, 8, 11, 14-eicosatraynoic acid and SK & F 64398 all inhibited the anti-IgE induced elevation in residual SRS-A and blocked SRS-A release. Indomethacin stimulated both the elevation of residual SRS-A and the amount released. Removal of the Tyrode's supernatant containing 209 +/- 73 U of released SRS-A/g of tissue 20 min after anti-IgE resulted in the release of an additional 239 +/- 69 U/g; residual SRS-A levels remained at the plateau level. Incubation of the Tyrode's supernatant from challenged, but not control, tissue with fresh lung tissue caused a 90 +/- 7% inhibition of SRS-A release from the fresh tissue. Leukotriene D4 at 5 to 50 ng/ml (concentrations relevant to SRS-A release) showed a concentration-dependent inhibition of SRS-A release, but no effect on histamine release. Leukotriene C4 at 5 to 50 ng/mg failed to significantly alter the amount of SRS-A release. However, at 150 ng/ml, significant inhibition was observed which, in part, may have been produced by metabolism to leukotriene D4. These results demonstrate a potential role for LTD in regulating the amount of SRS-A released from monkey lung.

Animals↗
PubMed1981

Immunologic histamine release in vitro from the heart and lung of the cynomolgus monkey.

Immunologic histamine release was evoked from the sensitized fragmented cardiac and pulmonary tissue of the cynomolgus monkey by a reverse anaphylactic reaction. Ventricular and pulmonary tissue released a similar fraction (approximately 6%) of the total tissue histamine when challenged with antihuman IgE, presumably reflecting the 'active' sensitization of the monkey in vivo. Passive sensitization of these tissues in vitro resulted in significantly greater immunologic histamine release in 6 of the 14 ventricles and d a similar fraction (approximately 6%) of the total tissue histamine when challenged with antihuman IgE, presumably reflecting the 'active' sensitization of the monkey in vivo. Passive sensitization of these tissues in vitro resulted in significantly greater immunologic histamine release in 6 of the 14 ventricles and d a similar fraction (approximately 6%) of the total tissue histamine when challenged with antihuman IgE, presumably reflecting the 'active' sensitization of the monkey in vivo. Passive sensitization of these tissues in vitro resulted in significantly greater immunologic histamine release in 6 of the 14 ventricles and in the lungs. The antiallergic compounds, disodium cromoglycate and SK&F 64398, inhibited immunologic histamine release from passively sensitized monkey ventricular tissue. These results demonstrate that ventricular histamine may be immunologically released and that this release process can be pharmacologically inhibited in a manner similar to that of pulmonary tissue.

Anaphylaxis↗