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Biomedical subjects

M A Wasserman

Publications and source records attributed to M A Wasserman.

At least 55 records · Page 3Linked to original sources
PubMed1986

Thromboxane as a mediator of pulmonary dysfunction during intravascular complement activation in sheep.

Intravascular complement activation results in thromboxane (TxA2) production, pulmonary hypertension, hypoxemia, and increased lung vascular permeability. The purpose of this study was to determine the role of TxA2 as a mediator of these responses. Experiments were made in anesthetized sheep subjected to intravenous injections of zymosan-activated plasma (ZAP) every 30 min for 4 h. Sheep were pretreated with dazoxiben, a TxA2 synthetase inhibitor, or SK and F 88046, a TxA2 end-organ antagonist, and the results were compared with those from untreated sheep. Dazoxiben, but not SK and F 88046, inhibited TxA2 release. The hypertensive response averaged 74 +/- 3 cm H2O after each injection of ZAP in untreated sheep. Neither drug altered this response. Pao2 decreased an average of 20 +/- 1 mmHg in untreated sheep, 3 +/- 1 mmHg in dazoxiben-treated sheep, and 11 +/- 1 mmHg in SK and F 88046-treated sheep. Increases in lung lymph flow and lymph protein clearance were unaffected by treatment. TxA2 appears to be an important mediator of hypoxemia during intravascular complement activation.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Endotoxin-induced changes in pulmonary hemodynamics and respiratory mechanics. Role of lipoxygenase and cyclooxygenase products.

We investigated the role of leukotrienes and cyclooxygenase products in endotoxin-induced pulmonary vascular and airway changes. In 11 conscious sheep, measurements of pulmonary vascular resistance (PVR), lung resistance (RL), arterial PO2, leukocyte count (WBC), and plasma thromboxane B2 (TxB2), 6-keto-PgF1 alpha and PgF2 alpha were obtained, before and at predetermined intervals after a 10-min infusion of E. coli endotoxin (0.3 microgram/kg). On a separate occasion, 5 sheep received an infusion of the leukotriene end-organ receptor antagonist FPL-57231 (0.7 to 1 mg/kg/min), before and for as long as 4 h after endotoxin infusion; and 6 sheep received a single injection of the cyclooxygenase inhibitor indomethacin (2 mg/kg) 1 h before endotoxin infusion. Endotoxin caused a biphasic response with an increase in mean PVR and RL to 441 and 353% of baseline, respectively, during the early phase (0 to 1 hr), and lesser increases to 168 and 195% of baseline during the late phase (1.5 to 4 h). These changes were associated with mild hypoxemia, marked leukopenia, and marked increases in plasma TxB2, 6-keto-PgF1 alpha and PgF2 alpha. The FPL-57231 completely blocked the endotoxin-induced changes in PVR, RL, and PaO2 during both phases without preventing the increases in TxB2; however, it partly attenuated the increases in 6-keto-PgF1 alpha and enhanced the generation of PgF2 alpha. Indomethacin, which blocked the endotoxin-induced increases in TxB2, 6-keto-PgF1 alpha, PgF2 alpha, and RL, only partly blocked the increase in PVR during the early phase, followed by an exaggerated increase of PVR during the late phase.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Effects of calcium channel entry blockers, nifedipine and nilvadipine, on colonic motor activity.

The effects of the dihydropyridine calcium channel entry blockers nifedipine and nilvadipine on colonic contractions were determined in vitro and in vivo. In circular muscle strips prepared from the canine proximal colon, cumulative concentration-response curves were generated to potassium chloride (KCl), acetylcholine (ACh) and substance P, and the effects of electrical field stimulation were determined. Responses to KCl and ACh were examined in circular muscle strips prepared from the monkey proximal and distal colon. Nifedipine (10(-8) - 10(-6) M) significantly decreased KCl-induced contractions, whereas equimolar concentrations of nilvadipine were less effective at modifying these responses. Both calcium channel entry blockers produced similar significant decreases in ACh, substance P and electrical field stimulation contractions. In anesthetized dogs, strain gauge force transducers were oriented to record proximal colonic circular muscle contractions. Colonic contractions to i.a. infusions of ACh, cholecystokinin-(26-33) and substance P were produced in a small segment of the proximal colon. Nifedipine and nilvadipine (200 micrograms/kg i.v.) significantly decreased maximal ACh contractions. Nilvadipine also decreased maximum cholecystokinin-(26-33) and substance P contractions. Both calcium channel entry blockers decreased systolic and diastolic blood pressure significantly at 100 micrograms/kg i.v. These results indicate that nifedipine and nilvadipine are equieffective at reducing colonic contractile activity to a variety of colonic stimulants and illustrate the importance of extracellular calcium in the mediation of colonic motility

Acetylcholine↗
PubMed1986

Characterization of substance P-induced contractions of guinea-pig trachea.

In light of current interest in substance P as a bronchoconstrictor, several pharmacologic antagonists of known mediators of anaphylaxis were tested for possible activity against this neuropeptide. Concentration-dependent contractions of the isolated guinea-pig tracheal strips to substance P (10(-8) to 10(-5) M) were elicited. These contractions were inhibited by substance P receptor antagonists, D-Arg1-D-Trp7,9-Leu11 and D-Pro2-D-Trp7,9-substance P (10(-6) to 10(-4) M). Substance P-induced contractions were not inhibited by histamine, alpha and beta adrenergic receptor antagonists or by cyclooxygenase inhibition. However, atropine enhanced contractions to substance P. Both vasoactive intestinal polypeptide (10(-7), 10(-6) and 10(-4) M) and isoproterenol (10(-7) M) were able to reverse an ongoing substance P (10(-5) M)-induced contraction. Also, at a concentration of 10(-5) M, substance P increased cyclic GMP accumulation, but had no effect on the concentration of cyclic AMP. A 15-min pretreatment with either verapamil or nifedipine (10(-8) M) had no effect on substance P-induced contractions, whereas the purported intracellular Ca++ antagonist, 8-[N,N-diethylamino]-octyl 3,4,5-trimethoxybenzoate hydrochloride (10(-4) M) produced a rightward shift of a substance P concentration-response curve. A selective calmodulin inhibitor, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (10(-4) M) failed to affect the contraction produced by 10(-5) M substance P. When guinea-pig tracheal strips were washed and allowed to re-equilibrate in 0 Ca++ buffer, the initial maximum contractions to substance P (10(-5) M) were equal for both regular (1.8 mM) Ca++ and 0 Ca++ buffer.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Effects of SK&F 93944 (Temelastine), a potent histamine H1-receptor antagonist in pharmacologic and antigen-induced bronchoconstriction.

SK&F 93944, a previously reported non-sedating histamine H1-receptor antagonist, was evaluated for its ability to block pharmacologic-and antigen-induced bronchoconstriction. In the isolated guinea pig trachea, SK&F 93944 (10(-9)-10(-7) M) produced a concentration-dependent inhibition of contractions produced by histamine (pKB = 9.5). Another histamine antagonist, mepyramine (10(-8)-10(-6) M), was less potent (pKB = 8.5). SK&F 93944 (10(-8), 10(-7) M) also significantly depressed the rapid initial phase of antigen-induced contraction of the guinea pig trachea from animals actively sensitized to ovalbumin, while having no effect on the later, more protracted phase of the contractile response. In anesthetized mongrel dogs, selective inhibition of histamine (20 micrograms/kg, i.v.)-induced bronchoconstriction was achieved by SK&F 93944 in doses as low as 30 micrograms/kg, i.v. Terfenadine, a purportedly selective histamine H1-receptor antagonist, blocked both histamine and acetylcholine-induced bronchoconstriction at doses similar to SK&F 93944. In mongrel dogs natively allergic to Ascaris suum antigen, pretreatment with aerosols of either SK&F 93944 or mepyramine (1%; 50 tidal breaths) significantly inhibited bronchospasm elicited by increasing aerosol concentrations of antigen. Thus, SK&F 93944 is a highly potent, selective histamine H1-receptor antagonist which is efficacious vs. pharmacologic and antigen-induced bronchoconstriction.

Animals↗
PubMed1986

Role of alpha-adrenergic receptors in cartilaginous and non-cartilaginous human airways.

An imbalance between the density of alpha- and beta-adrenergic receptors in airway smooth muscle has been suggested as one of the potential underlying mechanisms of bronchial asthma. Therefore, the present study was conducted to examine the presence and functional behavior of alpha-adrenoceptors in isolated human bronchi and bronchioles. Human airway tissues did not show any spontaneous tone during equilibration in physiological solution. Sensitivity of non-cartilaginous airways (8th generation and smaller) to histamine was approximately 3 times more than cartilaginous (2nd-7th generation) airways. In the presence of beta-adrenoceptor blockade, norepinephrine (3 X 10(-4) M) evoked approximately 14-40% of maximum histamine contraction in cartilaginous and non-cartilaginous airways from three donors. When tone in these tissues was elevated by pretreatment with histamine (10(-5) M), leukotriene D4 (10(-10) M), carbachol (1 X 10(-6) M-3 X 10(-6) M) or KCl (10(-2) M), the sensitivity to norepinephrine was potentiated. Airway tissue from one donor was found to be highly reactive to norepinephrine and the maximum contractions were 118 and 145% of maximum histamine contraction for cartilaginous and non-cartilaginous airways, respectively. Time to reach maximum contraction in cartilaginous airways was 80 min compared to 21 min for non-cartilaginous airways from the same donor. These data suggest that human airways contain contractile alpha-adrenoceptors in addition to relaxant beta-adrenoceptors, which haven been reported previously in the literature. Though activation of alpha-adrenoceptors induces contractions in human airway smooth muscle, the potency of norepinephrine for alpha-adrenoceptors in these airways is low compared to that reported for vascular smooth muscle.

Adult↗
PubMed1986

Differential effects of methacholine and leukotriene D4 on cyclic nucleotide content and isoproterenol-induced relaxation in the opossum trachea.

The effects of leukotriene D4 and methacholine on cyclic nucleotide content and isoproterenol-induced relaxation were examined in the isolated opossum trachea. Although leukotriene D4 (-log EC50 = 6.70) was a more potent contractile agent than methacholine (-log EC50 = 5.78), the maximal response to leukotriene D4 was only 65% of the maximum response to methacholine. Contraction of tracheal strips with leukotriene D4 was accompanied by a 3-fold increase in cyclic GMP accumulation. Methacholine-induced contraction was not associated with an increase in cyclic GMP. Neither agent altered basal cyclic AMP content. Additional experiments were carried out to examine functional inhibitory interactions between bronchoconstricting and bronchodilating pathways. In these studies, cumulative isoproterenol concentration-response curves were constructed in tracheal strips contracted with three different concentrations of methacholine and in tissues contracted with three corresponding equieffective concentrations of leukotriene D4. Although the relaxant response to isoproterenol decreased as tissues were contracted with higher concentrations of either agent, the inhibitory effect of methacholine on isoproterenol-induced relaxation was much greater than the inhibitory effect of leukotriene D4. Previous studies from our laboratory suggested that a potential explanation for the greater inhibitory effect of methacholine on the mechanical response to isoproterenol was that methacholine may inhibit isoproterenol-stimulated cyclic AMP accumulation whereas leukotriene D4 may not. However, neither methacholine nor leukotriene D4 inhibited isoproterenol-stimulated cyclic AMP accumulation in the opossum trachea. The results of this study indicate that the sensitivity of airway smooth muscle to beta adrenoceptor agonists is influenced both by the initial contractile state of the tissue and by the type of agent used to induce tone.

Airway Resistance↗
PubMed1985

SK&F 88046: inhibition of thromboxane-induced bronchoconstriction in anesthetized dogs.

In addition to its well-described pro-aggregatory action, thromboxane A2 (TxA2) has been shown to be a potent bronchoconstrictor. The present study was designed to evaluate whether SK&F 88046 [N,N'-bis-7-(3-chlorobenzeneaminosulfonyl)-1,2,3,4- tetrahydroisoquinolyl disulfonylimide] had any inhibitory effects against canine bronchoconstriction induced by U-44069, a functional TxA2 mimic. Bronchopulmonary responses were measured by computer analyses in spontaneously breathing, pentobarbital-anesthetized mongrel dogs. In a dose range of 0.3-3.0 micrograms/kg i.v., U-44069 produced potent, dose-related increases in pulmonary airway resistance (RL) and decreases in dynamic lung compliance (CDYN), which were indicative of severe bronchoconstriction. The onset of agonist activity was prompt (1-2 min) and recovery usually occurred within 5-10 min. Pretreatment with varying doses of SK&F 88046 (1, 3 and 5 mg/kg) as a 10 min i.v. infusion, produced a significant inhibition of the RL and CDYN effects of U-44069. In addition, SK&F 88046, as well as UK 37248 (dazoxiben), a thromboxane synthetase inhibitor, was effective vs. arachidonic acid-induced decreases in CDYN; however, SK&F 88046 failed to alter significantly bronchopulmonary effects induced by other known bronchoconstrictors, e.g., PGF2 alpha, PGD2, histamine or acetylcholine. Therefore, SK&F 88046 represents an antagonist of TxA2-mediated changes in airway mechanics in the anesthetized dog.

Acetylcholine↗
PubMed1984

Differential inhibition of LTD4-mediated bronchopulmonary effects by salbutamol.

The effects of systemically administered salbutamol on LTD4-induced changes in pulmonary mechanics and tracheal microvascular permeability in the anesthetized guinea pig were compared. Salbutamol (50 micrograms/kg i.v.) virtually abolished the decreases in Cdyn and Gaw produced by i.v. LTD4, but did not alter the LTD4-induced increase in tracheal microvascular permeability. Thus, it appears that although the spasmolytic properties of salbutamol may profoundly inhibit LTD4-mediated bronchoconstriction, salbutamol might only be of limited value in reducing the airway inflammatory effects of LTD4.

Airway Resistance↗
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

The effects of nifedipine and verapamil on antigen-induced bronchoconstriction in dogs.

The effects of calcium channel blockers, nifedipine and verapamil (i.v. and aerosol), were investigated in beagle dogs natively allergic to Ascaris suum antigen. Control exposures to an aerosol of Ascaris antigen provoked significant bronchopulmonary changes, i.e., increases in pulmonary resistance (RL) and decreases in dynamic lung compliance (CDYN). Pretreatment with either nifedipine or verapamil (200 micrograms/kg, i.v.) provided significant inhibition in the RL responses to Ascaris antigen (P less than 0.015) while neither agent significantly affected CDYN changes. When administered as an aerosol, verapamil (1.0%; 10 breaths) significantly inhibited both the RL and CDYN responses to Ascaris antigen (P less than 0.05), whereas a similar concentration of nifedipine was without effect. Resting basal levels of RL and CDYN were unaffected by either the i.v. route or by aerosols of either nifedipine or verapamil. These results suggest that calcium channel blockers may have beneficial effects against allergen-provoked bronchoconstriction; however, differences appear to exist in the choice of agent, route of administration and site of action.

Animals↗
PubMed1983

Enhanced bronchoconstriction responses to prostaglandin F2 alpha following inhalation of sulfur dioxide.

The effect of chronic sulfur dioxide (SO2) inhalation was investigated in pharmacologic-induced bronchoconstriction in beagle dogs. Increases in pulmonary resistance (RL) and decreases in dynamic lung compliance (CDYN) were observed with i.v. and aerosol administration of prostaglandin F2 alpha (PGF2 alpha). After control historical data were accumulated, the animals received exposures of 500 ppm of SO2 for two hours twice a week. After six months of chronic SO2 exposure, a significant enhancement in the RL response to i.v. and aerosolized PGF2 alpha was observed as compared to pre-SO2 data. Tracheobronchial inflammation, as observed by fiberoptic bronchoscopy, occurred as a result of the chronic inhalation of SO2; however, only a small increase in mucous production was observed visually. In addition, hypercapnic and acidotic changes in blood gas profiles were found. Therefore, beagle dogs chronically exposed to SO2, developed hyperactive airways as seen by increased sensitivity to PGF2 alpha. This model appears to reflect many of those changes observed in clinical bronchial hyperreactivity and may provide an additional insight into obstructive airways disease.

Animals↗
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↗