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Biomedical subjects

M A Wasserman

Publications and source records attributed to M A Wasserman.

At least 37 records · Page 2Linked to original sources
PubMed1988

Effects of the thromboxane receptor antagonist SK&F 88046 in the canine, monkey and human coronary vasculature.

U-46619, a stable "functional" thromboxane/endoperoxide receptor agonist, produced potent contractile responses in isolated canine, rhesus monkey and human left circumflex coronary arteries (EC50 = 9.11 x 10(-9)M, 1.98 x 10(-8)M and 3.50 x 10(-9)M, respectively). Canine intrapulmonary veins were also contracted potently by U-46619 (EC50 = 1.22 x 10(-9)M). SK&F 88046, a thromboxane A2 (TxA2) end-organ receptor antagonist, blocked the vasoconstrictor effects of U-46619 in the canine circumflex artery (KB = 1.33 x 10(-8)M), canine intrapulmonary vein (KB = 1.46 x 10(-9)M), monkey circumflex artery (KB = 8.47 x 10(-8)M), and human circumflex artery (KB = 8.49 x 10(-7)M). SK&F 88046 was 10-60 times more potent in the canine and rhesus monkey coronary vasculature than in the human coronary preparations. Intracoronary administration of U-46619 to anesthetized, open chest dogs produced a dose-related decrease in left circumflex coronary artery blood flow which resulted in decreases in left ventricular developed pressure, left ventricular positive and negative dP/dt, ascending aortic blood flow, and an increase in left ventricular end-diastolic pressure. The decrease in coronary blood flow and the hemodynamic changes were either attenuated or completely inhibited by i.v. administration of SK&F 88046 (2.5 mg/kg + 0.05 mg/kg/min or 5.0 mg/kg + 0.1 mg/kg/min). SK&F 88046 was compared to two other TxA2 receptor antagonists in canine isolated intrapulmonary veins. SQ 29,548 was approximately 2-times more potent than SK&F 88046 as an antagonist of U-44619 mediated contractions (KB = 7.0 x 10(-10)M). In contrast, BM 13.177 was 150-fold less potent (KB = 2.19 x 10(-7)M) than SK&F 88046. Thus, the present study demonstrates species variability in response to TxA2 agonists and antagonists and reconfirms the relative importance of species selection in studying these agents.

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

Regional differences in the reactivity of guinea-pig airways.

Regional differences in the sensitivity of guinea-pig airways to cholinergic and beta-adrenoceptor stimulation as well as Schultz-Dale responses were studied in vitro. Carbachol and isoproterenol produced a 27% and 39% greater response, respectively, in the trachea as compared to the bronchus. Contractions to histamine in tracheal and bronchial tissues were significantly less than those evoked by carbachol (P less than 0.05); however, lung parenchymal strips did not show any difference in maximal contractility to these agonists. Responses to antigen in airways from sensitized guinea-pigs or responses to anaphylactic mediators, LTD4 and PGD2, in normal airways did not show any differences in maximum tissue contractility (trachea and bronchus). Among the airway tissues examined, lung parenchymal strips were more responsive to these mediators as compared to tracheal and bronchial tissues. Threshold and sub-threshold concentrations of LTD4 had no effect on tracheal and bronchial airway contractions to PGD2; however, PGD2-induced contractions of the lung parenchymal strip were significantly inhibited in the presence of LTD4 (P less than 0.0001). Our data suggest that: (1) considerable regional differences exist in the reactivity of guinea-pig airways; (2) the maximum responses of bronchial airways to cholinergic and beta-adrenergic stimuli appear less than that observed in the trachea; (3) small peripheral airways appear more responsive to some mediators of anaphylaxis than are the larger central airways. Therefore, it would appear that the trachea and bronchus are more responsive to cholinergic stimuli, while the lung parenchyma is more responsive to PGD2, LTD4 and also to in vitro anaphylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Flushing and haemodynamic responses to vasopressin peptides in the rhesus monkey.

1. The mechanism of the flushing, hypotension and tachycardia associated with i.v. administration of desGlyd(CH2)5D-Tyr(Et)VAVP (SK&F 101926; 25 micrograms kg-1) and the selective V2 antidiuretic agonist, desamino-8-D-arginine vasopressin (dDAVP; 3 micrograms kg-1) was studied in ketamine-anaesthetized rhesus monkeys. 2. The flushing associated with SK&F 101926 was reduced by pretreatment with a mast cell stabilizer and by repeated administration of peptide (within 2-4 weeks). A similar desensitization to dDAVP-associated flushing was observed on repeated administration. 3. Treatment with dDAVP also resulted in reduced SK&F 101926-associated flushing. 4. The hypotension associated with SK&F 101926 was not affected by pretreatment with a mast cell stabilizer. A similar degree of hypotension was observed with repeated administration of either SK&F 101926 or dDAVP. 5. The tachycardia associated with SK&F 101926 was reduced by pretreatment with a mast cell stabilizer or repeated administration of SK&F 101926. Repeated administration of dDAVP, however, resulted in an enhanced tachycardia. 6. Indomethacin (5 mg kg-1 i.v.) did not alter the flushing or the hypotension associated with the administration of either SK&F 101926 or dDAVP, but resulted in an enhanced tachycardia to SK&F 101926. 7. Administration of a selective V1 vasopressor antagonist did not result in flushing, hypotension or tachycardia. 8. It was concluded that the flushing response to vasopressin-like peptides in rhesus monkeys may be due to an action on mast cells, whereas the haemodynamic responses are not, but probably involve direct vasodilator actions.

Animals↗
PubMed1988

Effect of sulfidopeptide leukotrienes D4 and E4 on ileal ion transport in vitro in the rat and rabbit.

Effects of leukotrienes D4 and E4 (LTD4 and LTE4) on electrolyte transport were examined, employing stripped segments of rat and rabbit ileum mounted in Ussing chambers. Addition of LTD4 or LTE4 to the serosal but not the mucosal bathing solution elicited a transient increase in short-circuit current (Isc) with maximal responses seen at 10(-5) M and 10(-8) M in rat and rabbit respectively and a sustained decrease in transepithelial conductance (Gt) in the rat only. In the rat, Cl replacement, reduction of bathing solution [Ca2+] to 1 microM or pretreatment with 1 microM indomethacin or meclofenamic acid inhibited the LTD4- or LTE4-induced Isc changes with no effect on the decrease in Gt. LTD4 (10 microM) transiently increased net Cl secretion and produced a sustained decrease in both unidirectional and net Na transport and mucosal-to-serosal Cl flux in rat ileum. The decrease in unidirectional Na fluxes is accounted for predominantly by a change in the potential independent flux of Na. These results suggest that the increase in Isc in both rat and rabbit is mediated by arachidonic acid metabolites, whereas the decrease in Gt and net Na absorption in rat ileum is mediated by a cyclooxygenase-independent pathway.

Animals↗
PubMed1988

Characterization of the conjunctival vasopermeability response to leukotrienes and their involvement in immediate hypersensitivity.

The microvascular permeability response of the guinea pig conjunctiva to sulfidopeptide leukotrienes (LTs) was quantified as extravasation of radiolabeled bovine serum albumin. The LTs were potent inducers of increased microvascular permeability, with relative potencies LTE4 greater than or equal to LTD4 greater than LTC4. The response to LTs was unaffected by indomethacin or a pyrilamine/cimetidine combination, but the LT antagonists FPL 55712 and SKF 102922 significantly inhibited the response to LTC4, LTD4 and LTE4. In guinea pigs actively sensitized to ovalbumin, topical ocular administration of ovalbumin markedly increased conjunctival microvascular permeability; this response was reduced by approximately 50% following histaminergic blockade by pyrilamine/cimetidine. FPL 55712 and SKF 102922 and the 5-lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) had no effect on the response to antigen when used alone. However, each agent significantly reduced the non-histaminergic component of the response when given in conjunction with pyrilamine/cimetidine. Thus, it appears that the immediate hypersensitivity response in guinea pig conjunctiva has a possible non-histaminergic component which is at least partly mediated by LTs.

Animals↗
PubMed1988

Functional antagonism by salbutamol suggests differences in the relative efficacies and dissociation constants of the peptidoleukotrienes in guinea pig trachea.

To assimilate information about the relative efficacies and affinities of the peptidoleukotrienes, the ability of the beta adrenoceptor agonist salbutamol to antagonize functionally contractions produced by leukotrienes (LT)C4, LTD4 and LTE4 was examined in the guinea pig trachea. There was a marked gradation in the sensitivity of LT-induced responses to antagonism by pretreatment with salbutamol (0.01-1.0 microM): LTC4 less than LTD4 less than LTE4. These data suggest marked differences in the receptor reserve for the LTs. However, this postulate is not supported by the finding that the magnitude of the ratio for the estimated dissociation constant, KA, and EC50 values, which provides an indirect measure of the relative receptor reserve, were similar: LTC4 = 4.50, LTD4 = 10.54 and LTE4 = 3.18. Substantial differences were apparent in the estimated KA values: LTC4 = 2.88 nM, LTD4 = 11.8 and LTE4 = 46.4 nM. In the presence of a maximally effective concentration of LTE4 (1 or 10 microM), addition of LTD4 (1 or 10 microM) produced further contraction of the tissue whereas the reverse was not the case. Furthermore, in the presence of salbutamol (70 nM), LTE4 (0.1 microM) produced a 3.6-fold rightward shift in LTD4 concentration-response curves with no effect on the maximum contractile response; a pKB of 7.42 was calculated for LTE4. The results suggest that the large differences in the ability of pretreatment with salbutamol to inhibit contractions produced by LTC4, LTD4 or LTE4 are not attributable solely to corresponding differences in receptor reserve for the individual LTs.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuterol↗
PubMed1988

Effects of putative thromboxane receptor agonists and antagonists on rat small intestinal ion transport.

Effects of a thromboxane mimic, U46619, on electrolyte transport were examined in vitro using stripped segments of rat ileal mucosa mounted in Ussing chambers. Addition of U46619 to the serosal bathing solution elicited a transient increase in short-circuit current (Isc) and decrease in transepithelial conductance (Gt). The increase in Isc was accompanied by a transient increase in Cl- secretion and decrease in Na+ absorption. In the steady-state, Isc was not increased whereas Gt remained decreased and Na+ and Cl- absorption were inhibited. Removal of Cl- or pretreatment with serosal and mucosal indomethacin (1 microM) or the thromboxane receptor antagonist, SK&F 88046, added to the serosal bathing solution, inhibited the increase in Isc stimulated by U46619 (apparent KB approximately 8 nM). The effects of U46619 on both Isc and Gt are qualitatively similar to those resulting from stimulation with leukotriene D4. However, the changes in Isc with leukotriene D4 (10 microM) are antagonized by SK&F 88046 only at high concentrations (1-10 microM). In addition, the secretagogues prostaglandin F2 alpha, lys-bradykinin, serotonin and histamine, produce qualitatively similar changes in Isc to those seen with U46619 without altering Gt. With the exception of prostaglandin F2 alpha, the effects of these secretagogues are not inhibited by SK&F 88046 (10 microM). These results indicate that U46619 acts at a thromboxane receptor to stimulate intestinal Cl- secretion and inhibit Na+ and Cl- absorption. These changes are inhibited selectively by the thromboxane receptor antagonist, SK&F 88046.

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

Beneficial effects of the peptidoleukotriene receptor antagonist, SK&F 104353, on the responses to experimental endotoxemia in the conscious rat.

The purpose of this study was to examine the effects of the peptidoleukotriene receptor antagonist, SK&F 104353, on the responses to endotoxin in conscious male Sprague-Dawley rats. Administration of Salmonella enteritidis endotoxin (30 mg/kg i.v.; LD90) resulted in a decrease in the number of circulating platelets, leukopenia, an increase in hematocrit, and 0% survival at 24 hr. Pretreatment with SK&F 104353 (1 mg/kg, i.v. bolus followed by 3 mg/kg/hr, i.v. infusion for 6 hr) 5 min before injection of endotoxin produced steady state plasma drug levels of 1.6 micrograms/ml in naive animals and levels of approximately 3.4 micrograms/ml in endotoxemic animals (P less than 0.05). SK&F 104353 significantly attenuated the endotoxin-induced thrombocytopenia (P less than 0.05) but had no effect on either the endotoxin-induced early leukopenia or late leukocytosis. Additionally, SK&F 104353 significantly reduced the endotoxin-induced hemoconcentration (P less than 0.05) and improved survival to 30% at 48 hr (P less than 0.05). A higher dose of SK&F 104353 (2 mg/kg, i.v. bolus followed by 10 mg/kg/hr, i.v. infusion for 6 hr) did not produce any further benefit. These data indicate clearly the pathophysiologic role of peptidoleukotrienes in endotoxemia and suggest SK&F 104353 could be useful for ameliorating some of the deleterious sequelae associated with this condition.

Animals↗
PubMed1988

Prevention and reversal of endotoxin-induced pulmonary hypertension by a leukotriene antagonist.

We investigated the role of leukotrienes in endotoxin-induced changes in pulmonary circulation. In six conscious sheep, haemodynamic measurements were obtained for the calculation of pulmonary vascular resistance (PVR), along with measurements of arterial oxygen tension (PaO2), leucocyte count (WBC), thromboxane B2 (TxB2), 6-Keto-PgF1 alpha and PgF2 alpha, before and at predetermined intervals after a 10-min infusion of E. coli endotoxin (0.3 microgram/kg), with and without treatment with the leukotriene receptor antagonist, FPL-57231. Endotoxin caused a biphasic response (i.e., phase I = 0-1 h, phase II = 1.5-4 h), with a mean +/- SE increase in PVR to 415 +/- 112% of baseline during phase I and a lesser increase of 175% (range = 153-199%) of baseline during phase II. Mean +/- SE PaO2 decreased from 86 +/- 4 to 67 +/- 6 mmHg and WBC count decreased from 8.6 +/- 0.6 to 2.8 +/- 0.7 thousand/mm3 during phase I, whereas TxB2 increased from 145 +/- 28 to 3164 +/- 1082 pg/ml, 6-Keto-PgF1 alpha from 129 +/- 14 to 438 +/- 114 pg/ml and PgF2 alpha from 122 +/- 7 to 242 +/- 43 pg/ml. One hour infusion of FPL-57231 (1 mg/kg/min) administered prior to and throughout phase I attenuated the phase I increases in PVR without preventing the increases in TxB2; however, it partly attenuated 6-Keto-PgF1 alpha and enhanced generation of PgF2 alpha during phase I. Discontinuation of FPL-57231 was followed by an exaggerated response of PVR during phase II to an average of 209% of baseline (range = 186-235%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Enhancement of leukotriene D4-induced contraction of guinea-pig isolated trachea by platelet activating factor.

The effect of platelet activating factor (PAF), a potent lipid mediator of inflammation, was examined in the induction of airway hyperreactivity to known mediators of anaphylaxis. Concentration-dependent contractions of the isolated guinea-pig trachea to PAF (10(-7)-10(-5) M) were produced and an EC50 value was found to be 7.5 X 10(-7) M. Pretreatment for 30 min with a known PAF inhibitor, CV-3988 (10(-5) or 10(-4) M), produced significant inhibition of PAF contractions; however, at 10(-6) M, CV-3988 had no effect. In the presence of meclofenamic acid (10(-6) M), the concentration-response curve to PAF was shifted significantly upward and to the left. This potentiation could be reversed by pretreating the tissues with the peptidoleukotriene antagonists, FPL 55712 or SK&F 102922 (10(-5) M). Pretreatment with PAF concentrations having essentially no intrinsic activity (10(-8), 10(-7)) significantly enhanced the contraction of guinea-pig trachea to various concentrations of LTD4 and to certain concentrations of a thromboxane mimic (U-46619). Pretreatment with lyso-PAF failed to potentiate the LTD4 response, while pretreatment with CV-3988 reverse the potentiation by PAF of the lower concentrations of LTD4. However, PAF failed to enhance contractions (with or without the presence of meclofenamic acid) to acetylcholine, histamine, PGD2 or LTC4 (in the presence of serine borate). These results indicate a possible role for PAF as a mediator of airway hyperreactivity.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

Inhibition of leukotriene D4-induced coronary vasoconstriction by leukotriene antagonists in the anesthetized dog.

Anesthetized open-chest dogs were instrumented for the measurement of left circumflex coronary artery (LCX) blood flow and aortic blood flow, systemic arterial blood pressure, heart rate, lead II ECG, left ventricular end-diastolic pressure, left ventricular developed pressure and left ventricular positive and negative dP/dt to study the hemodynamic effects of leukotriene D4 (LTD4) and selective LTD4 antagonists on the coronary vasculature. Administration of LTD4 alone into the LCX (0.625-10 micrograms) produced a dose-dependent decrease in LCX blood flow, dP/dt and aortic blood flow and an increase in left ventricular end-diastolic pressure. Systemic arterial blood pressure, left ventricular developed pressure and heart rate were unchanged by LTD4. During i.v. infusions of the LTD4 antagonists, SK&F 102922 or FPL 55712 (1 mg/kg/min), the dose-dependent decreases in LCX flow, dP/dt and aortic blood flow were blocked whereas the increase in left ventricular end-diastolic pressure remained unchanged. The thromboxane A2 antagonist, SK&F 88046 (5 mg/kg + 0.1 mg/kg/min), which has been reported previously to block the coronary blood flow reducing action of LTC4, had no effect on the LCX blood flow responses to intracoronary LTD4. In a separate study, dogs instrumented in a similar manner were given bolus injections of arginine-vasopressin (1 microgram), the thromboxane A2 mimetic, U-46619 (10 micrograms), LTD4 (10 micrograms), angiotensin II (1 microgram) and prostaglandin F2 alpha (100 micrograms) directly into the LCX to provoke coronary vasoconstriction. SK&F 102922 and FPL 55712 selectively blocked the coronary vasoconstriction produced by LTD4, but had no effect on vasoconstriction produced by the other agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1987

Is the guinea pig trachea a good in vitro model of human large and central airways? Comparison on leukotriene-, methacholine-, histamine- and antigen-induced contractions.

To analyze comprehensively the relevance of the guinea pig trachea as a model of human large and central airways, the contractile effects of the peptidoleukotrienes (LTs), histamine, methacholine and antigen on guinea pig and human airways were compared in vitro. Although some differences were apparent, LTC4, LTD4, LTE4, histamine and methacholine had comparable EC50 values and elicited similar maximal responses in both guinea pig trachea and human bronchus (second-seventh generation). In the presence of l-serine borate (45 mM), LTC4 concentration-response curves were shifted significantly to the left in guinea pig trachea but not in human bronchus. Furthermore, the LT receptor antagonists (SK&F 102922 and FPL 55712) had similar potencies against LTC4- and LTD4-induced contractions of human bronchus, whereas, in the guinea pig trachea, they were much more effective antagonists of responses produced by LTD4 than those elicited by LTC4. These results provide further evidence that, unlike in human bronchus, LTC4- and LTD4-induced contractions in the guinea pig trachea are mediated via distinct leukotriene receptors. Ovalbumin-induced contractions of actively sensitized guinea pig tracheae exhibited the same profile as anti-immunoglobulin E-induced contractions of the passively sensitized human bronchus. Furthermore, antigen-induced contractions in both the guinea pig trachea and human bronchus possessed a similar sensitivity to inhibition by mepyramine (10 microM) and the LT antagonists (10 microM), added either alone or in combination. These results indicate that the isolated guinea pig trachea is a suitable model of human large and central airways.

Adult↗
PubMed1987

Pharmacologic profile of SK&F 104353: a novel, potent and selective peptidoleukotriene receptor antagonist in guinea pig and human airways.

In this report, we describe the in vitro and in vivo pharmacologic profile of 2(S)-hydroxy-3(R)-[(2-carboxyethyl)thio]-3-[2-(8-phenyloctyl)pheny l]- propanoic acid (SK&F 104353) in guinea pig and human airways. In the isolated guinea pig trachea, SK&F 104353 was a potent, competitive antagonist of leukotriene (LT) D4-induced contractions (pA2 = 8.6). In contrast, SK&F 104353 produced little effect on LTC4 concentration-response curves under conditions where the bioconversion of LTC4 to LTD4 was inhibited. LTE4-induced contractions in guinea pig trachea were sensitive to inhibition by SK&F 104353 (pKB greater than 8.9). SK&F 104353 (10 microM) had no intrinsic contractile activity and was without effect on contractions produced by KCl, histamine, prostaglandin D2, platelet-activating factor or U-44069 in guinea pig trachea. Furthermore, unlike other purported LT antagonists, LT 171883 and FPL 55712, SK&F 104353 (30 microM) did not inhibit cyclic nucleotide phosphodiesterase activity measured in homogenates from canine tracheal smooth muscle. In the isolated human bronchus, SK&F 104353 produced concentration-dependent rightward shifts in LTD4 concentration-response curves and, unlike in guinea pig trachea, was an effective antagonist of LTC4-induced contractions with a pKB of 8.0 to 8.4. This provides further evidence that, in contrast to guinea pig airways, responses produced by LTC4 and LTD4 in human bronchus appear to be mediated via the same LT receptor population. SK&F 104353 was also an effective antagonist of LTE4-induced responses in human bronchus (pKB greater than 8.2).(ABSTRACT TRUNCATED AT 250 WORDS)

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1987

Effect of alpha-adrenoceptor stimulation of isolated canine, ferret and guinea pig airways.

Functional responses and subtypes of alpha-adrenoceptors in canine trachealis smooth muscle were investigated using the agonists; epinephrine, norepinephrine, SK&F 89748 (alpha 1-selective) and BHT-933 (alpha 2-selective) in the presence of a beta-adrenoceptor antagonist. Tissue contractility to these agonists was in the range of 16 to 46% of the maximum response to serotonin. SK&F 89748 was most effective in canine airways; however, the contractions could be abolished by methysergide. Neither precontraction of the airways by KCl nor degree of beta-adrenoceptor blockade increased the reactivity of SK&F 89748 in this tissue. Reactivity of ferret and guinea pig airways to norepinephrine in the presence of beta-adrenoceptor blockade was insignificant. Responses of guinea pig airways to tyramine was about 1,000-fold less than those observed for vascular smooth muscle. Taken together these data suggest that alpha-adrenoceptors do not have any significance in the pathogenesis of airway hyperreactivity in dog, ferret and guinea pig airways. Moreover, adrenoceptors in guinea pig airways appear to be hormonal beta-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1986

Differences in the ability of salbutamol to prevent and reverse LTC4-induced contractions of the guinea-pig isolated trachea: influence of l-serine borate.

In the presence of l-serine borate, salbutamol was much more effective in reversing rather than preventing LTC4-induced contractions of guinea-pig trachea. This suggests that different mechanisms are involved in initiating versus maintaining LTC4-induced contractions. In addition, the ability of salbutamol pretreatment to prevent LTC4-induced contractions was reduced substantially in the presence of l-serine borate, suggesting that the metabolites of LTC4 (LTD4 and LTE4) are more sensitive to inhibition by beta-adrenoceptor agonists than is LTC4 itself.

Albuterol↗
PubMed1986

The effect of calcium antagonists on histamine and leukotriene-induced tracheal microvascular permeability in the guinea pig.

The effects of several calcium antagonists, i.e., nifedipine, verapamil and 8-[N,N-diethylamino]-octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8), were evaluated in situ on agonist-induced increases in permeability of the airway microvasculature in anesthetized guinea pigs. Vascular permeability was measured as tracheal extravascular albumin content by using 125I-bovine serum albumin and the utilization of 51Cr labelled-erythrocytes to correct for blood volume. Intratracheal injections of histamine (1, 10 and 100 micrograms) or leukotriene (LT) D4 (1, 10 and 100 ng) produced dose-dependent increases in extravasated radiolabelled albumin in the trachea. Although histamine produced a greater maximal response than LTD4, the latter provocation was ten times more potent than the former. Nifedipine, a dihydropyridine calcium slow channel blocker, exhibited dose-dependent (30, 100 and 300 micrograms/kg) inhibitory activity against histamine-induced increases in extravascular albumin, while another calcium slow channel blocker, verapamil (100, 300 and 1000 micrograms/kg), exhibited much less activity. TMB-8, a purported intracellular calcium antagonist (1 and 10 mg/kg), was observed to have some inhibitory activity versus histamine. Similar doses of all three calcium antagonists failed to significantly inhibit increases in tracheal microvascular permeability evoked by LTD4. These results suggest that differences in mediator-induced microvascular permeability in the guinea pig trachea are evident depending upon the agonist selected and the pool of calcium utilized.

Animals↗
PubMed1986

Synthesis and structure-activity relationship studies of a series of 5-aryl-4,6-dithianonanedioic acids and related compounds: a novel class of leukotriene antagonists.

A series of 5-alkynyl- and 5-aryl-4,6-dithianonanedioic acids and related compounds has been prepared for evaluation of leukotriene antagonist activity. The alkynyl compounds were prepared by thioacetal exchange from the corresponding acetylenic acetals. The aryl derivatives were synthesized from the appropriate benzaldehydes, most of which were prepared by one of three general routes: Meyers' oxazolin method, a palladium coupling procedure, and a hydroxybenzaldehyde alkylation. The analogues were examined in vitro for their ability to antagonize an LTD4-induced contraction of isolated guinea pig tracheal smooth muscle and to compete with [3H]LTD4 for receptor sites on guinea pig lung membrane. A number of structure-activity relationships have emerged from this study. There is an optimal chain length of 10-12 atoms (or its equivalent) in the lipid tail and two methylenes in the polar region. In the aromatic series, the ortho- and meta-substituted compounds have comparable activity, whereas the para derivatives are inactive. Substitution in the aromatic ring and lipid tail is generally well tolerated, with the terminal phenyl (6) and acetylene (33) analogues having especially good activity. Conformational restriction of either the polar region or lipid tail produced compounds devoid of activity. A number of selected analogues were also evaluated in vivo as antagonists of LTD4-induced bronchoconstriction in the guinea pig. The data established these compounds as a novel class of leukotriene antagonists with potential utility for the treatment of asthma and other immediate hypersensitivity diseases.

Alkynes↗