Precursor role of arachidonic acid in release of slow reacting substance from rat basophilic leukemia cells.
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The release of slow reacting substance (SRS) from rat basophilic leukemia cells (RBL-1) by the ionophore A23187 (5-10 mug/ml) was stimulated 5-fold by arachidonate and inhibited 78% by 5,8,11,14-eicosatetraynoate (an inhibitor of both fatty acid cyclooxygenase and lipoxygenase). Linoleic acid and linolenic acid both inhibited SRS formation, whereas indomethacin (a cyclooxygenase inhibitor) had no effect. Radiolabel from [14C]- or [3H]arachidonate was incorporated into SRS as indicated by comigration of radioactivity and bioreactivity in several chromatographic systems after purification to apparent radiochemical homogeneity. The radiolabeled SRS was clearly separated chromatographically from other known arachidonate metabolites. Thus, SRS appears to be a previously undescribed product of arachidonic acid metabolism, probably formed through the lipoxygenase pathway. The ability to prepare purified, biosynthetically labeled, SRS should be of considerable help in further studies of its structure, biologic function, and catabolism. (+info)
Combined contribution of endothelial relaxing autacoides in the rat femoral artery response to CPCA: an adenosine A2 receptor agonist.
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Inhibitory effect of N-(3,4-dimethoxycinnamoyl)anthranilic acid on release of SRS from alveolar macrophages in vitro.
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The effects of N-(3,4-dimethoxycinnamoyl)anthranilic acid (N-5') on the release of the slow-reacting substance (SRS) by zymosan- or Ca ionophore-stimulated rat and human alveolar macrophages (AM) were examined in vitro. Disodium cromoglycate (DSCG) was used as a control. N-5' at concentrations of 10(-4)-10(-3) M significantly inhibited the release of SRS from both rat and human AM stimulated by zymosan. N-5' had almost the same inhibitory effect when added to the AM culture system at any time from 180 min before to 30 min after the addition of zymosan. N-5' (10(-4)-10(-3) M) also significantly inhibited the release of SRS by Ca ionophore-stimulated rat AM. N-5' (10(-6)-10(-3) M) had no significant effect on phagocytosis of yeast particles by rat AM. DSCG (10(-6)-10(-3) M) did not inhibit the release of SRS from the zymosan-stimulated rat AM. N-5' was concluded to have a relatively specific inhibitory effect on the non-immunological release of SRS from stimulated AM. It is postulated that N-5' inhibits the process of release of SRS from AM by acting after the initial stage. (+info)
Alteration of fate of vasoactive autacoids in pulmonary circulation following monocrotaline-induced lung vascular injury in rats.
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1. To learn how pulmonary vascular injury alters the ability of the lung to metabolize vasoactive autacoids, lung vascular lesions were produced in rats by a single subcutaneous injection of monocrotaline (90 mg kg-1), and the blood pressure responses to angiotensin I (AI), angiotensin II (AII), bradykinin, prostaglandin E2 (PGE2) and substance P were examined. Vasoactive agents were given intravenously or intra-arterially. 2. On histological examination of the lung at 3 weeks after monocrotaline treatment, degeneration or necrotization of endothelial cells was evident. 3. The conversion of AI to AII was only slightly depressed by monocrotaline treatment. On the other hand, the depressor response to intravenously injected bradykinin was enhanced in monocrotaline-treated rats. When the rats were pretreated with indomethacin the depressor response to intravenous bradykinin was the same for both control and monocrotaline-treated groups which suggests that endogenous prostaglandins are involved in the enhancement of the response to bradykinin. 4. In monocrotaline-treated rats the depressor response to intravenous PGE2 was significantly enhanced depending on the period following the treatment, while that to the intra-arterial injection did not differ from control. 5. The data suggest that monocrotaline-induced lung injury impairs the metabolism of PGE2 during pulmonary circulation but has little effect on the conversion of AI to AII and the degradation of bradykinin in rats. (+info)
Pharmacologic effects of autacoids on subsets of T cells. Regulation of expression/function of histamine-2 receptors by a subset of suppressor cells.
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Autacoids (principally histamine, beta adrenergic catecholamines, and prostaglandins E and A) have only recently been recognized as substantive moderators of a number of immune functions. If autacoids are to be considered as potential therapeutic immunomodulators, it is necessary to understand their effects on subsets of T cells while they are and are not in contact with each other. This report demonstrates that autacoid receptors are nonrandomly distributed on phenotypically and functionally distinct subsets of human T cells. Each human T cell subset responded to both histamine and isoproterenol, but the dose response curve and maximal efficacy varied widely between the subsets. The suppressor T cells were more responsive to both histamine and isoproterenol than helper/inducer T cells (TH) or cytotoxic T cells (Tc). We found that after mitogenic stimulation the response to histamine, but not isoproterenol, was greatly increased only in TH (Leu 3+) and Tc (Leu 2+, 9.3+) subsets, and that this effect may be regulated by suppressor T cells (Leu 2+, 9.3-). The dramatic rise in cAMP accumulation in response to histamine in mitogen-treated TH and Tc was totally blocked by an H2 antagonist (cimetidine), but not by an H1 antagonist (mepyramine). These findings indicate interdependence of (a) immunologically uncommitted subsets in their response to selected drugs, and (b) control of basal- and autacoid-induced cAMP production, as well as (c) increased qualitative and quantitative selectivity, which is caused by mitogen. If we had performed these experiments only on unseparated cells we would not have observed the remarkable selectivity of autacoid effects on subsets of T cells. (+info)
Characteristics of neuro-effector transmission in the smooth muscle layer of dog bronchiole and modifications by autacoids.
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Electrical and mechanical properties of smooth muscle cells and of neuro-effector transmission in the smooth muscle layer of the dog bronchiole (about 1 mm in diameter) were studied with double-sucrose-gap, micro-electrode or tension recording methods. Electrical field stimulation of short duration (50 microseconds) applied to the whole tissue excited the intrinsic nerves, and evoked excitatory junction potentials (e.j.p.s) followed by a twitch-like tension; these were abolished by tetrodotoxin (10(-7) M) or by atropine (10(-6) M). 5-Hydroxytryptamine (10(-5) M) produced a tonic contracture of the bronchiole, and electrical field stimulation applied during the tonic contracture produced an initial phasic contraction and a subsequent relaxation. Atropine (10(-6) M) and propranolol (10(-6) M) selectively abolished the phasic contraction and relaxation, respectively, indicating that dog bronchiolar muscles are innervated by excitatory cholinergic and inhibitory adrenergic nerve fibres. E.j.p.s and twitch contractions evoked by electrical field stimulation at 3 min intervals showed a gradual reduction in amplitude during superfusion with normal Krebs solution, and this reduction was overcome by pre-treatment with indomethacin (10(-5) M). The mean value of the resting membrane potential of the bronchiole smooth muscle cells was -70.2 +/- 2.2 mV (+/- S.D., n = 150), and an action potential was superimposed on e.j.p.s in 50% of the muscle cells examined when the amplitude of e.j.p.s exceeded 35 mV. During repetitive field stimulation at 0.1-0.2 Hz, the amplitude of the e.j.p.s gradually increased (facilitation); this phenomenon was markedly enhanced by indomethacin (10(-5) M) and was depressed by exogenously applied prostaglandins in low concentrations (10(-11)-10(-8) M). Histamine (5 X 10(-8)-5 X 10(-7) M) enhanced the amplitude of e.j.p.s and twitch contraction evoked by field stimulation, and this effect was antagonized by mepyramine (10(-7) M). Histamine (10(-7) M) enhanced the amplitude of the ACh-induced contraction when a relatively low concentration (10(-7) M) of ACh was applied, but not when concentrations of 10(-6) M- or 10(-5) M-ACh were applied. Histamine had no effects on the facilitation of e.j.p. Bronchiolar smooth muscle cells therefore showed larger resting potentials and a greater tendency to fire action potentials than trachealis muscle, and prostaglandins and histamine are involved in inhibitory and accelerative mechanisms related to excitatory neuro-effector transmission, respectively. (+info)
Effect of exogenous 5,8,11,14,17-eicosapentaenoic acid on cardiac anaphylaxis.
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The effects of infusions of eicosapentaenoic acid (EPA) (6 X 10(-8) mol min-1 and 15 X 10(-8) mol min-1) on the coronary constriction and the release of immunoreactive sulphidopeptide-leukotrienes (SP-LT), thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha) from perfused anaphylactic guinea-pig hearts were investigated. EPA dose-dependently inhibited the profound early coronary flow reduction after antigen injection. The less pronounced late phase of anaphylactic coronary flow reduction was, however, not significantly affected. EPA (15 X 10(-8) mol min-1) significantly shortened the average duration of antigen-induced arrhythmias. EPA dose-dependently decreased release of immunoreactive TXB2 and 6-keto-PGF1 alpha from anaphylactic guinea-pig hearts. Release of immunoreactive SP-LT was dose-dependently increased after antigen challenge in the presence of EPA. Inhibiton of the release of SP-LT by the lipoxygenase inhibitor esculetin (1 X 10(-7) mol min-1) was accompanied by a significant attenuation of flow reduction during the late phase of anaphylactic vasoconstriction. Reversed phase h.p.l.c. of perfusates from anaphylactic guinea-pig hearts revealed immunoreactivity comigrating with authentic leukotriene C4 (LTC4), LTD4, and LTE4. In perfusates from hearts treated with EPA infusions, additional immunoreactivity was detected comigrating with LTC5, LTD5 and LTE5. In addition to immunoreactivity migrating with LTB4, as observed in control heart perfusates, in perfusates from EPA-treated hearts, a second peak was observed, which coincides with the retention time described for LTB5. Exogenous LTC5 (1 X 10(-12) mol min-1 and 20 X 10(-12) mol min-1) induced dose-dependent reductions of coronary flow and was found to be a slightly weaker constrictor than LTC4, but no significant differences were observed. Coronary vasoconstriction elicited by infusion of exogenous LTC4 (20 X 10(-12) mol min-1) was dose-dependently inhibited by infusions of EPA. However, the negative inotropic effect of LTC4 remained unaffected. Thus, in the isolated anaphylactic heart of the guinea-pig exogenous EPA was effectively metabolized via the 5-lipoxygenase pathway whereas the cyclo-oxygenase pathway of polyunsaturated fatty acid metabolism was found to be inhibited. The results are in agreement with the suggestion that cyclo-oxygenase products are mediators of the early phase of the anaphylactic coronary constriction, while vasoconstrictor SP-LT are involved in the later phase. However, in spite of enhanced release of SP-LT, EPA infusion did not result in increased coronary constriction. Considering the fact that EPA antagonizes LTC4-induced coronary constriction, it seems possible, that EPA might act as a functional antagonist of vasoconstrictor eicosanoids including EPA-derived SP-LT. (+info)
Characterization of the activity of a platelet activating factor antagonist, CV-3988.
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CV-3988 inhibited the vascular permeability increase induced by C16-PAF and C18-PAF in rat skin in a dose-dependent manner. The inhibition was shown to be specific and competitive with PAF on its receptor by the following observations: parallel shift of the dose-response curve; crossing of double reciprocal plots on the intersection of the ordinate; and no inhibition on other autacoids such as bradykinin, histamine, 5-hydroxytryptamine and LTC4. PAF-induced blood pressure fall in rats was also suppressed by pretreatment with CV-3988 selectively. (+info)