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Action of platelet-activating factor (PAF) antagonists on the bronchopulmonary effects of PAF in the guinea-pig.

Intravenous injection of BN 52021 in anesthetized guinea-pigs, 5 min before challenge, inhibited in a dose-dependent fashion with an IC50 of 0.90 mg/kg the bronchoconstriction induced by PAF (60 ng/kg i.v.). However, BN 52021 did not prevent the leukopenia following PAF injection but significantly inhibited the thrombocytopenia induced by PAF. The dioxolan compound, BN 52111, dose-dependently reduced the bronchoconstriction (IC50 = 0.27 mg/kg) and at doses higher than 1 mg/kg partially antagonized the decrease in the number of circulating platelets and leukocytes induced by PAF. BN 52115 also markedly inhibited the bronchoconstriction (IC50 = 0.36 mg/kg) as well as the thrombocytopenia induced by PAF, but was without significant effect on the leukopenia. These results demonstrate that the two dioxolan compounds, BN 52111 and BN 52115, are more potent than BN 52021 in inhibiting the in vivo bronchopulmonary alterations induced by PAF. Since these alterations are related to the activation of platelets by the autacoid, these blood elements are probably the targets of BN 52111 and BN 52115. Injection of PAF (10 and 100 ng) via the pulmonary artery of ventilated and perfused guinea-pig lungs induced dose-dependent increases in pulmonary inflation pressure (PIP) and pulmonary perfusion pressure (PPP), associated with a dose-dependent release of thromboxane B2 (TxB2). Addition of BN 52021, BN 52111 or BN 52115 (0.1, 1 or 10 microM) to the perfusion medium, 15 min before challenge, dose-dependently inhibited the bronchopulmonary effects of PAF. Although BN 52111 was the more potent in inhibiting the PAF-induced increase in PIP, BN 52021 was the more active with respect to the PAF-evoked generation of TxB2, suggesting that the two phenomena are not directly related.

Animals↗
PubMed1989

Stimulation of platelet-activating factor synthesis by a nonmetabolizable bioactive analog of platelet-activating factor and influence of arachidonic acid metabolites.

Platelet-activating factor (PAF) is a potent neutrophil agonist operating through specific receptors located on the cell surface. Binding of PAF to its receptor may also stimulate further PAF synthesis, thus providing a means of amplifying the PAF signal for the cell of origin and/or other responsive cells. In this report we demonstrate that 1-O-alkyl-2-N-methylcarbamyl-sn-glycero-3-phosphocholine (C-PAF), a nonmetabolizable bioactive analog of PAF, stimulates human neutrophils to synthesize PAF, as detected by [3H]acetate incorporation into PAF. This approach allowed us to conclude that [3H]acetate-labeled PAF was formed from endogenous precursor rather than mere turnover of the stimulatory dose of PAF. PAF's ability to initiate further PAF synthesis was confirmed by measuring the PAF-stimulated conversion of 1-O-[3H]alkyl-2-acylglycerophosphocholine to 1-O-[3H]alkyl-2-acetylglycerophosphocholine by prelabeled human neutrophils and by determining the molecular species of 1-O-alkyl-2-[3H]acetylglycerophosphocholine produced by cells stimulated with a single molecular species of PAF (C15:0). Degradation of exogenously added [3H]PAF was not inhibited by C-PAF/5-hydroxyeicosatetraenoic acid treatment. Thus, inhibition of PAF degradation was ruled out as the mechanism accounting for the appearance of labeled PAF in the stimulated cells. Synthesis of PAF in response to C-PAF was not dependent on cytochalasin B pretreatment but was dramatically potentiated by 5-hydroxyeicosatetraenoic acid, which alone was without effect. Additionally, we have demonstrated that another major arachidonate metabolite of neutrophils, leukotriene B4, stimulates PAF production. Thus, at least three products of activated neutrophils, including PAF itself, can promote PAF synthesis by these cells. This positive feedback effect may amplify autacoid production and the final cellular response.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1989

An electrophysiological study of microvascular permeability and its modulation by chemical mediators.

In continuous microvessels the permeability barrier is constituted by the endothelium, consisting of a single layer of endothelial cells separated by hydrophilic clefts. Ions and small hydrophilic solutes permeate the endothelium via the intercellular spaces, and the dimensions of this pathway determine the permeability. Endothelial permeability characteristics have been extensively studied by physiological techniques used on whole organs. It is known that permeability of venules increases after stimulation with inflammatory mediators, probably by a mechanism involving formation of widenings of the interendothelial cleft, termed leaks. To the present knowledge about the function of the microvascular endothelium my studies have added the following information: 1. The electrical resistance or conductance of endothelium recorded on single frog microvessels in vivo vary by at least three orders of magnitude from the tight brain endothelium (Rm = 1870 omega cm2, Gm = 0.53 mScm-2) to the microvascular endothelia of skin (Rm = 24-70 omega cm2, Gm = 14-42 mScm-2), muscle (Rm = 23-36 omega cm2, Gm = 28-43 mScm-2) and mesentery (Rm = 1-3 omega cm2, Gm = 0.33-1.0 Scm-2). 2. Potassium ion permeabilities calculated from the electrical conductances average 8.5 x 10(-7), 3.4 x 10(-5), 5.7 x 10(-5), and 80 x 10(-5) cm sec-1 for brain, skin, muscle and mesenteric microvessels, respectively. These values comply with what has been predicted from whole-organ experiments. 3. Venules are 1.5-2 x more permeable to ions than arterioles. 4. Ion permeabilities of capillaries are not much different from those of venules, and since the surface area of venules is comparable to that of capillaries, venules may be important exchange vessels for small solutes. 5. The specific electrical resistance of frog blood-brain barrier is similar to that of a tight epithelium, resembling brain endothelium by several criteria. 6. The electrical resistance of brain endothelium is at least one order of magnitude smaller than that of the endothelial cell membrane, strongly indicating that microvascular permeability to small solutes is mainly paracellular in brain, as it is in other organs. 7. Ion permeability of frog blood-brain barrier is reversibly increased by various autacoids: serotonin, bradykinin, ATP, ADP, AMP, og LTC4. These receptor-agonists all induce similar changes: permeability increases within 1-2 sec after administration, rapidly peaks with values less than two-fold the control value and reverses at a much slower rate (5-15 min).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

G proteins control diverse pathways of transmembrane signaling.

Hormones, neurotransmitters, and autacoids interact with specific receptors and thereby trigger a series of molecular events that ultimately produce their biological effects. These receptors, localized in the plasma membrane, carry binding sites for ligands as diverse as peptides (e.g., glucagon, neuropeptides), lipids (e.g., prostaglandins), nucleosides and nucleotides (e.g., adenosine), and amines (e.g., catecholamines, serotonin). These receptors do not interest directly with their respective downstream effector (i.e., an ion channel and/or an enzyme that synthesizes a second messenger); rather, they control one or several target systems via the activation of an intermediary guanine nucleotide-binding regulatory protein or G protein. G proteins serve as signal transducers, linking extracellularly oriented receptors to membrane-bound effectors. Traffic in these pathways is regulated by a GTP (on)-GDP (off) switch, which is regulated by the receptor. The combination of classical biochemistry and recombinant DNA technology has resulted in the discovery of many members of the G protein family. These approaches, complemented in particular by electrophysiological experiments, have also identified several effectors that are regulated by G proteins. We can safely assume that current lists of G proteins and the functions that they control are incomplete.

Animals↗
PubMed1989

Identification of receptors for platelet-activating factor in rat Kupffer cells.

Ligand binding studies demonstrated that isolated rat Kupffer cells possess high affinity binding sites for platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, AGEPC). AGEPC binding reached saturation within 10 min at 25 degrees C and was reversible. A Scatchard analysis revealed a single class of AGEPC receptors numbering about 10,600 sites/cell and possessing a dissociation constant of 0.45 nM. Similar values for the dissociation constant for AGEPC (0.12 and 0.34 nM) were obtained independently by kinetic analysis of specific AGEPC binding. AGEPC binding was stereospecific and was inhibited by Zn2+ and AGEPC receptor antagonists including BN52021 and U66985. The AGEPC receptor was functionally active since it was shown to mediate arachidonic acid release and eicosanoid production in Kupffer cells, and these events were inhibited by AGEPC receptor antagonist BN52021. The receptor-mediated arachidonic acid release was extracellular calcium-dependent and was abolished by calcium channel blocker prenylamine and by [ethylenebis(oxyethylenenitrilo)]tetraacetic acid, indicating that calcium influx through a receptor-regulated calcium channel in the plasma membrane is involved in the AGEPC-induced arachidonic acid release. It is suggested that rat Kupffer cells have specific and functionally active AGEPC receptors which are involved in signaling mechanisms which govern the production of several other autacoid-type mediators in the liver.

Animals↗
PubMed1989

Cyclic guanosine 3',5' monophosphate mediates the inhibitory effect of atrial natriuretic factor in adrenergic, neuronal pheochromocytoma cells.

This study tests the hypothesis that atrial natriuretic factor (ANF) inhibits catecholamine release from rat pheochromocytoma cells by increasing levels of intracellular cyclic GMP (cGMP). Rat differentiated pheochromocytoma cells are a model of adrenergic nerves and allow the exploration of the effects of various hormones, autacoids, drugs and neuromodulators on adrenergic neurotransmission in cell culture. Synthetic rat ANF (99-126) inhibited K+-induced norepinephrine and dopamine release, as measured by high-performance liquid chromatography, in a concentration-dependent manner over the concentration range of 10(-11) to 10(-8) M. ANF stimulated intracellular cGMP accumulation, as measured by specific radioimmunoassay, in a concentration-dependent manner over the same concentration range. The cGMP analog, N2-2'-O-dibutyryl cGMP also inhibited K+-induced norepinephrine and dopamine release in a concentration-dependent manner. The results of this study are consistent with the hypothesis that ANF acts as an inhibitory neuromodulator in adrenergic nerves via the second messenger, cGMP.

Animals↗
PubMed1989

Differential sensitivity to cAMP among human cord and maternal/adult peripheral lymphocytes discloses differences between PHA- and OKT3-induced activation pathways.

Previous studies have demonstrated that human cord blood lymphocytes are resistant to the anti-proliferative action of prostaglandin E2 (PGE2) in phytohaemagglutinin (PHA)-induced mitogenesis, whereas the same cells activated by OKT3 are at least as sensitive to PGE2 as the corresponding cells from their mothers or other adults. In the present investigation it was found that: (i) PHA-induced proliferation of cord peripheral blood mononuclear leucocytes (PBML) is less sensitive to inhibition by forskolin--a direct activator of adenylate cyclase (AC)--and dibutyryl cAMP--a permeant cAMP analogue--than the proliferation of the corresponding maternal cells; (ii) OKT3-induced proliferation of cord as well as maternal PBML is highly sensitive to inhibition by forskolin and dibutyryl cAMP; (iii) cord PBML show an overall lower rate of AC activity compared with maternal PBML, in response to PGE2 and other autacoids as well as to receptor-independent stimulation; (iv) cord PBML also display a significantly lower rate of degradation of cAMP through cAMP-phosphodiesterase compared with maternal cells; (v) unbroken cord and maternal PBML show comparable rates of cAMP accumulation after stimulation with PGE2. The results suggest a lower sensitivity to the effect of cAMP in cord compared with maternal/adult lymphocytes in PHA-induced proliferation. Moreover, the data illustrate differences between PHA- and OKT3-mediated activation pathways, as well as differences in cell regulation mechanisms between cord and maternal PBML.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages.

Generation of nitric oxide (NO.), an autacoid with vasorelaxant and cytotoxic properties, requires at least three cytosolic components in mouse macrophages besides L-arginine and NADPH. One or more components appear after induction by immunologic stimuli; two or more are present in both activated and non-activated macrophages. The constitutive factors can be separated on a Mr approximately 30,000 cut-off filter into high Mr fraction (HF) and low Mr fraction (LF) (Stuehr, D. J., Kwon, N. S., Gross, S. S., Thiel, B. A., Levi, R., and Nathan, C. F. (1989) Biochem. Biophys. Res. Commun. 161, 420-426). Herein we characterize the major active component in LF. The active component was dialyzable (Mr less than approximately 1,000), water soluble, and cationic at acidic to neutral pH. Fractionation on a C18 column in an acetonitrile/water gradient yielded one broad peak of activity, most of which corresponded to a fluorophore with the excitation/emission spectra of biopterins. Gas chromatography isolated a species in this peak with the mass spectrum of biopterin. Of 14 pteridines tested, only 7,8-dihydrobiopterin (H2biopterin) or 5,6,7,8-tetrahydrobiopterin (H4biopterin) could replace LF in synergizing with HF and the inducible component(s) to generate NO-2 and NO-3, the accumulating oxidation products of NO.. Half-maximal activity required 20-30 nM reduced biopterins. LFs from three cell lines were active in proportion to their content of biopterins; addition of reduced biopterins restored activity to LF from biopterin-deficient cells. Enhancement of NO-2 generation in the presence of H2biopterin but not H4biopterin was abolished by methotrexate and aminopterin, inhibitors of dihydrofolate reductase. These findings implicate a redox cycle in which the generation of NO. is facilitated by catalytic amounts of H4biopterin.

Aminopterin↗
PubMed1989

Albumin redirects platelet eicosanoid metabolism toward 12(S)-hydroxyeicosatetraenoic acid.

Albumin is a major determinant of eicosanoid formation, affecting autacoids important in cell-cell interactions. We delineated three mechanisms by which albumin controlled platelet eicosanoid formation: 1) Albumin diverted free arachidonate toward 12-lipoxygenation. 2) Albumin enhanced release of arachidonate from phospholipids. 3) Albumin inhibited incorporation of arachidonate from the medium into platelet phospholipids. 12(S)-Hydroxyheptadecatrienoic acid (12-HHTrE) formation was reduced 70% by albumin as compared to that formed in albumin-free medium. In sharp contrast, formation of 12(S)-hydroxyeicosatetraenoic acid (12-HETE), the platelet lipoxygenase product, was much less influenced by albumin. Moreover, 12-HETE production in the presence of albumin was markedly increased and prolonged after aspirin treatment. These data suggested that albumin redirected released endogenous arachidonate from cyclooxygenase to lipoxygenase. Therefore, the metabolic fate of arachidonate present in the medium of stimulated platelets was studied by adding tracer [3H]arachidonate 30 sec before thrombin. Albumin increased arachidonate metabolism by lipoxygenase 7-fold as compared to albumin-free controls, while cyclooxygenation increased 2.7-fold. Redirection of eicosanoid metabolism by albumin toward lipoxygenase products constitutes a heretofore undescribed and potentially important physiological role for albumin. In vitro utilization of albumin may reflect in vivo events in thrombosis and hemostasis more accurately than previous studies without albumin could appreciate.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1989

Vasodynamic and angiogenic effects of eicosanoids in the eye.

In the eye, the main vascular response to PGs is vasodilation. Although its effect has not been studied in detail, TxA2 can be expected to cause vasoconstriction in the eye, as it does in other tissues. When applied in high doses, PGs also increase the permeability of the microvasculature in the anterior segment, especially in rabbits. This may contribute to protein leakage associated with disruption of the BAB. The peptidoleukotrienes seem to reduce blood flow in the anterior segment, although more data will be required to substantiate this observation. It has been suggested over the years that PGs have a physiologic role in the autoregulation of the retinal blood flow. It has also been hypothesized that PGs, particularly those of the E series, play an important role in corneal neovascularization. The evidence obtained thus far in support of such hypothesis is not conclusive. It is possible that in the course of corneal vascularization or its induction, PGs are released, together with other mediators such as lipoxygenase products, but the pathophysiologic mechanisms are poorly understood. The role of eicosanoids in CME remains speculative. It is possible that other compounds in the cyclooxygenase pathway such as thromboxane and prostacyclin or some lipoxygenase products play a more important role in CME than the classical PGs, but, there is insufficient data so far to implicate any one eicosanoid or any other autacoids in the initiation of the vascular changes that are associated with CME.

Animals↗
PubMed1989

Myogenic tone and reactivity: definitions based on muscle physiology.

This paper suggests definitions of myogenic tone and reactivity in blood vessels on the basis of general muscle physiology and discusses some aspects of the cellular mechanisms involved. Tone is defined as a sustained state of contraction in a muscle. The word says nothing about the exact cellular events except that it is an active process in the contractile proteins. Myogenic implies that the stimulus for the tone originates in the muscle itself without involving nerves, hormones or specific autacoids. When working with isolated vascular smooth muscle we conclude that it has myogenic tone if we can demonstrate contractile force in standard physiological salt solution without the addition of vasoconstrictor agents or abnormal ion concentrations. Tone can occur in any type of muscle, principally through two different patterns of cellular activity: (1) The individual cells or motor units all contract in a tonic way, either by graded depolarization and contracture or by frequent action potentials and fused tetanus; and (2) the muscle as a whole shows tone as an integrated result of asynchronous phasic contractions in its separate units. These principles are discussed below in relation to vascular tone in various parts of the circulation. Myogenic reactivity in a blood vessel is defined as the ability of the vascular smooth muscle to contract in response to stretch or to an increase in transmural pressure. Many different components of the cellular machinery of the smooth muscle may respond to the applied force but the present discussion is concerned with excitation of the cell membrane by stretch (mechano-electrical coupling).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The effect of the platelet-activating factor antagonist, BN 52021, on human natural killer cell-mediated cytotoxicity.

The influence of the platelet-activating factor (PAF) antagonist, BN 52021, on human natural killer (NK) cell cytotoxicity against K 562 target cells was determined. Cytotoxicity was measured by a short-term (4 hr) 51Cr-release assay. The cytotoxicity was significantly reduced in the presence of PAF antagonist at concentrations from 30 to 120 microM. This reduction of killing was not due to the impairment of binding of effector cells to target cells. Pretreatment of K 562 target cells with the PAF antagonist led to a greater inhibition of NK cell cytotoxicity compared with that observed when the effector cells were preincubated with BN 52021. Thus, the inhibition of cytotoxicity appears to be due to an effect of BN 52021 on target cells rather than on lymphocytes. Furthermore, the increase in NK activity induced by interferon was less pronounced when BN 52021 was added in the incubation medium. The natural cytotoxicity of platelet-depleted or large granular lymphocyte-enriched effector cell populations was inhibited by the PAF antagonist in a similar manner. The effect of BN 52021 appears to be related to its specific PAF antagonistic activity since a similar action on NK cells was noted with two other structurally unrelated PAF antagonists, BN 52111 and WEB 2086. In contrast, Ginkgolide J (BN 52024), which is structurally related to BN 52021 but lacks PAF antagonistic activity, was ineffective in inhibiting NK cell cytotoxicity. Finally, synthetic PAF induces a dose-dependent cytotoxic action on K 562 cells and this effect of the autacoid is inhibited by BN 52021. These observations provide indirect evidence that PAF could play a role in the mechanism(s) of NK cytotoxity.

Cells, Cultured↗
PubMed1988

Leukotriene B4 production in human atherosclerotic plaques.

We evaluated the hypothesis that leukotriene (LT) B4, a potent chemotactic and endothelium-permeabilizing autacoid, may be a factor in the progression of the atherosclerotic lesion. Human vascular fragments, freshly obtained at vascular surgery from saphenous veins, atrial appendages, normal aortas and atherosclerotic lesions (histologically classified as fibrous plaques, fatty plaques and complicated lesions) were incubated at 37 degree C with mechanical agitation, for various times ranging between 5 and 60 minutes, sequentially, with buffer (basal), ionophore A23187 (IONO), and arachidonic acid (AA). After each step medium was assayed for LTB4 production by radioimmunoassay. Incubations were also performed in a chamber allowing selective exposure of the endothelial surface to the medium. Basal production (15 minute incubation, ng/g, mean +/- SD) was lowest for fibrous plaques (0.9 +/- 0.2, n = 38) and saphenous veins (1.0 +/- 0.3, n = 32) and much higher (P less than 0.01) for fatty plaques (7.3 +/- 2.2, n = 35) and complicated lesions (5.3 +/- 3.0, n = 28). A virtual abolition of production was observed after boiling of the vascular fragment. Production was increased in the presence of AA and IONO (in atheromas: 11.5 +/- 4.2 AND 14.3 +/- 5.3, respectively, with 15 minutes incubation), and decreased after incubation with 5-lipooxigenase inhibitors. Peak of ionophore or arachidonic acid-stimulated production in kinetic studies was reached at 20 minutes. LTB4 production was able to reach the luminal surface in both basal and stimulated conditions. There was no relationship with concomitantly measured prostacyclin production (mainly endothelial), while a correlation was found between LTB4 levels and degree of white cell infiltration in the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acid↗
PubMed1987

Production of platelet-activating factor by stimulated human polymorphonuclear leukocytes. Correlation of synthesis with release, functional events, and leukotriene B4 metabolism.

Platelet-activating factor (PAF) is a phospholipid mediator of inflammation that is synthesized by several human cell types including polymorphonuclear leukocytes (PMN). We examined the synthesis and release of PAF by stimulated human PMN under several conditions, assayed by the incorporation of [3H]acetate into PAF and by bioassay. PAF synthesis was induced by calcium ionophore A23187 (IoA), opsonized zymosan (OpsZ), and N-formyl-methionyl-leucyl-phenylalanine (FMLP) with the relative order of potency IoA much greater than OpsZ greater than FMLP. A variety of other agonists, including phorbol myristate acetate, an activator of protein kinase C and of PMN functional responses, did not stimulate PAF synthesis. PAF synthesis by PMN in response to IoA, OpsZ, and FMLP was concentration- and time-dependent but release of the phospholipid was not: little PAF (1 to 10%) was released from PMN in suspension regardless of the total amount produced, the agonist, its concentration, the time of incubation, or the concentration of extracellular albumin. This was also the case with functionally altered neutrophils that had been "primed" with cytochalasin B or lipopolysaccharide or that had adhered to surfaces. PAF synthesis was tightly coupled with leukotriene B4 production by adherent PMN as well as by neutrophils in suspension, supporting the hypothesis that the two lipid autacoids may be derived from a common precursor. However, PAF synthesis could be dissociated from aggregation and surface adhesion, indicating that it is not absolutely required for these responses of activated PMN. The total amount of PAF that accumulated, but not the percentage that was released, was altered in adherent PMN compared to cells in suspension. These experiments demonstrate that PAF production and its subsequent processing by human neutrophils are highly regulated events. PAF synthesis is associated with PMN activation, but it is not a requisite for early adhesive responses of neutrophils. Because little of the PAF produced by stimulated PMN is released from the cells, it appears that PAF has an intracellular role in PMN function and/or that it may have novel intercellular effects that do not require release into the fluid phase.

Calcimycin↗
PubMed1988

[Recent data on the mechanism of action of theophylline].

Since Sutherland's work simply based on the inhibition of phosphodiesterase was questioned, other researches have been carried out, indicating that many mechanisms located in the nervous system, the smooth muscle, and the immunity system interfere. The participation of receptors to adenosine, intracellular calcium ions, regulating calciproteins and autacoids such as prostaglandins was the purpose of numerous experimental researches that allow today to fill up the gap left by the fact that the inhibitor of phosphodiesterase was questioned. However, there are not sufficient but there are many seducing research and hypotheses.

Adenosine↗
PubMed1986

Modulation of solute permeability in microvascular endothelium.

Modulation of macromolecular permeability involves creation of venular leaks in response to receptor-operated mechanisms in the endothelial cell membrane elicited by various autacoids (histamine, serotonin, bradykinin). Reversible modulations may occur within seconds in response to specific agents, which indicates receptor-mediated events that act via the endothelial cells' contractile apparatus, leading to subtle changes in junctional microtopography and allowing faster passage of small solutes. This mechanism probably involves activation of the actin-myosin system in endothelial cells. Ca2+ is an important signal substance, as reflected in the permeability-increasing effect of calcium ionophores. The junctional control system may share functional similarities with the contractile system in various types of muscle cells, in particular, smooth muscle. This suggests a function for the extensive vesicular invaginations of the plasmalemmal membrane present in endothelial cells. Rather than being a system to carry macromolecules across the endothelium, its physiological role may be to regulate free cytosolic calcium concentration. It is reminiscent of similar membrane invaginations found in muscle cells. Thus intracellular free calcium may be regulated by a combination of energy-requiring extrusion and passive influx through receptor-operated calcium channels located in the invaginated vesicular membranes, with short diffusion distances to the actin-myosin filaments in the cytoplasm.

Animals↗
PubMed1986

Characterization of the responses to serotonin and prostanoids in human umbilical arteries perfused in vitro.

In order to characterize the action of some vasoactive autacoids on the umbilical artery, pressure responses of serotonin, PGE2, PGF2 alpha and U46619 (a thromboxane A2 mimetic) have been investigated during in vitro perfusion. Serotonin, PGE2 and PGF2 alpha caused biphasic responses in which both the dilator and the constrictor phases were found to be dose-dependent. Indomethacin or SQ 29.548 (a thromboxane A2 receptor antagonist) did not affect the response to serotonin, whereas indomethacin reduced or abolished the vasodilator and vasoconstrictor action of PGE2 and PGF2 alpha. U46619 induced monophasic pressor responses which were abolished by SQ 29.548. The results indicate that PGE2 and PGF2 alpha, but not serotonin, interfere with the local production of vasoactive prostanoids. The altered synthetic activity modify the responses to PGE2 and PGF2 alpha in the umbilical artery.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed1988

Negative inotropic effect of platelet-activating factor: association with a decrease in intracellular sodium activity.

Platelet-activating factor (PAF) is an autacoid whose cardiovascular actions include a potent negative inotropic effect. The mechanism of this decrease in myocardial contractility is still at issue, as both a decrease and an increase in trans-sarcolemmal Ca++ influx have been reported. Because changes in intracellular sodium activity (aiNa) are known to influence myocardial contractility, we investigated whether PAF affects aiNa. Thus, we have measured contractile responses to PAF (1 nM-1 microM) in isolated guinea pig right ventricular papillary muscles paced at constant rate, and recorded transmembrane action potential and aiNa with conventional and sodium-selective microelectrodes, respectively. Our findings suggest that PAF does not affect slow inward Ca++ current, because PAF neither affected nor prevented histamine-induced restoration of contractile responses in K+-depolarized papillary muscles. On the other hand, we found the negative inotropic effect of PAF to be associated with a shortening of the action potential duration and with a decrease in aiNa. The specific PAF antagonist compound CV-3988 inhibited all three electro-mechanical responses. Our findings imply that the decrease in contractile force caused by PAF may depend on the reduction in aiNa; as aiNa falls, intracellular Ca++ may be lost via the Na+/Ca++ exchange and contractility decreases. The shortening of the action potential duration by PAF may reflect a decrease in Na+ influx and the consequent reduction in aiNa.

Action Potentials↗