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PubMed1981

Actions on the cardiovascular system of an inhibitory material extracted from the bovine retractor penis.

1 A partially purified material has been isolated from methanol extracts of the bovine retractor penis muscle. This material exerts biological activity only after treatment with acid and subsequent neutralisation. The active principle in this extract, which appears to be no known autacoid, mimics the response to stimulation of the non-adrenergic, non-cholinergic nerves in the bovine isolated retractor penis muscle. 2 This inhibitory extract did not alter the heart rate or blood pressure of the anaesthetized rat when administered either by intravenous or intra-arterial injection, nor did it have any obvious effect on isolated cardiac muscle. 4 The extract produced relaxation of spiral strips of various arteries isolated from ox, cat, rabbit or rat, in which tone was induced by noradrenaline, K+ of Ba2+. 5 The extract also produced dilatation of the resistance vessels of the rat isolated mesenteric circulation and the rat hindquarters perfused with Krebs solution; tone was induced in these vessels by adrenaline or noradrenaline. 6 Lack of vasodilator activity of the extract in the whole animal appeared to be due to rapid inactivation in the blood, probably by binding to the erythrocytes.

Anesthesia↗
PubMed1990

Tachykinins activate guinea-pig alveolar macrophages: involvement of NK2 and NK1 receptors.

1. The effects of substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) were evaluated on superoxide anion (O2-.) production by guinea-pig alveolar macrophages (AM). 2. SP dose-dependently (ED50 = 0.7 nM) evoked O2-. production from guinea-pig AM; the N-terminal heptapeptide, SP(1-7), was ineffective. In the presence of thiorphan (10(-5) M), an enkephalinase inhibitor, the stimulating effects of SP were not significantly modified. NKA and NKB were both able to induce O2-. production from guinea-pig AM, ED50 values being 0.1 and 1.3 nM, respectively. Therefore, the rank order of activity of natural tachykinins was NKA greater than SP greater than NKB. Tachykinin-evoked effects were quantitatively similar to those elicited by the autacoid mediator PAF-acether and less than those induced by the synthetic peptide N-formylmethionyl-leucyl-phenylalanine (FMLP). 3. The NK2 receptor agonist [beta-Ala8]-NKA (4-10) dose-dependently evoked O2-. production from guinea-pig AM; the NK1 receptor agonist [Pro9]-SP sulphone acted only at high concentrations, while the NK3 receptor agonist [Me,Phe7]-NKB was ineffective. 4. These findings indicate that guinea-pig AM possess NK2 and possibly some NK1 tachykinin receptors and further suggest tachykinin involvement in lung pathophysiology.

Animals↗
PubMed1993

Endothelin-induced contraction and mediator release in human bronchus.

1. To elucidate the role of acetylcholine and various autacoids in endothelin-1 (ET-1)-induced contraction in human bronchus, the effects of various receptor antagonists were examined. In addition, the ability of ET-1 to stimulate the release of histamine, peptidoleukotrienes and prostanoids was determined. 2. ET-1 was a potent and effective contractile agonist in human bronchus, possessing similar potency and efficacy to leukotriene D4 (LTD4); EC50 (-log M): ET-1 = 7.76 +/- 0.09, n = 7; LTD4 = 8.46 +/- 0.53, n = 7; P > 0.2; maximum response (% 10 microM pre-carbachol): ET-1 = 103.8 +/- 17.4, n = 7; LTD4 = 95.5 +/- 9.3, n = 7; P > 0.6. 3. The cyclo-oxygenase inhibitor, sodium meclofenamate (1 microM) or the potent and selective thromboxane receptor antagonist, SQ 29,548 (1 microM) were without significant effect on ET-1 concentration-response curves. 4. In the presence of sodium meclofenamate (1 microM), the muscarinic receptor antagonist, atropine (1 microM), the platelet activating factor (PAF) receptor antagonist, WEB 2086 (1 microM) or the combination of the H1-histamine receptor antagonist, mepyramine (10 microM) and the leukotriene receptor antagonist, SK&F 104353 (10 microM), were without marked effect on ET-1 concentration-response curves. In addition, the combination of all four receptor antagonists did not antagonize ET-1-induced contraction. 5. ET-1 (0.3 microM) did not stimulate the release of histamine or immunoreactive leukotrienes from human bronchus. 6. ET-1 (0.3 microM) significantly stimulated the release of prostaglandin D2 (PGD2), 9alpha, 11beta PGF2 (PGD2 metabolite), PGE2, 6-keto PGF1alpha (PGI2 metabolite), PGF2alpha, and thromboxane B2 (TxB2) a lower concentration, 10 nM, was without effect on prostanoid release. The production of PGD2 was increased 7.5 fold, whereas the release of the other prostanoids was stimulated only about 1.6 to 2.7 fold.7. These data provide evidence that ET-1 elicits contraction of human isolated bronchus predominantly via a direct mechanism with no significant involvement of the release of acetylcholine, leukotrienes,histamine or PAF. Although ET-1 increased the release of several prostanoids they did not have a significant modulatory effect on the smooth muscle contraction.

Acetylcholine↗
PubMed1994

Study of the effector mechanism involved in the production of haemorrhagic necrosis of the small intestine in rat passive anaphylaxis.

1. The effector mechanism of intestinal necrosis in rat anaphylaxis was studied following several complementary approaches: (i) the use of monoclonal antibodies (mAb) belonging to different classes (IgG1, IgG2b and IgE anti-DNP), (ii) the assay of mediators, and (iii) the use of pharmacological tools. 2. Lethality and haemorrhagic necrosis of the small intestine were observed in IgE-sensitized rats, whereas IgG mAb produced milder physiological disturbances. 3. Inhibition of leukotriene biosynthesis reduced the drop of systemic blood pressure (BP) and the extent of protein-rich plasma exudation but it did not influence the haemorrhagic component of intestinal necrosis. 4. The antihistamine, pyrilamine, partially diminished the haemorrhagic component of the intestinal necrosis. 5. The involvement of mediators related to platelet-activating factor (PAF) was studied by examining the pharmacological effects of these autacoids and of PAF-receptor antagonists (PCA4248, UR12460 and BB823). PAF induced intestinal lesions similar to those observed in IgE-sensitized rats and PAF-receptor antagonists markedly decreased haemorrhage in IgE-sensitized rats. 6. PAF levels were transiently increased after dinitrophenol (DNP)- bovine serum albumin (BSA) challenge in the small intestine of IgE-sensitized rats. 7. These data stress differences in the outcome of anaphylaxis related to the type of receptors for the Fc portion of immunoglobulins that are involved. IgE is the antibody class that elicits the most severe response due to the activation of mast cells via Fc epsilon RI (surface receptors that bind IgE antibodies with high affinity), and the only one able to produce intestinal haemorrhagic necrosis. 8. The mast-cell-derived mediators PAF/acyl-PAF and histamine, most probably associated with tumour necrosis factor alpha/cachectin (TNF-alpha), seem to play a central role in the production of the vascular changes required for the extravasation of erythrocytes in the small intestine mucosa.

Anaphylaxis↗
PubMed1996

Involvement of nitric oxide and eicosanoids in platelet-activating factor-induced haemodynamic and haematological effects in dogs.

1. Platelet-activating factor (PAF) is a phospholipid mediator with potent cardiovascular and haematological actions. But its mechanisms of action in vivo have not been fully elucidated, probably due to difficulties arising from previous findings that the effects of PAF are largely mediated by the release of a variety of other autacoids. In the present study, the roles of nitric oxide and eicosanoids in the effects of PAF (0.01-0.25 microgram kg-1 i.v.) on systemic and pulmonary vasculatures and circulating blood cell count were pharmacologically evaluated in anaesthetized dogs. 2. Higher doses of PAF (> 0.1 microgram kg-1) produced a biphasic systemic hypotension. The first hypotension seen 30 s after the injection was accompanied by a decrease in systemic vascular resistance, thrombocytopenia and leukopenia, while the second hypotension seen 1-2 min after PAF was accompanied by a marked rise in pulmonary vascular resistance and decreases in aortic blood flow and cardiac contractility. Lower doses of PAF (0.01 - 0.05 microgram kg-1) caused only the first responses in a dose dependent manner. 3. Pretreatment with indomethacin inhibited the second responses to PAF without affecting the first responses. The thromboxane A2/prostaglandin H2 (TP)-receptor antagonist vapiprost blocked the PAF-induced rise in pulmonary vascular resistance. AA-861, a 5-lipoxygenase inhibitor, attenuated the PAF-induced cardiac depression. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester inhibited the PAF-induced early decrease in systemic vascular resistance. 4. All observed changes in haemodynamics and blood cell count after PAF were almost abolished by TCV-309, a PAF-receptor antagonist. 5. Reproducible hypotension and thrombocytopenia produced by a lower dose of PAF (0.05 microgram kg-1) were respectively attenuated and potentiated by pretreatment with NG-nitro-L-arginine, another nitric oxide synthase inhibitor. Administration of L-arginine reversed the effects of the nitric oxide synthase inhibitor. 6. These results indicate that PAF-receptor-mediated production of not only eicosanoids but also nitric oxide may contribute to the cardiovascular and haematological responses to PAF in the dog.

Animals↗
PubMed1996

Characterization of the PGE2 receptor subtype in bovine chondrocytes in culture.

1. Prostaglandin E2 (PGE2) is an autacoid that decreases proteoglycan synthesis, increases metalloprotease production by cultured chondrocytes, and can modulate some of the actions of interleukin-1 on cartilage. The objective of the present study was to characterize the subtype of prostaglandin E2 receptor present in bovine chondrocytes in culture. 2. Primary cultures of articular chondrocytes were prepared from slices of bovine carpal cartilage by sequential digestion with type III hyaluronidase, trypsin, type II collagenase, followed by overnight incubation in Dulbecco's Modified Eagle's Medium (DMEM) with type II collagenase, washing, and seeding at a density of 2 x 10(5) cells cm-2 in DMEM with 10% foetal bovine serum. 3. PGE2 and carbaprostacyclin induced dose-dependent increases in intracellular cyclic AMP in bovine chondrocytes in culture. The potencies of these compounds were different, and maximal doses of PGE2 and carbaprostacyclin had an additive effect. PGD2 induced a small increase in intracellular cyclic AMP only at a high concentration (10(-5) M). 4. PGE2 was more potent that the EP2 agonist 11-deoxy-PGE1 at inducing increases in intracellular cyclic AMP. The EP2 agonist butaprost, however, induced only a small increase at a concentration of 10(-5)M. 17-Phenyl-PGE2 (EP1 agonist), sulprostone and MB 28767 (15S-hydroxy-9-oxo-16-phenoxy-omega-tetranorprost-13E-enoic acid) (EP3 agonists) did not induce an increase in intracellular cyclic AMP at concentrations up to 10(-5)M. 5. The EP4 antagonist AH 23848B ([1 alpha(Z),2 beta, 5 alpha]-(+/-) -7-[5-[[(1,1'-biphenyl)-4-yl]methoxyl-2-(4-morpholinyl) -3-oxocyclopentyl]-5-heptenoic acid) antagonized PGE2 but not carbaprostacyclin effects on intracellular cyclic AMP. The Schild plot slope was different from 1 but this could be due to an interaction of PGE2 with IP receptors in high doses. The exact nature of the antagonism by compound AH 23848B could not be definitely established in these experimental conditions. 6. Neither PGE2 nor any of its analogues inhibited the increase in intracellular cyclic AMP induced by forskolin, and pertussis toxin did not alter the response to PGE2, suggesting that no Gi-coupled PGE2 receptors are present in these cells. Stimulation with PGE2 did not induce significant increases in intracellular inositol-trisphosphate levels nor increases in intracellular free calcium as determined by confocal microscopy, suggesting the absence of phospholipase-C-coupled or of calcium channel-coupled PGE2 receptors in bovine chondrocytes in these experimental conditions. 7. These results show for the first time that bovine chondrocytes in culture present a functional PGE2 receptor that has some pharmacological characteristics of an EP4 subtype, as well as an IP receptor.

Animals↗
PubMed1996

Mechanisms of L-NG nitroarginine/indomethacin-resistant relaxation in bovine and porcine coronary arteries.

1. Coronary arteries from bovines (BCA) and pigs (PCA) were used for measuring endothelium-dependent relaxation in the presence of L-NG nitroarginine and indomethacin. As some compounds tested have been found to have an inhibitory effect on autacoid-activated endothelial Ca2+ signalling, endothelium-dependent relaxation was initiated with the Ca2+ ionophore A23187. 2. The common compounds for modulating arachidonic acid release/pathway, mepacrine and econazole only inhibited L-NG nitroarginine-resistant relaxation in BCA not in PCA. In contrast, proadifen (SKF 525A) diminished relaxation in BCA and PCA. Mepacrine and proadifen inhibited Hoe-234-initiated relaxation in BCA and PCA, while econazole only inhibited Hoe 234-induced relaxation in PCA. Due to the multiple effects of these compounds, caution is necessary in the interpretation of results obtained with these compounds. 3. The inhibitor of Ca(2+)-activated K+ channels, apamin, strongly attenuated A23187-induced L-NG nitroarginine-resistant relaxation in BCA while apamin did not affect L-NG nitroarginine-resistant relaxation in PCA. 4. Pertussis toxin blunted L-NG nitroarginine-resistant relaxation in BCA, while relaxation of PCA was not affected by pertussis toxin. 5. Thiopentone sodium inhibited endothelial cytochrome P450 epoxygenase (EPO) in PCA but not in BCA, while L-NG nitroarginine-resistant relaxation of BCA and PCA were unchanged. Protoporphyrine IX inhibited EPO in BCA and PCA and abolished L-NG nitroarginine-resistant relaxation of BCA not PCA. 6. An EPO-derived compound, 11,12-epoxy-eicosatrienoic acid (11,12-EET) yielded significant relaxation in BCA and PCA in three out of six experiments. 7. These findings suggest that L-NG nitroarginine-resistant relaxation in BCA and PCA constitutes two distinct pathways. In BCA, activation of Ca(2+)-activated K+ channels via a pertussis-toxin-sensitive G protein and EPO-derived compounds might be involved. In PCA, no selective inhibition of L-NG nitroarginine-resistant relaxation was found.

8,11,14-Eicosatrienoic Acid↗
PubMed2000

Role of macula densa nitric oxide and cGMP in the regulation of tubuloglomerular feedback.

BACKGROUND: Previous studies have suggested that nitric oxide (NO) produced within cells of the macula densa (MD) modulates tubuloglomerular feedback (TGF). We tested the hypothesis that NO produced in the MD acts locally as an autacoid to activate soluble guanylate cyclase and cGMP-dependent protein kinase in the MD itself. METHODS: Rabbit afferent arterioles (Af-Arts) and attached MD were simultaneously microperfused in vitro. The TGF response was determined by measuring the Af-Art diameter before and after increasing NaCl in the MD perfusate (from 17 mmol/L of Na and 2 of Cl to 65 mmol/L of Na and 50 of Cl). TGF was studied before (control TGF) and after inhibiting components of the NO-cGMP-dependent cascade in the tubular or vascular compartment. RESULTS: Increasing NaCl concentration in the MD perfusate decreased the Af-Art diameter by 3.2 +/- 0.5 microm (from 18.5 +/- 1.3 to 15.4 +/- 1.3 microm, P < 0.001). Adding a soluble guanylate cyclase inhibitor (LY83583) to the MD increased TGF response to 6.3 +/- 1.1 microm (P < 0.031 vs. control TGF). Similarly, when cGMP-dependent protein kinase was inhibited with KT5823, TGF was augmented from 2.6 +/- 0.3 to 4.0 +/- 0.7 microm (P < 0.023). An analogue of cGMP in the MD reversed the TGF-potentiating effect of both 7-nitroindazole (7NI; an nNOS inhibitor) and LY83583. Inhibition of MD guanylate cyclase did not alter the effect of acetylcholine (a NO-cGMP-dependent vasodilator) on the Af-Art. Perfusing the Af-Art with the guanylate cyclase inhibitor did not potentiate TGF, suggesting that the effect of NO occurred at the MD via a cGMP-dependent mechanism. To determine whether the effect of NO in the MD was entirely mediated by cGMP, TGF was studied after giving (1) LY83583 or (2) LY83583 plus 7NI. Adding the nNOS inhibitor to the MD did not potentiate the TGF response further. CONCLUSIONS: We concluded the following: (1) NO produced by the MD inhibits TGF via stimulation of soluble guanylate cyclase, generating cGMP and activating cGMP-dependent protein kinase; (2) NO acts on the MD itself rather than by diffusing to the Af-Art; and (3) most, if not all, of the effect of NO in the MD is due to a cGMP-dependent mechanism rather than to other NO mediators.

Animals↗
PubMed1990

Haem-dependent activation of guanylate cyclase and cyclic GMP formation by endogenous nitric oxide: a unique transduction mechanism for transcellular signaling.

The interaction between nitric oxide (NO) synthesized in one cell and the haem group of cytosolic guanylate cyclase located in target cells to form NO-haem-guanylate cyclase represents a unique signal transduction mechanism that links extracellular stimuli to the synthesis of cyclic GMP in nearby target cells. Autacoids, neurotransmitters, and macrophage- and neutrophil-activating factors interact with selective extracellular receptors to trigger formation of NO from L-arginine. NO may be viewed as a second messenger. The NO diffuses into adjacent target cells and causes haem-dependent activation of guanylate cyclase, thereby stimulating cyclic GMP accumulation. Guanylate cyclase-bound haem serves as a transducer in transferring the signal from NO to guanylate cyclase. Cyclic GMP acts as a third messenger in causing vascular smooth muscle relaxation, inhibition of platelet aggregation and adhesion, and modulation of macrophage, neutrophil, and other phagocytic cell functions. The unique physical and chemical properties of NO allow it to function as an intercellular modulator within a localized environment. This intercellular or transcellular signaling mechanism involving a common signal transduction mechanism permits the rapid initiation of localized complementary cellular functions leading to increased local blood flow, inhibition of local thrombosis, and modulation of phagocytosis and cytotoxicity.

Animals↗
PubMed1997

Arterial function in mineralocorticoid-NaCl hypertension: influence of angiotensin-converting enzyme inhibition.

Angiotensin-converting enzyme inhibitors have been suggested to improve the function of arterial endothelium and smooth muscle not only through inhibition of angiotensin II formation and reduction of blood pressure, but also via additional pathways, e.g. potentiation of endogenous kinins and enhancement of endothelial autacoid formation. Therefore, we investigated whether 10-week-long quinapril therapy (10 mg kg-1 day-1) could beneficially influence the function of mesenteric arterial rings in vitro in deoxycorticosterone-NaCl-treated Wistar-Kyoto rats, a model of hypertension which is known to be resistant to angiotensin-converting enzyme inhibition. The quinapril treatment had no long-term blood pressure-lowering effect nor did it reduce the associated cardiac hypertrophy in deoxycorticosterone-NaCl hypertension. In noradrenaline-precontracted arterial rings the endothelium-dependent relaxations to acetylcholine and adenosine 5'-diphosphate as well as the endothelium-independent relaxations to nitroprusside and isoprenaline were clearly attenuated in the deoxycorticosterone-NaCl-treated rats. However, the quinapril therapy was without significant effect on any of these dilatory responses. In the presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, the relaxations to acetylcholine in untreated and quinapril-treated hypertensive animals were practically absent, whereas in normotensive rats distinct relaxations to higher concentrations of acetylcholine were still present. Interestingly, when endothelium-dependent hyperpolarization was prevented by precontracting the preparations with potassium chloride, no differences were found in relaxations to acetylcholine and adenosine 5'-diphosphate between the study groups. Exogenous bradykinin induced small comparable contractions in endothelium-intact mesenteric arterial rings from all study groups. In conclusion, the 10-week-long quinapril therapy did not have any significant effects on arterial function in deoxycorticosterone-NaCl hypertensive rats. Therefore, the present results stress the roles of reduced blood pressure and diminished angiotensin II formation in the beneficial vascular effects of long-term angiotensin-converting enzyme inhibition in the present model of hypertension. Furthermore, since the relaxations to acetylcholine and adenosine 5'-diphosphate in the deoxycorticosterone-NaCl-treated rats were attenuated in the absence and presence of nitric oxide synthase inhibition but not under conditions which prevented hyperpolarization, impaired endothelium-dependent relaxation to agonists can be attributed to diminished endothelium-dependent hyperpolarization in this model of hypertension.

Acetylcholine↗
PubMed1987

Biological activities of lipoxin A include lung strip contraction and dilation of arterioles in vivo.

Lipoxin A ([5S,6R,15S]-5,6,15-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid), a recently characterized lipoxygenation product of arachidonic acid, in submicromolar concentrations elicited long-lasting contractions of the guinea-pig lung strip. The response to lipoxin A was not due to release of acetylcholine, histamine, noradrenaline or cyclo-oxygenase products. 15-hydroperoxyeicosatetraenoic acid (15-HPETE), one precursor of lipoxin A, also contracted the lung strip, but 15-HPETE was less potent on the guinea-pig trachea whereas 15-HPETE relaxed this preparation. Lipoxin A was also inactive on the guinea-pig ileum. Intravital microscopy of the hamster cheek pouch disclosed that lipoxin A, as well as 15-HPETE, induced arteriolar dilation but had no effects on microvascular permeability or leucocyte adherence to venular endothelium. Taken together, the leucocyte product lipoxin A displayed a pattern of activity in spasmogenic assays and on the microvasculature that was distinct from those known for prostaglandins, thromboxanes and leukotrienes. The findings indicate that lipoxin A is an additional arachidonic acid derived autacoid with biological actions on smooth muscle in vitro and in vivo.

Animals↗
PubMed1989

External messengers and erythropoietin production.

We have presented a model for the role of external messenger substances in hypoxic stimulation of kidney production of erythropoietin. These autacoids probably act in concert to activate the adenylate cyclase system to enhance production and/or secretion of erythropoietin. The phosphoproteins generated in this system could act at the level of transcription and translation of erythropoietin as well as at the level of release of erythropoietin from the cell. Even though eicosanoids and beta-2-adrenergic agonists may be involved in mild to moderate hypoxia, it seems more likely that adenosine is more involved in erythropoietin production with increasing severity of hypoxia. Adenosine may play a very early role in hypoxia following the decrease in ATP to trigger erythropoietin production, and hydrogen peroxide may be generated from hypoxanthine, a metabolite of adenosine, during reoxygenation and regional changes in blood flow in the normal kidney and perhaps in certain renal and hepatic tumors. Further work is necessary in vivo to completely clarify the role of adenosine and oxygen free radicals in regulating kidney production of erythropoietin.

Adenosine↗
PubMed1991

Metabolism of platelet activating factor in lung.

PAF is known to be produced by two independent enzymatic pathways. The remodeling route involves structural modification of a membrane phospholipid (1-alkyl-2-acyl-sn-glycero-3-phosphocholine) by substitution of an acetate for the acyl group at the sn-2 position. In contrast, the de novo pathway includes a sequence of acetylation, dephosphorylation, and phosphocholine addition, starting with the alkyl analog of lyso-phosphatidic acid. Hypersensitivity reactions with PAF as the autacoid are triggered by activation of the remodeling enzymes to produce excessive amounts of PAF. Inactivation of PAF occurs primarily by hydrolysis of the acetate group in a reaction catalyzed by acetylhydrolase. Results of our studies indicate that biosynthesis and catabolism of PAF by membrane preparations from both lung tissue and alveolar macrophages are qualitatively similar to that found in other cells. All of the enzymatic activities for both the remodeling and de novo pathways of PAF biosynthesis occur in the lung. Recent experiments indicate the initial reaction that produces lyso-PAF in the remodeling pathway of PAF biosynthesis is under the control of a CoA-independent transacylase that is capable of catalyzing both the hydrolysis of the acyl moiety of the alkylacylglycerophosphocholine precursor and its transfer to another lyso-phospholipid. The substrate specificity for the phospholipase A2 component of this reaction is for alkylacylglycerophosphocholines possessing arachidonate at the sn-2 position. Other polyunsaturated alkylacylglycerophosphocholines appear to be utilized as PAF precursors too, albeit to a lesser extent than the 20:4 species. The CoA-independent transacylase and its high affinity for the transfer of arachidonate to lyso-PAF appears to be a very prominent enzyme activity in rat lung membranes.

Animals↗
PubMed2000

Vasoactive intestinal peptide mediation of development and functions of T lymphocytes.

The first phase in investigating neural regulation of immunity has delineated anatomical connections, shared mediators and receptors for mediators with distinctive effects, and the immune functional consequences of altering relevant neural activities. Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating peptide (PACAP) are represented prominently in immune organs. They have potent novel effects on many aspects of immunity, are derived from and serve as autacoids in some sets of immune cells, and they participate in both physiological and pathological immune responses. The present phase of neuroimmune research has begun to elucidate the genetic determinants of expression and functions of neuromediators in immunity. Our evolving understanding of the novel mechanisms for adaptation and specificity in the VIP/PACAP neuroimmune network suggests the importance of immunoselective transcriptional control of expression of VIP/PACAP receptors in T cells, a dominant role for numerous cytokines, and the critical involvement of small subsets of VIP-/PACAP-responsive thymocytes and T cells.

Animals↗
PubMed1991

MDL 72222 (a selective 5-HT3 receptor antagonist) prevents stimulation of intrapulmonary C fibres by pulmonary embolization in anaesthetized rabbits.

We have investigated the effects of the intravenous administration of 5-hydroxytryptamine upon the discharge frequency of pulmonary stretch receptors, irritant receptors and C fibres. Only C fibres were stimulated by this autacoid. MDL 72222 a selective 5-HT3 receptor antagonist blocks the C fibre stimulation by 5-hydroxytryptamine. It also blocks the C fibre response to miliary pulmonary embolism. These data confirm the hypothesis that 5-hydroxytryptamine is the humoral link between pulmonary embolism and tachypnoea.

Animals↗
PubMed1976

Facilitated transport of prostaglandins across the blood-cerebrospinal fluid and blood-brain barriers.

1. Ventriculo-cisternal perfusions were performed on rabbits with artificial cerebrospinal fluid containing blue dextran and tritium-labelled prostaglandin F(2alpha) ([(3)H]PGF(2alpha)). In order to study the nature of prostaglandin (PG) transfer across the blood-brain barrier, high concentrations of PGF(2alpha) or potential PG transport inhibitors were added to the perfusion fluid after the normal rate of [(3)H]PGF(2alpha) clearance was established.2. The [(3)H]PGF(2alpha) clearance was inhibited by 10(-6) to 10(-3)M PGF(2alpha), PGF(2beta), probenecid, iodipamide or bromcresol green but not by perchlorate.3. The (3)H content of the brain, relative to the (3)H-activity in the ventricular system, was also increased by high concentrations of PGF(2alpha), iodipamide or bromcresol green.4. It is concluded that the removal of PGs from the extracellular fluids of the brain is mediated by saturable, facilitated transport processes across both the choroidal and extrachoroidal regions of the blood-brain barrier system. In the case of the mammalian brain, such facilitated PG transport appears to be the primary mechanism for the termination of the action of these potent, endogenously produced autacoids.

Journal Article↗
PubMed2002

Subplasmalemmal endoplasmic reticulum controls K(Ca) channel activity upon stimulation with a moderate histamine concentration in a human umbilical vein endothelial cell line.

This study was designed to elucidate the role of the subplasmalemmal endoplasmic reticulum (sER) in autacoid-induced stimulation of Ca(2+)-dependent K(+) channels in the umbilical vein endothelial cell-derived cell line EA.hy926. Cells were transfected with the Ca(2+) probe cameleon targeted to the ER for visualization of the ER network. A patch pipette was then placed close to or far (> 5 microm away) from the sER, single channel recordings (patch clamp technique) were monitored simultaneously with measurements of either ER Ca(2+) concentration (using the Ca(2+) probe Cam4-ER) or cytosolic free Ca(2+) concentration ([Ca(2+)](i); using fura-2) using a deconvolution imaging device. A voltage-dependent, large conductance Ca(2+)-dependent K(+) channel (BK(Ca); single channel conductance (gamma), 250 pS) was found. At membrane potentials of +40 and -40 mV, the EC(50) for Ca(2+) was 2.7 and 49.7 microM, respectively. In the vicinity of the sER, the BK(Ca) channel activity induced by 10 microM histamine was 32 times higher (open probability (P(o)) = 0.083 +/- 0.026) than in areas away from the sER (P(o) = 0.0026 +/- 0.002). However, at supramaximal histamine stimulation (100 microM), BK(Ca) channel activation was similar in patches in the vicinity of or away from the sER (P(o) = 0.18 +/- 0.09 and 0.25 +/- 0.07, respectively). In contrast to BK(Ca) channel activity, ER Ca(2+) depletion (Cam4-ER) and elevation of [Ca(2+)](i) in response to 10 and 100 microM histamine were not influenced by the pipette position. We conclude that in endothelial cells, the activation of BK(Ca) channels in response to moderate histamine concentration essentially depends on the proximity of the sER domains to the mouth of this K(+) channel. These findings further support our concept of the subplasmalemmal Ca(2+) control unit (SCCU) and add the local activation of Ca(2+)-activated K(+)-channels to the function of the SCCU.

Calcium↗
PubMed2004

Ligand-directed functional heterogeneity of histamine H1 receptors: novel dual-function ligands selectively activate and block H1-mediated phospholipase C and adenylyl cyclase signaling.

The autacoid and neurotransmitter histamine activates the H(1) G protein-coupled receptor (GPCR) to stimulate predominantly phospholipase C (PLC)/inositol phosphate (IP) signaling and, to a lesser extent, adenylyl cyclase (AC)/cAMP signaling in a variety of mammalian cells and tissues, as well as H(1)-transfected clonal cell lines. This study reports that two novel H(1) receptor ligands developed in our laboratory, (-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (trans-PAT) and (+/-)-cis-5-phenyl-7-dimethylamino-5,6,7,8-tetrahydro-9H-benzocycloheptane (cis-PAB), activate H(1) receptors to selectively stimulate AC/cAMP formation and PLC/IP formation, respectively, in Chinese hamster ovary cells transfected with guinea pig H(1) receptor cDNA. trans-PAT and cis-PAB also are shown to be functionally selective antagonists of H(1)-linked PLC/IP and AC/cAMP signaling, respectively. Whereas cis-PAB H(1) receptor activity is shown to be typically competitive, trans-PAT displays a complex interaction with the H(1) receptor that is not competitive regarding antagonism of saturation binding by the standard H(1) antagonist radioligand [(3)H]mepyramine or H(1)/PLC/IP functional activation by histamine. trans-PAT, however, does competitively block H(1)/PLC/IP functional activation by cis-PAB. Molecular determinants for trans-PAT versus cis-PAB differential binding to H(1) receptors, which presumably leads to differential activation of AC/cAMP versus PLC/IP signaling, likely involves stereochemical factors as well as more subtle steric influences. Results suggest the trans-PAT and cis-PAB probes will be useful to study molecular mechanisms of ligand-directed GPCR multifunctional signaling. Moreover, because most untoward cardiovascular-, respiratory-, and gastrointestinal H(1) receptor-mediated effects proceed via the PLC/IP pathway, PAT-type agonists that selectively enhance H(1)-mediated AC/cAMP signaling provide a mechanistic basis for exploiting H(1) receptor activation for drug design purposes.

Adenylyl Cyclases↗