| 1. |
- Grip, Olof, et al.
(författare)
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Pravastatin down-regulates inflammatory mediators in human monocytes in vitro
- 2000
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Ingår i: European Journal of Pharmacology. - 0014-2999. ; 410:1, s. 83-92
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Tidskriftsartikel (refereegranskat)abstract
- There is experimental evidence that pravastatin, which is designed to inhibit the rate-limiting enzyme of cholesterol synthesis, can affect cell metabolism and proliferation. We therefore studied the effects of pravastatin on the generation of inflammatory mediators in non-stimulated and stimulated primary human monocytes in vitro. In our experimental model, pravastatin induced a dose-dependent inhibition of monocyte cholesterol synthesis (up to 67%), up-regulation of low density lipoprotein receptor mRNA (by about 35%) and reduction in intracellular cholesterol accumulation. In parallel, exposure of non-stimulated monocytes to various doses of pravastatin resulted in inhibition of monocyte chemoattractant protein-1 protein expression (up to 15-fold), reduction of tumour necrosis factor alpha (TNF-α) levels (up to 2.4-fold) and a total loss of metalloproteinase-9 activity in stimulated cells. Pravastatin at concentrations of 5, 100 and 500 μM caused an inhibition of TNF-α-induced cellular oxygen consumption from 2.4- to 5.5-fold. These data extend the findings of potential anti-inflammatory actions of statins and also suggest the possibility for pravastatin use in a broader spectrum of inflammatory situations.
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| 2. |
- Grundemar, L, et al.
(författare)
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Activation of neuropeptide Y1 and neuropeptide Y2 receptors by substituted and truncated neuropeptide Y analogs : identification of signal epitopes
- 1993
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 232:2-3, s. 271-278
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Tidskriftsartikel (refereegranskat)abstract
- Neuropeptide Y (NPY-(1-36)) acts on Y1 and Y2 receptors at the sympathetic neuroeffector junction. Various truncated NPY analogs were tested in the isolated guinea-pig caval vein where NPY is a vasoconstrictor (Y1 receptors) and in isolated rat vas deferens, by monitoring the suppression of electrically evoked contractions (Y2 receptors). The aim of this study was to define which parts of the NPY-(1-36) molecule were required to activate these receptors. NPY-(1-36), [Pro34]NPY and [Glu16,Ser18,Ala22,Leu28,31]NPY (ESALL-NPY), the latter being an analog with increased alpha-helicity in the 14-31 region, evoked vasoconstriction with similar potency and efficacy. Cyclic as well as linear NPY analogs having the 4 to 7 N-terminal amino acid residues linked to the 9 to 19 C-terminal residues by an 8-aminooctanoic acid (Aoc) residue were 25-50 times less potent than NPY-(1-36) itself. In the cyclic analogs, a disulfide bond was introduced to bring the N- and C-termini close together. Linear Aoc-2-27-NPY was virtually inactive. The Y1 receptor needs an intact N-terminal end of NPY in order to become fully activated. The requirements for the C-terminus are less stringent, since substitutions in this part of the molecule resulted in fully active analogs. The central portion of the molecule may impose steric constraints on the N- and C-terminal ends, thereby facilitating Y1 receptor activation, but it does not seem to be essential for receptor recognition. NPY-(2-36) and NPY-(5-36) were only slightly less potent than the parent molecule in suppressing electrically evoked twitches in the vas deferens.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 3. |
- Grundemar, L, et al.
(författare)
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Biphasic blood pressure response to neuropeptide Y in anesthetized rats
- 1990
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 179:1-2, s. 83-87
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Tidskriftsartikel (refereegranskat)abstract
- The effects of neuropeptide Y (NPY) on systemic arterial blood pressure and heart rate were studied in anesthetized intact and pithed rats. I.v. doses of NPY (0.3-30 nmol/kg) raised the mean arterial blood pressure dose dependently. At doses of greater than or equal to 3.0 nmol/kg, the initial pressor response was followed by a dose-dependent fall in blood pressure in intact and pithed rats. The depressor response was accompanied 1-2 min after the NPY injection by a slight increase in heart rate in pithed rats but not in intact rats, and 10 min after the injection by a decrease in heart rate in intact rats. After repeated injections of NPY, the depressor effect vanished, whereas the integrated pressor response over time was markedly enhanced. After pretreatment with the histamine H1-receptor antagonist, mepyramine, or with the histamine liberator, compound 48/80, the pressor response to NPY remained but the depressor response disappeared. We suggest that the marked fall in blood pressure can be attributed to NPY-evoked histamine release from mast cells.
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| 4. |
- Grundemar, L, et al.
(författare)
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Neuropeptide Y and truncated neuropeptide Y analogs evoke histamine release from rat peritoneal mast cells. A direct effect on G proteins?
- 1994
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 258:1-2, s. 163-166
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Tidskriftsartikel (refereegranskat)abstract
- Several regulatory peptides, including neuropeptide Y, can release histamine from mast cells. In the present study we investigated which parts of the neuropeptide Y molecule are required to evoke the release of histamine from isolated rat peritoneal mast cells. In addition, we examined whether the histamine release evoked by neuropeptide Y (and by compound 48/80) is sensitive to the G protein inhibitors pertussis toxin and benzalkonium chloride. Neuropeptide Y released histamine in a concentration-dependent manner. Also a neuropeptide Y analog with the center part substituted by 8-aminooctanoic acid, [Aoc2-27]neuropeptide Y, and the cyclic form of the C-terminal hexapeptide, cyclic neuropeptide Y-(31-36), released histamine. The three peptides were equally effective and equally potent. Neuropeptide Y-(1-24)NH2 also released histamine, but its efficacy was low. The rank order of potency of the analogs tested did not agree with that of any of the previously known or postulated neuropeptide Y receptors. Pretreatment of mast cells with pertussis toxin or benzalkonium chloride markedly inhibited the histamine release evoked by neuropeptide Y, [Aoc2-27]neuropeptide Y and compound 48/80. In conclusion, most of the histamine-releasing activity of neuropeptide Y resides in the six C-terminal amino acid residues. The release appears to be G protein-dependent and is probably not receptor mediated.
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| 5. |
- Kannisto, P, et al.
(författare)
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Evidence for prejunctional GABAB receptors mediating inhibition of ovarian follicle contraction induced by nerve stimulation
- 1986
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 122:1, s. 9-123
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Tidskriftsartikel (refereegranskat)abstract
- The motor effects of gamma-aminobutyric acid (GABA) on the bovine ovarian follicle were studied in vitro using strips from follicle walls. Electrical field stimulation of nerves in the preparation, secured by tetrodotoxin blockade, caused a contraction that was almost totally abolished by phentolamine and only slightly affected by atropine. This mainly adrenergic neurogenic response was inhibited by GABA in a dose-dependent way. The GABAA-receptor antagonists, bicuculline and picrotoxin, did not affect the GABA action whereas the GABAB-receptor antagonist, homotaurine, significantly inhibited the GABA effect. The GABAA-receptor agonist, muscimol, did not affect the contractile response while the GABAB-receptor agonist, baclofen, imitated the action of GABA. On the other hand, GABA had no direct contractile or relaxing effect on the follicle strips nor did it interfere with the contractile response induced by noradrenaline or acetylcholine. The findings suggest that activation of prejunctional GABAB receptors inhibits transmitter release from mainly adrenergic nerves associated with the follicle, thereby affecting nerve-mediated tension in the follicle wall.
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| 6. |
- Kannisto, Päivi, et al.
(författare)
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Extracellular and intracellular calcium sources mediating contractile responses of smooth muscle in bovine ovarian follicle and ovarian artery
- 1987
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 144:3, s. 299-308
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Tidskriftsartikel (refereegranskat)abstract
- The relative importance of extracellular and intracellular calcium sources mediating smooth muscle contraction in ovarian follicle and ovarian artery was assessed in experiments on the influence of nifedipine, D-600, amrinone, diethylstilbestrol (DES), lanthanum and/or calcium removal on contractions induced by K+ depolarization, by noradrenaline, histamine and acetylcholine. The K+-induced response was biphasic in the ovarian artery but not in the ovarian follicle. The K+-induced contraction in both preparations was greatly inhibited by nifedipine (1 μM), D-600 (10 μM) and lanthanum (2 mM). Although both phases of the responses in the ovarian artery appeared to be completely dependent on extracellular calcium, phase I was significantly more sensitive to nifedipine than phase II. Incubation in calcium-free medium for 15 min almost abolished the K+-induced contraction. Noradrenaline- and histamine-induced contractions of ovarian follicle were essentially unaffected by nifedipine (1 μM) and D-600 (10 μM) whereas the noradrenaline-induced contraction in ovarian artery was inhibited significantly by D-600 (1 and 10 μM) but not nifedipine (1 μM). In calcium-free medium containing EGTA (1 mM) the responses of ovarian follicle to noradrenaline and histamine were reduced by 26 and 22% respectively. When preparations were stimulated with noradrenaline more than one in calcium-free medium, the contraction decreased progressively compared to time-matched controls. The response was 34% of the control after 50 min in calcium-free medium containing EGTA. In the ovarian artery the response obtained (6% of control) was significantly smaller (P < 0.05) than that in the follicle. Amrinone (100 μM) inhibited both noradrenaline- and K+-induced contractions to a similar degree (about 40%) in the follicle wall. The results indicate that agonist-induced responses of ovarian follicle and artery are mediated by the release of calcium from intracellular stores in addition to influx of extracellular calcium. In contrast, the K+-induced contraction seems to be totally dependent on extracellular calcium. The difference in sensitivity to nifedipine of the two phases of the K+ response in ovarian artery strongly suggests the presence of two different types of K+-activated calcium channels in this smooth muscle.
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| 7. |
- Kawikova, Ivana, et al.
(författare)
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Bradykinin-induced release of thromboxane B2 into bronchoalveolar lavage fluid of guinea pigs: relationship to airflow obstruction
- 1995
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 280:3, s. 293-299
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate the role of thromboxane A2 in bradykinin-induced airflow obstruction in guinea pig in vivo. Airway insufflation pressure (Pi) was measured to assess airflow obstruction and the thromboxane B2 (a stable metabolite of thromboxane A2) concentration in bronchoalveolar lavage fluid was determined by radioimmunoassay. The animals were pretreated with propranolol (1 mg/kg i.v.) and suxamethonium (5 mg i.v.) prior to bradykinin administration. Bradykinin instillation into the trachea (300 nmol) induced a Pi increase (47.5 +/- 8.3 cm H2O versus 23.8 +/- 1.5 in sham) and significant thromboxane B2 release into bronchoalveolar lavage fluid (79 +/- 19 pg/ml versus 19 +/- 6 in sham). A thromboxane synthase inhibitor (OKY-046, 30 mg/kg i.v.; ((E-E)-3-[p(1H-imidazole-1-yl-methyl) phenyl]-2-propenoic acid hydrochloride mono-hydrate)) or a thromboxane A2 receptor antagonist (ICI192,605, 0.5 mg/kg i.v.; (4-(Z)-6-(2-o-chloro-phenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl) hexenoic acid)) reduced the Pi increase evoked by bradykinin (38.7 +/- 3.8 and 40.6 +/- 3.8 cm H2O, respectively). OKY-046 abolished the thromboxane B2 release. A platelet-activating factor receptor antagonist, WEB2086 (1 mg/kg i.v.; (3-[4-(chlorophenyl)-9-methyl-6H-thienol [3,2-f][1,2,4]trizolo-[4,3-a][1,4] diazepin-2-yl]1-4-(4-morpholinyl)-1-propanon) did not significantly affect any measured parameter. We conclude that, in guinea pigs, bradykinin-induced airway effects are associated with a local thromboxane A2 release.
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| 8. |
- Poljakovic, Mirjana, et al.
(författare)
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Signalling pathways regulating inducible nitric oxide synthase expression in human kidney epithelial cells
- 2003
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Ingår i: European Journal of Pharmacology. - 0014-2999 .- 1879-0712. ; 469:1-3, s. 21-28
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to elucidate the signalling pathways involved in the cytokine-activated inducible nitric oxide synthase (iNOS) response in a human kidney epithelial cell line, A498. Unstimulated cells did not express iNOS. Exposure of A498 cells to a cytokine mixture consisting of interferon gamma, interleukin-1 beta and tumor necrosis factor-alpha (TNF-alpha) increased nitrite production, iNOS mRNA and protein expression. Pharmacological inhibition of tyrosine kinases, including janus kinase (JAK2), and protein kinase C (PKC) inhibited cytokine-mediated nitrite production and iNOS protein expression. The involvement of mitogen-activated protein kinases (MAPKs) was investigated. Inhibition of p38 MAPK, but not of an upstream activator of extracellular signal-regulated kinase (ERK), caused a decrease in iNOS expression and nitrite production in response to cytokines. Electrophoretic mobility shift assay of nuclear extract from cytokine-stimulated cells demonstrated a pronounced binding to a nuclear factor kappa B (NF-kappa B) sequence present in the human iNOS promoter. Furthermore, the NF-kappa B inhibitor pyrrolidinedithiocarbamate (PDTC) decreased cytokine-activated iNOS protein expression and nitrite production. The present study has demonstrated that cytokine-stimulated iNOS expression in human kidney epithelial cells involves activation of tyrosine kinases, including JAK2, PKC, p38 MAPK and NF-kappa B.
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| 9. |
- Schmidt, Gunther, et al.
(författare)
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Alteration by histamine of the sympathetic nerve-mediated contractions in the bovine ovarian follicle wall in vitro
- 1987
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 135:1, s. 11-22
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Tidskriftsartikel (refereegranskat)abstract
- The histaminergic effect on electrically induced contractions and tritium release was studied in vitro, using strips from the wall of mature bovine ovarian follicles. Follicular fluid and blood plasma from the animals were analysed for electrolyte, bicarbonate, glucose and total protein concentrations in order to compare them with the concentrations of these components in the Krebs-Ringer solution used in the experiments. Electrical field stimulation (EFS) of the follicle strip caused a contraction which was completely blocked by tetrodotoxin and was predominantly of adrenergic origin since phentolamine, in contrast to atropine, blocked the response. The neurogenic response was inhibited by histamine in a concentration-dependent way via the H1-receptor since the H1-antagonist, pyrilamine, counteracted the inhibitory effect of histamine while the H2-antagonist, cimetidine, potentiated the effect. This histaminergic response of EFS-induced contractions could be reproduced in experiments where the H1-agonist, 2-methylhistamine, was inhibitory while the H2-agonist, 4-methylhistamine, had no obvious influence on the twitch response. Histamine reduced the contractile response to exogenous noradrenaline via the H1-receptor, because pyrilamine counteracted, and cimetidine potentiated the effect. The histamine-induced depression of the motor response to EFS and exogenous noradrenaline was probably due to a postjunctional effect mediated by the H1-receptor. Experiments utilizing [3H]noradrenaline release during EFS did not suggest prejunctional effects of histamine. Chemical determinations on follicle fluid and plasma showed that the artificial follicular fluid imitated well the environmental conditions the follicle wall is exposed to in situ.
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| 10. |
- Shen, G H, et al.
(författare)
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C-terminal neuropeptide Y fragments are mast cell-dependent vasodepressor agents
- 1991
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 204:3, s. 249-256
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Tidskriftsartikel (refereegranskat)abstract
- Neuropeptide Y (NPY) is a well-established vasopressor agent present in sympathetic perivascular nerves. Recently, it was found that high doses of the peptide cause a biphasic pressor-depressor response upon intravenous administration. We now report that C-terminal NPY fragments (NPY-(18-36) and NPY-(22-36] given intravenously to conscious or pithed (areflexive) male Sprague-Dawley rats mimic the depressor component of the NPY-(1-36) response while displaying very low pressor activity. Additionally, we have found that the depressor component is blocked by the histamine H1-antagonist, mepyramine. Since the fragment, NPY-(22-36), was equipotent with NPY in inducing histamine release from isolated peritoneal mast cells, we conclude that short C-terminal NPY fragments, like NPY itself, act on mast cells to initiate histamine-mediated cardiovascular actions. Such actions may conceivably be accounted for by the abundance of positively charged amino acid residues in the C-terminus. Moreover, these fragments have little affinity for vascular NPY receptors, as indicated by their poor ability to displace iodinated NPY or peptide YY (PYY) from specific binding sites on vascular smooth muscle cells derived from rat aorta. In conclusion, we propose that short C-terminal NPY fragments, which contain several positively charged amino acid residues, retain the ability of NPY to release histamine from rat mast cells while being essentially devoid of direct vascular motor activity.
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