| 1. |
- Erlinge, David, et al.
(author)
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Characterisation of an ATP receptor mediating mitogenesis in vascular smooth muscle cells
- 1995
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In: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0922-4106. ; 289:1, s. 135-149
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Journal article (peer-reviewed)abstract
- Adenosine triphosphate (ATP), a co-transmitter in sympathetic nerves and released from platelets, has recently been shown to stimulate growth of vascular smooth muscle cells. It might therefore contribute to the development of vascular hypertrophy seen in hypertension and atherosclerosis. We aimed at characterising the receptor mediating this mitogenic effect in rat aorta smooth muscle cells. The potency of agonists indicates a P2 purinoceptor since ATP > or = ADP >> AMP, adenosine. The P2x-receptor subtype, which is responsible for ATP induced vasoconstriction in rat aorta, does not mediate the mitogenic effect since alpha, beta-methyleneATP had no effect and beta, gamma-methyleneATP had lower potency than ATP. The P2Y-receptor subtype was excluded since the selective agonist 2-methylthioATP had weak effect with lower potency than ATP. When we studied the involvement of other nucleotides similar effects were seen of the purines ATP, GTP and ITP; also the pyrimidine UTP had powerful mitogenic effects (Emax = 52% of ATP) with similar potency. Nucleotides with fewer phosphate groups showed a stepwise fall in mitogenic effect. This indicates involvement of a nucleotide-receptor (P2U). Ap4A were of equal potency and effect as ATP. There was strong correlation between the mitogenic effects of the nucleotides and analogues with both 45Ca(2+)-influx and inositol phosphate (IP) production, indicating that they may participate in mediating the mitogenic response. This is the first study describing the potencies for the mitogenic effects of the selective ATP-analogues and other nucleotides in vascular smooth muscle cells. The receptor characterisation indicates a nucleotide-receptor similar to the receptor which stimulates 45Ca(2+)-influx and inositol phosphate-formation in rat aorta smooth muscle cells. Substances related to ATP such as GTP, ITP, UTP and Ap4A which also can be released extracellularly in vivo stimulate mitogenesis of rat aorta smooth muscle cells through the same receptor.
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| 2. |
- Kawikova, Ivana, et al.
(author)
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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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In: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 280:3, s. 293-299
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Journal article (peer-reviewed)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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| 3. |
- Cappendijk, Susanne L T, et al.
(author)
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A heroin-, but not a cocaine expecting, self-administration state preferentially alters brain endogenous peptides
- 1999
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In: European Journal of Pharmacology. - 0014-2999 .- 1879-0712. ; 365:2-3, s. 175-182
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Journal article (peer-reviewed)abstract
- The purpose of the current study was to assess neuropeptidergic alterations during a phase of the drug addiction cycle associated with drug craving as compared to a time period when the drug had been recently self-administered. Male Wistar rats were allowed to self-administer cocaine, heroin or saline for 6 h for 5 consecutive days. Immediately following the last self-administration session ('acute drug on board' state), and just before the next scheduled session ('drug expecting' state), the animals were decapitated and the levels of dynorphin A and B, [Met5]- and [Leu5]-enkephalin and substance P were measured in different brain areas. During the 'acute drug on board' state, peptide levels in animals that self-administered heroin or cocaine were not significantly changed. In contrast, during the 'drug expecting' state, heroin-treated animals had increased levels of dynorphin A, dynorphin B and [Met5]-enkephalin in the caudal striatum as compared to the cocaine- and saline-treated animals, and the level of [Leu5]-enkephalin was increased as compared to the cocaine-treated group. In the septum, an increase of [Met5]-enkephalin and substance P was observed in the animals expecting heroin as compared to the saline- and/or cocaine-treated animals. In the caudal striatum, substance P levels were elevated in the heroin- and cocaine-expecting animals. In conclusion, heroin, as compared to cocaine, appears to have a more pronounced effect on dynorphin, enkephalin and substance P levels in the caudal striatum and septum, especially during periods when self-administration of the drug is expected.
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| 4. |
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| 5. |
- Nilsson, J, et al.
(author)
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Mechanisms of bupivacaine action on Na+ and K+ channels in myelinated axons of Xenopus laevis
- 1998
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In: European Journal of Pharmacology. - : Elsevier Science B.V., Amsterdam.. - 0014-2999 .- 1879-0712. ; 360:1, s. 21-29
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Journal article (peer-reviewed)abstract
- The local anaesthetic bupivacaine has recently been proposed to inhibit Na+ channels indirectly by making the resting potential less negative. To test this hypothesis we analysed the effects of bupivacaine on voltage and current clamped nodes of Ranvier. Contrary to the hypothesis, the leak current and the resting potential were unaffected. The Na+ and K+ channels were, however, affected at relatively low concentrations (33 mu M). Steady-state activation curves were decreased without notable shift effects, whereas the Naf inactivation curve was decreased and shifted in negative direction. The effect on the Na+ current was tentatively explained by a single-site, state-dependent binding model (K-d = 44 mu M), while that on the K+ current was explained by two population-specific mechanisms, one open-state dependent (K-d = 550 mu M) and one state independent (K-d = 59 mu M). The binding stoichiometry was higher than 1:1 for the main sites of action. In conclusion, bupivacaine exerts its main anaesthetic action on myelinated nerve axons by a direct modification of Na+ channels.
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| 6. |
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| 7. |
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| 8. |
- Persson, Karin, et al.
(author)
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Nitric oxide modulates captopril-mediated angiotensin-converting enzyme inhibition in porcine iliac arteries
- 1999
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In: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 385:1, s. 21-27
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Journal article (peer-reviewed)abstract
- The influence of the angiotensin-converting enzyme inhibitor captopril on bradykinin-and angiotensin I-induced responses with special regard to nitric oxide (NO) was studied. Auxometric tension and angiotensin-converting enzyme activity was studied in isolated porcine iliac arteries. Captopril potentiated bradykinin-induced contraction of preparations with intact endothelium; this potentiation was not seen with the kininase I inhibitor mergepta or a bradykinin B1-receptor antagonist. Captopril did not affect bradykinin-induced relaxation. The captopril-mediated increase of bradykinin-induced contraction was only seen in preparations with intact endothelium, while captopril did not affect arterial strips treated with Nω-nitro-L-arginine. Angiotensin I-induced contractions was less reduced by captopril when the strips were pretreated with Nω-nitro-L-arginine. Both captopril and the NO donor S-nitroso-N-acetyl-penicillamine inhibited angiotensin-converting enzyme activity. An additional reduction in angiotensin-converting enzyme activity was seen when S-nitroso-N-acetyl-penicillamine was added to captopril-treated preparations. In conclusion, captopril increased bradykinin-induced contraction in a NO-dependent manner. This potentiation is probably mediated by the increased metabolism of bradykinin by kininase I, and the additive angiotensin-converting enzyme inhibitory effect of captopril and NO.
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| 9. |
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| 10. |
- Dalziel, J E, et al.
(author)
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A threonine residue in the M2 region of the beta1 subunit is needed for expression of functional alpha1beta1 GABA(A) receptors.
- 1999
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In: European Journal of Pharmacology. - 0014-2999 .- 1879-0712. ; 370:3, s. 345-8
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Journal article (peer-reviewed)abstract
- Although there is a high degree of homology in the M2 transmembrane segments of alpha1 and beta1 subunits, subunit-specific effects were observed in alpha1beta1 GABA(A) receptors expressed in Spodoptera frugipedra (Sf9) cells when the conserved 13' threonine residue in the M2 transmembrane region was mutated to alanine. When threonine 263 (13') was mutated to alanine in the beta1 subunit, high-affinity muscimol binding and the response to GABA were abolished. This did not occur when the threonine 263 (13') was mutated to alanine in the alpha1 subunit, but the rate of desensitisation increased and the effect of bicuculline, a competitive inhibitor, was reduced. The results show differential effects of subunits on receptor function and support a role for M2 in desensitisation.
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