European Journal of Pharmacology: Molecular Pharmacology最新文献

{"title":"Modulation of [35S]TBPS binding by ligands with preferential affinity for benzodiazepine BZ1 sites in the cerebral cortex of newborn and adult rats","authors":"Osvaldo Giorgi ,&nbsp;Daniele Lecca ,&nbsp;Enrico Cancedda ,&nbsp;Giuliana P. Serra ,&nbsp;Maria G. Corda","doi":"10.1016/0922-4106(95)90014-4","DOIUrl":"10.1016/0922-4106(95)90014-4","url":null,"abstract":"<div><p>The present study was designed to compare the allosteric coupling between the Cl⁻ channel of the GABA_A receptor and the different benzodiazepine recognition site subtypes (BZ sites) in the cerebral cortex of newborn (5-day-old) and adult rats (90-day-old). To this aim, we reexamined the heterogeneity of cortical GABA_A receptors in self- and cross-competition binding experiments using [³H]flunitrazepam and two ligands with higher affinity for benzodiazepine BZ₁ sites relative to benzodiazepine BZ₂ sites, the triazolopyridazine 3-methyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo [4,3-b] pyridazine (CL 218,872) and the imidazopyridine <em>N</em>,<em>N</em>,6-trimethyl-2-(4- methylphenyl)-imidazo[1,2-a-pyridine-3-acetemide hemitratrate (zolpidem). Benzodiazepine BZ₁ sites accounted for 52% of the total number of binding sites in adult rats, but were not detected in newborn rats. On the other hand, two classes of benzodiazepine BZ₂ sites with high and low affinity for zolpidem were present in newborn and adult rats. These sites were designated as benzodiazepine BZ_2H (high affinity for zolpidem, <em>K</em>_d ∼ 150 nM) and benzodiazepine BZ_2L (low affinity for zolpidem, <em>K</em>_d ∼ 3000 nM). High densities of benzodiazepine BZ_2H sites were measured in both newborn and adult rats (75% and 41% of the total number of [³H]flunitrazepam binding sites, respectively), whereas benzodiazepine BZ_2L sites accounted for 25% and 7% of the total number of cortical sites in neonates and adults, respectively. Flunitrazepam, CL 218,872 and zolpidem inhibited in a concentration-dependent manner the binding of <span><math><mtext>[</mtext><msup><mi></mi><mn>35</mn></msup><mtext>S</mtext><mtext>]t-</mtext><mtext>butylbicyclophosphorothionate</mtext></math></span> ([³⁵S]TBPS) to the convulsant site of cortical GABA_A receptors in newborn and adult rats. The IC₅₀ for flunitrazepam was about 3-fold greater in adults than in neonates. This rightward shift in the concentration-response curve may be due to a decrease with age in the intrinsic efficacy of flunitrazepam. In contrast, CL 218,872 and zolpidem were 4-fold more potent at inhibiting [³⁵S]TBPS binding in adult rats relative to neonates. The different affinities of CL 218,872 and zolpidem for benzodiazepine BZ₁ and BZ₂ receptors may account, at least in part, for the age-related changes in their inhibitory potencies. These results demonstrated that benzodiazepine BZ₂ sites mediate the modulation of [³⁵S]TBPS binding by benzodiazepine recognition site ligands in the cerebral cortex of newborn rats. Further, benzodiazepine BZ₂ sites may be involved in the inhibition of [³⁵S]TBPS binding by flunitrazepam, CL 218,872 and zolpidem in the cerebral ","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 1","pages":"Pages 37-47"},"PeriodicalIF":0.0,"publicationDate":"1995-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90014-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18666997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficiency of β-adrenoceptor subtype coupling to cardiac adenylyl cyclase in cardiomyopathic and control hamsters","authors":"Klaus Witte ,&nbsp;Anke Schnecko ,&nbsp;Hans-Georg Olbrich ,&nbsp;Björn Lemmer","doi":"10.1016/0922-4106(95)90010-1","DOIUrl":"https://doi.org/10.1016/0922-4106(95)90010-1","url":null,"abstract":"<div><p>Densities of β-adrenoceptor subtypes and their contributions to stimulation of adenylyl cyclase were studied in heart ventricles from cardiomyopathic (BIO 8262) and control Syrian hamsters (CLAC) at 4 different ages: 30, 100, 200 and 300 days. In BIO ventricles neither total β-adrenoceptor density nor that of the <em>β</em>₁-adrenoceptor subtype differed from the controls, whereas the density of <em>β</em>₂-adrenoceptors was significantly higher in myocardium from 200- and 300-day-old BIO compared to that from age-matched CLAC hamsters. Stimulation of adenylyl cyclase by the non-selective β-adrenoceptor agonist isoprenaline did not differ between strains, but the <em>β</em>₁-adrenoceptor mediated component was significantly reduced in cardiomyopathic hamsters of all age groups. In 300-day-old animals <em>β</em>₁-adrenoceptors accounted for 83% (CLAC) and 68% (BIO) of total β-adrenoceptor binding sites, whereas only 26% (CLAC) and 6% (BIO) of the isoprenaline effect on cAMP formation were mediated via <em>β</em>₁-adrenoceptors. Thus, the present study shows a lower coupling efficiency of <em>β</em>₁-adrenoceptors compared to the <em>β</em>₂-adrenoceptor subtype in ventricles from healthy Syrian hamsters and a progressive, further reduction in <em>β</em>₁-adrenergic function in cardiomyopathic animals.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 1","pages":"Pages 1-10"},"PeriodicalIF":0.0,"publicationDate":"1995-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90010-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71839874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Involvement of botulinum C3-sensitive GTP-binding proteins in α1-adrenoceptor subtypes mediating Ca2+-sensitization","authors":"Noriko Kokubu,&nbsp;Mitsutoshi Satoh,&nbsp;Issei Takayanagi","doi":"10.1016/0922-4106(95)90012-8","DOIUrl":"https://doi.org/10.1016/0922-4106(95)90012-8","url":null,"abstract":"<div><p>The mechanisms of α₁-adrenoceptor agonist-mediated sensitization of the contractile apparatus of smooth muscle to Ca²⁺ were studied in β-escin-permeabilized thoracic artreal smooth muscle of rabbit. Addition of norepinephrine (10 μM) plus guanosine 5′-triphosphate (GTP, 50 μM) significantly enhanced Ca²⁺ sensitivity as compared with the addition of 0.3 μM Ca²⁺ alone (pCa6.5). In β-escin-skinned smooth muscle of chloroethylclonidine-treated tissues, the enhancement of Ca²⁺-contraction produced by norepinephrine or clonidine was completely inhibited by guanosine 5′-O-(β-thiodiphosphate) (GDPβ-S, 1 mM). In addition, Clostridium botulinum C₃, which inactivates low molecular weight GTP-binding protein families, abolished norepinephrine- or clonide-induced Ca²⁺-sensitization, but did not affect clonidine-induced of protein kinase C to the membrane. The norepinephrine-enhanced Ca²⁺ sensitivity was partially reversed by a pretreatment with a selective myosin light chain kinase inhibitor (8R^∗, 9S^∗, 11S^∗-(−)-9-hydroxy-9- methoxycarbonyl-8-methyl-14-<em>n</em>-propoxy-2,3,9,10-tetrahydro-8,11-epoxy,1H,8H,11H-2,7b, 11a-triazadibenzo[a,g]cycloocta[cde]trinden-1- one (KT5926, 500 nM), but those of clonidine and in the chloroethylclonidine-treated tissues norepinephrine were not. These results suggest that Ca²⁺-sensitization produced by the activation of the α₁-adrenoceptor subtypes is linked via a low molecular weight GTP-binding protein (Rho), and the regulations of phosphorylation in contractile elements.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 1","pages":"Pages 19-27"},"PeriodicalIF":0.0,"publicationDate":"1995-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90012-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71839948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional characterization of the human dopamine D4.2 receptor using vaccinia virus as an expression system","authors":"Claudia Bouvier ,&nbsp;James R. Bunzow ,&nbsp;Hong-Chang Guan ,&nbsp;Anja Unteutsch ,&nbsp;Olivier Civelli ,&nbsp;David K. Grandy ,&nbsp;Hubert H.M. Van Tol","doi":"10.1016/0922-4106(95)90011-X","DOIUrl":"10.1016/0922-4106(95)90011-X","url":null,"abstract":"<div><p>Recombinant vaccinia viruses harboring the human dopamine D₄ receptor cDNA containing two 48 base pair-repeats (D_4.2) or the rat dopamine D₂ short (D_2s) receptor cDNA were used to infect rat-1 fibroblasts. Heterologous expression of both dopamine receptors was demonstrated in binding assays. The affinity constants of these receptors were consistent with values previously reported, including D_4.2's higher affinity for the antipsychotic clozapine and raclopride's selectivity for D₂ receptors. In the presence of 200 μM 5′-guanylyl- imidodiphosphate (Gpp[NH]p) both receptors exhibited reduced affinities for dopamine. Furthermore, when rat-1 cells were infected with the D_2s or the D_4.2 recombinant vaccinia viruses and exposed to dopamine agonists, the inhibition of adenylyl cyclase activity was prevented in pertussis toxin-treated cells. This study demonstrates the utility of recombinant receptor-vaccinia viruses in studies of expression, pharmacology and functional coupling of inhibitory G protein-coupled receptors.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 1","pages":"Pages 11-17"},"PeriodicalIF":0.0,"publicationDate":"1995-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90011-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18666994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pimobendan directly sensitizes reconstituted thin filament to slide on cardiac myosin","authors":"Masataka Sata ,&nbsp;Seiryo Sugiura,&nbsp;Hiroshi Yamashita,&nbsp;Teruhiko Aoyagi,&nbsp;Shin-ichi Momomura,&nbsp;Takashi Serizawa","doi":"10.1016/0922-4106(95)90016-0","DOIUrl":"10.1016/0922-4106(95)90016-0","url":null,"abstract":"<div><p>To elucidate the mechanism of the Ca²⁺-sensitizing action of pimobendan, cardiac thin filaments were reconstituted from actin and tropomyosin-troponin complex and made to slide on a myosin layer. Although filaments showed Brownian movement with a low Ca²⁺ concentration, they slid at a constant velocity above a certain level of Ca²⁺ concentration, showing that the sliding was regulated by Ca²⁺ within a narrow pCa range. Acidosis, addition of inorganic phosphate, and phosphorylation of troponin I increased the threshold Ca²⁺ concentration. Addition of pimobendan reversed these desensitization effects. These results clearly demonstrated that pimobendan directly increases the Ca²⁺ sensitivity of thin filament.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 1","pages":"Pages 55-59"},"PeriodicalIF":0.0,"publicationDate":"1995-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90016-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18666999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Further evidence that the classical α1A- and cloned α1c-adrenoceptors are the same subtype","authors":"Carmen Pimoule,&nbsp;Salomon Z. Langer,&nbsp;David Graham","doi":"10.1016/0922-4106(95)90015-2","DOIUrl":"https://doi.org/10.1016/0922-4106(95)90015-2","url":null,"abstract":"<div><p>We compared the inactivation of [³H]prazosin binding sites in membrane preparations of cell-lines expressing the cloned <em>α</em>_1b, <em>α</em>_1c and <em>α</em>_1d-adrenoceptors after pretreatment with the alkylating agents, 10 μM chlorethylclonidine or 10 nM SZL-49 (1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-bicyclo[2.2.2]octa-2,5-diene-Z-carbonyl)-piperazine). The cloned <em>α</em>_1b-adrenoceptor exhibited a similar inactivation profile to that of the classical <em>α</em>_1B-adrenoceptor of rat liver in that chlorethylclonidine in contrast to SZL-49 produced a marked degree of inactivation. A similarity between the cloned <em>α</em>_1c-adrenoceptor and the classical <em>α</em>_1A-adrenoceptor of rat submaxillary gland was also noted in that both subtypes were highly sensitive to SZL-49 but relatively insensitive to chlorethylclonidine. The cloned <em>α</em>_1d-adrenoceptor displayed a unique profile in that both chlorethylclonidine and SZL-49 produced a marked inactivation of this subtype. The similarity of the alkylation-inactivation profiles between the cloned <em>α</em>_1c and classical <em>α</em>_1A-adrenoceptors support the recent proposal that these two <em>α</em>₁-adrenoceptors in fact correspond to the same subtype.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 1","pages":"Pages 49-53"},"PeriodicalIF":0.0,"publicationDate":"1995-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90015-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71733995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors","authors":"Joachim Mierau ,&nbsp;Franz J. Schneider ,&nbsp;Helmut A. Ensinger ,&nbsp;Christopher L. Chio ,&nbsp;Mary E. Lajiness ,&nbsp;Rita M. Huff","doi":"10.1016/0922-4106(95)90013-6","DOIUrl":"10.1016/0922-4106(95)90013-6","url":null,"abstract":"<div><p>Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzthiazole-dihydrochloride) is a potent dopamine autoreceptor agonist. We have carried out an analysis of the binding affinities of dopamine D_2L, D_2S, D₃, and D₄ receptors for pramipexole using both [³H]pramipexole and [³H]spiperone as radioligands at cloned and heterologously expressed receptors. Studies were carried out using rat and human D_2L, D_2S and D₃ receptors with equivalent results. When the binding of pramipexole to the high affinity, guanine nucleotide-sensitive state of each receptor was analyzed, pramipexole is most selective for D₃ compared to D₂ and D₄ receptors. These results indicate a 5-fold selectivity of pramipexole for D₃ receptors, while quinpirole and bromocriptine are non-selective or more D₂/D₄ receptor selective. Two measurements of receptor activation for dopamine D₂, D₃, and D₄ receptors also show that pramipexole is most potent for activation of D₃ receptors. The dopamine D₃ receptor selectivity of pramipexole may explain the previously described properties of this drug, including its potent autoreceptor preference.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"290 1","pages":"Pages 29-36"},"PeriodicalIF":0.0,"publicationDate":"1995-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90013-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18666996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The functional role of the binding site aspartate in muscarinic acetylcholine receptors, probed by site-directed mutagenesis","authors":"Karen M. Page,&nbsp;Carol A.M. Curtis,&nbsp;Philip G. Jones,&nbsp;Edward C. Hulme","doi":"10.1016/0922-4106(95)90151-5","DOIUrl":"10.1016/0922-4106(95)90151-5","url":null,"abstract":"<div><p>Mutation of the Asp in transmembrane domain three of the muscarinic receptors to Asn (M₁) or Glu (M₁ and M₂) strongly reduced the high-affinity component of agonist binding, and the M₁ phosphoinositide response. Formation of the acetylcholine-receptor binary complex was also strongly inhibited. In contrast, binary complex formation by other agonists, as well as the antagonist (−)-<em>N</em>-methyl-scopolamine, was less affected. Ionic bonding between the carboxylate oxyanion and the positively-charged headgroup probably anchors acetylcholine when it is bound in its active conformation, but alternative, non-productive, binding modes, promoted by non-polar forces, may contribute to binary complex formation by other ligands.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"289 3","pages":"Pages 429-437"},"PeriodicalIF":0.0,"publicationDate":"1995-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90151-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18564289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anatoxin-a is a potent agonist of the nicotinic acetylcholine receptor of bovine adrenal chromaffin cells","authors":"Leah Molloy ,&nbsp;Susan Wonnacott ,&nbsp;Timothy Gallagher ,&nbsp;Paul A. Brough ,&nbsp;Bruce G. Livett","doi":"10.1016/0922-4106(95)90153-1","DOIUrl":"10.1016/0922-4106(95)90153-1","url":null,"abstract":"<div><p>(+)-Anatoxin-a is a neurotoxic alkaloid produced by the cyanobacterium <em>Anabaena flos-aquae</em>. In this study synthetic (±)-anatoxin-a was tested on isolated bovine adrenal chromaffin cells to determine its ability to evoke secretion of endogenous catecholamines through neuronal-type nicotinic receptor activation. Anatoxin-a was found to act as a potent agonist of the secretory response of chromaffin cells with an EC₅₀ of 1–2 μM, compared with an EC₅₀ of 4–5 μM for nicotine. The cells responded to anatoxin-a and nicotine with bell-shaped concentration-response curves consistent with desensitisation at concentrations of anatoxin-a greater than 5 μM and of nicotine greater than 20 μM. The secretion of catecholamines stimulated by anatoxin-a was completely inhibited in a non-competitive manner by the nicotinic antagonist mecamylamine with an IC₅₀ of 0.4–0.5 μM. In the presence of depolarising concentrations of K⁺ (15 or 50 mM), anatoxin-a increased the secretion of catecholamines in a concentration-dependent manner up to the same maximum as that achieved by anatoxin-a alone. It is concluded that anatoxin-a acts as a potent and selective nicotinic agonist, capable of evoking secretion of endogenous catecholamines from chromaffin cells via their neuronal-type nicotinic receptor.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"289 3","pages":"Pages 447-453"},"PeriodicalIF":0.0,"publicationDate":"1995-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90153-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18564291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic interaction of adenylate cyclase activators and nitric oxide donor SIN-1 on platelet cyclic AMP","authors":"Andreas Fisch,&nbsp;Jutta Michael-Hepp,&nbsp;Jürgen Meyer,&nbsp;Harald Darius","doi":"10.1016/0922-4106(95)90154-X","DOIUrl":"10.1016/0922-4106(95)90154-X","url":null,"abstract":"<div><p>The molecular mechanism of the synergistic platelet inhibition by activators of adenylate cyclase and guanylate cyclase in human platelets was investigated. The adenylate cyclase activators iloprost and prostaglandin E₁ and the guanylate cyclase activator 3-morpholino-synonimine (SIN-1) dose-dependently inhibited thrombin-induced aggregation of washed human platelets. Furthermore, SIN-1 at a concentration inhibiting platelet aggregation by only 10% shifted the IC₅₀ values of iloprost and prostaglandin E₁ by one order of magnitude to the left, indicating a synergistic action of adenylate cyclase and guanylate cyclase activators. Iloprost and prostaglandin E₁ dose-dependently elevated platelet cAMP without a significant influence on cGMP. In contrast, the platelet cGMP level was dose-dependently elevated by SIN-1. In addition, SIN-1 markedly increased cAMP level induced by low concentrations of adenylate cyclase activators (0.1–0.3 nM iloprost or 10–150 nM prostaglandin E₁). In contrast, the rise in cAMP induced by higher adenylate cyclase activator concentrations (3 nM iloprost or 30 μM prostaglandin E₁) was significantly reduced in the presence of SIN-1. The same biphasic mode of action of SIN-1 was observed with forskolin, an adenylate cyclase stimulator acting receptor independently, indicating a prostacyclin-receptor independent mechanism. The cAMP elevating effect of SIN-1 in the presence of low prostanoid concentrations was completely abolished by piroximone, a selective inhibitor of phosphodiesterase type III. Therefore, the inhibition of phosphodiesterase III by cGMP seems to be the mechanism for the elevation of cAMP levels by SIN-1 in the presence of low concentration of adenylate cyclase activators in human platelets. In contrast, the mechanism by which SIN-1 reduces platelet cAMP levels induced by higher concentrations of prostaglandin E₁, iloprost, and forskolin, remains to be clarified.</p></div>","PeriodicalId":100502,"journal":{"name":"European Journal of Pharmacology: Molecular Pharmacology","volume":"289 3","pages":"Pages 455-461"},"PeriodicalIF":0.0,"publicationDate":"1995-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0922-4106(95)90154-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18564292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}