{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T07:52:35Z","timestamp":1761292355401},"reference-count":61,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2009,2,10]],"date-time":"2009-02-10T00:00:00Z","timestamp":1234224000000},"content-version":"vor","delay-in-days":4303,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[1997,5]]},"abstract":"\n\nPrevious studies in our laboratory have shown that the synthetic xanthine analogue denbufylline, a selective type 4 phosphodiesterase (PDE\u20104) inhibitor, is a potent activator of the hypothalamo\u2010pituitary\u2010adrenal (HPA) axis when given orally or intraperitoneally (i.p.) to adult male rats. This paper describes the results of experiments in which well established in vivo<\/jats:italic> and in vitro<\/jats:italic> methods were used to compare the effects of denbufylline on HPA function with those of two other selective PDE\u20104 inhibitors, rolipram and BRL 61063 (1,3\u2010dicyclopropylmethyl\u20108\u2010amino\u2010xanthine). For comparison, parallel measurements of the immunoreactive\u2010 (ir\u2010) luteinising hormone (LH) were made where appropriate.<\/jats:p><\/jats:list-item>\nWhen injected intraperitoneally, rolipram (40 and 200\u2003\u03bcg\u2003kg\u22121<\/jats:sup>, P<\/jats:italic><0.005), denbufylline (0.07\u20130.6\u2003\u03bcg\u2003kg\u22121<\/jats:sup>, P<\/jats:italic><0.05) and BRL 61063 (30\u2003\u03bcg\u2003kg\u22121<\/jats:sup>, P<\/jats:italic><0.005) each produced marked rises in the serum ir\u2010corticosterone concentrations. However, lower doses of rolipram (1.6 and 8\u2003\u03bcg\u2003kg\u22121<\/jats:sup>) and BRL 61063 (0.25\u20136\u2003\u03bcg\u2003kg\u22121<\/jats:sup>) were without effect (P<\/jats:italic>>0.05). By contrast, intracerebroventricular (i.c.v.) injection of rolipram (8\u2003ng\u20131\u2003\u03bcg\u2003kg\u22121<\/jats:sup>) or denbufylline (50\u2003ng\u20131\u2003\u03bcg\u2003kg\u22121<\/jats:sup>) failed to influence the serum ir\u2010corticosterone concentration. BRL 61063 (8\u2013120\u2003ng\u2003kg\u22121<\/jats:sup>, i.c.v.) was also ineffective in this regard although at a higher dose (1\u2003\u03bcg\u2003kg\u22121<\/jats:sup>, i.c.v.) it produced a small but significant (P<\/jats:italic><0.05) increase in ir\u2010corticosterone release. Denbufylline also increased the serum ir\u2010LH concentration when given peripherally (0.2\u20130.6\u2003\u03bcg\u2003kg\u22121<\/jats:sup>, i.p., P<\/jats:italic><0.05) or centrally (100\u2003ng\u2003kg\u22121<\/jats:sup>, i.c.v., P<\/jats:italic><0.05) but rolipram (1.6\u2013200\u2003\u03bcg\u2003kg\u22121<\/jats:sup>, i.p. or 8\u2003ng\u20131\u2003\u03bcg\u2003kg\u22121<\/jats:sup>, i.c.v.) and BRL 61063 (0.25\u201330\u2003\u03bcg\u2003kg\u22121<\/jats:sup>, i.p. or 1\u2003ng\u20131\u2003\u03bcg\u2003kg\u22121<\/jats:sup>, i.c.v.) did not (P<\/jats:italic>>0.05).<\/jats:p><\/jats:list-item>\nIn vitro<\/jats:italic> rolipram (10\u2003\u03bcM<\/jats:sc>, P<\/jats:italic><0.01), denbufylline (1\u2002mM<\/jats:sc>, P<\/jats:italic><0.001) and BRL\u200261063 (1 and 10\u2002\u03bcM<\/jats:sc>, P<\/jats:italic><0.05) stimulated the release of corticotrophin releasing hormone (ir\u2010CRH\u201041) but lower concentrations of the drugs were without effect as also was BRL 61063 at 100\u2003\u03bcM<\/jats:sc> (P<\/jats:italic>>0.05); the rank order of potency was thus BRL 61063>rolipram>denbufylline. The adenylyl cyclase activator forskolin (100\u2003\u03bcM<\/jats:sc>, P<\/jats:italic><0.01) also stimulated the release of ir\u2010CRH\u201041, producing effects which were additive with those of rolipram and denbufylline but not with those of BRL 61063. The secretory responses to forskolin (100\u2003\u03bcM<\/jats:sc>) were accompanied by a highly significant increase in the cyclic AMP content of the hypothalamic tissue (P<\/jats:italic><0.005). Rolipram (10\u2003\u03bcM<\/jats:sc>) also significantly (P<\/jats:italic><0.05) elevated the hypothalamic cyclic AMP but denbufylline (10\u2003mM<\/jats:sc>) and BRL 61063 (10\u2003\u03bcM<\/jats:sc>) did not. However, all three PDE\u2010inhibitors potentiated the rise in cyclic AMP induced by forskolin (P<\/jats:italic><0.05). None of the drugs tested, alone or in combination, modified the release of arginine vasopressin (ir\u2010AVP) from the hypothalamus.<\/jats:p><\/jats:list-item>\nRolipram (100\u2003\u03bcM<\/jats:sc>), denbufylline (100\u2003\u03bcM<\/jats:sc>) and BRL 61063 (100\u2003\u03bcM<\/jats:sc>) stimulated the release of corticotrophin (ir\u2010ACTH) from pituitary tissue in vitro<\/jats:italic> (P<\/jats:italic><0.05) but in lower concentrations they were without significant effect. In addition, rolipram (10\u2003\u03bcM<\/jats:sc>, P<\/jats:italic><0.05), denbufylline (0.1\u2003\u03bcM<\/jats:sc>, P<\/jats:italic><0.05) and BRL 61063 (10\u2003\u03bcM<\/jats:sc>, P<\/jats:italic><0.05) potentiated the significant (P<\/jats:italic><0.05) rises in ir\u2010ACTH secretion induced by forskolin (100\u2003\u03bcM<\/jats:sc>). Forskolin (100\u2003\u03bcM<\/jats:sc>) also produced a highly significant increase (P<\/jats:italic><0.01) in the tissue cyclic AMP content which was further potentiated by rolipram (10\u2003\u03bcM<\/jats:sc>), denbufylline (10\u2003\u03bcM<\/jats:sc>) and BRL 61063 (10\u2003\u03bcM<\/jats:sc>) which, alone did not affect the cyclic AMP content of the tissue.<\/jats:p><\/jats:list-item>\nSince both denbufylline and BRL 61063 possess significant adenosine A1<\/jats:sub> receptor blocking activity, further studies examined the potential influence of these receptors on the secretion in vitro<\/jats:italic> of CRH\u201041, AVP and ACTH. The release of ir\u2010CRH\u201041 was increased significantly by adenosine deaminase (ADA, 5\u2003u\u2003ml\u22121<\/jats:sup>, P<\/jats:italic><0.05) and the A1<\/jats:sub>\u2010receptor antagonist, 1,3\u2010dicyclopropyl\u20108\u2010cyclopentylxanthine (DPCPX, 0.1\u201310\u2003nM<\/jats:sc>, P<\/jats:italic><0.05). The responses to ADA were abolished by the A1<\/jats:sub> receptor agonist N6<\/jats:sup>\u2010cyclo\u2010hexyladenosine (CHA, 100\u2003nM<\/jats:sc>, P<\/jats:italic><0.05) which alone had no significant effect on ir\u2010CRH\u201041 release. ADA (0.1\u201310\u2003u\u2003ml\u22121<\/jats:sup>) and DPCPX (1\u2003nM<\/jats:sc>) had weak stimulant and inhibitory effects, respectively, on the release of ir\u2010ACTH from the pituitary gland while CHA (0.1\u201310\u2003nM<\/jats:sc>) was without effect. Ligand binding studies with [3<\/jats:sup>H]\u2010DPCPX as a probe demonstrated the presence of specific high affinity A1<\/jats:sub> binding sites in the hypothalamus (K<\/jats:italic>d<\/jats:sub>=0.7\u2003nM<\/jats:sc>; Bmax<\/jats:sub>=367\u00b132\u2003fmol\u2003mg\u22121<\/jats:sup> protein) and in the hippocampus (K<\/jats:italic>d<\/jats:sub>=1\u2003nM<\/jats:sc>; Bmax<\/jats:sub>=1165\u00b1145\u2003fmol\u2003mg\u22121<\/jats:sup> protein). In both tissues binding of the ligand was displaced by CHA (IC50<\/jats:sub>=1\u2003nM<\/jats:sc> (hypothalamus) and 2\u2003nM<\/jats:sc> (hippocampus)), BRL 61063 (IC50<\/jats:sub>=80\u2003nM<\/jats:sc> (hypothalamus) and 100\u2003nM<\/jats:sc> (hippocampus)) and denbufylline (IC50<\/jats:sub>=5\u2003\u03bcM<\/jats:sc> (hypothalamus) and 9\u2003\u03bcM<\/jats:sc> (hippocampus)) but not by rolipram.<\/jats:p><\/jats:list-item>\nThe results suggest that rolipram, denblufylline and BRL 61063 stimulate the HPA axis in the rat, acting at the levels of both the hypothalamus and the pituitary gland. Their actions may be explained, at least in part, by inhibition of PDE\u20104 but additional actions including blockade of hypothalamic adenosine A1<\/jats:sub> receptors by denbufylline and BRL 61063 cannot be excluded.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p>","DOI":"10.1038\/sj.bjp.0701158","type":"journal-article","created":{"date-parts":[[2006,7,21]],"date-time":"2006-07-21T14:37:20Z","timestamp":1153492640000},"page":"459-468","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Stimulation of the hypothalamo\u2010pituitary\u2010adrenal axis in the rat by three selective type\u20104 phosphodiesterase inhibitors: in vitro<\/i> and in vivo<\/i> studies"],"prefix":"10.1111","volume":"121","author":[{"given":"Meena","family":"Kumari","sequence":"first","affiliation":[]},{"given":"Patricia O.","family":"Cover","sequence":"additional","affiliation":[]},{"given":"Robert H.","family":"Poyser","sequence":"additional","affiliation":[]},{"given":"Julia C.","family":"Buckingham","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2009,2,10]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"crossref","first-page":"8039","DOI":"10.1016\/S0021-9258(20)82024-9","article-title":"Mechanisms of action of corticotropin\u2010releasing factor and other regulators of corticotropin release in rat pituitary cells","volume":"258","author":"Aguilera G.","year":"1983","journal-title":"J. Biol. Chem."},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0039-128X(81)80015-3"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00228276"},{"key":"e_1_2_5_5_1","first-page":"1","article-title":"Multiple isozymes of cyclic nucleotide phosphodiesterase","volume":"22","author":"Beavo J.A.","year":"1988","journal-title":"Adv. Second Messenger Phosphorylation Res."},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-6147(90)90066-H"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(92)90845-Z"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.13.10.6558"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1974.sp010568"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.0720187"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1977.sp012054"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm00030a007"},{"key":"e_1_2_5_13_1","first-page":"1244","article-title":"Adenosine 3\u2032,5\u2010phosphate in biological materials. 1. Purification and properties of cyclic 3\u2032,5\u2010nucleotide phosphodiesterase and use of this enzyme to characterise adenosine 3\u2032,5\u2010phosphate in human urine","volume":"237","author":"Butcher R.W.","year":"1962","journal-title":"J. Biol. Chem."},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/edrv-16-3-370"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2826.1991.tb00296.x"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1159\/000122910"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(83)91045-4"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-126-6-3016"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-96-1-85"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(87)92961-7"},{"key":"e_1_2_5_21_1","first-page":"285","volume-title":"Endocrine Toxicology","author":"Garside D.A.","year":"1992"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-111-5-1752"},{"key":"e_1_2_5_23_1","doi-asserted-by":"crossref","first-page":"5535","DOI":"10.1016\/S0021-9258(18)99390-7","article-title":"Adenosine 3\u2032,5 monophosphate as the intracellular mediator of the action of adrenocorticotrophic hormone on the adrenal cortex","volume":"242","author":"Grahame\u2010Smith D.G.","year":"1967","journal-title":"J. Biol. Chem."},{"key":"e_1_2_5_24_1","first-page":"50","article-title":"A role for adenosine receptors in the regulation of ACTH and LH secretion","volume":"127","author":"Hadley A.J.","year":"1990","journal-title":"J. Endocrinol."},{"key":"e_1_2_5_25_1","first-page":"283","article-title":"Effects of selective phosphodiesterase inhibitors on the release of ACTH and LH from the rat anterior pituitary gland in vitro","volume":"3","author":"Hadley A.J.","year":"1993","journal-title":"Pharmacol. Communications"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1996.tb15695.x"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1220719"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1320057"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/136.1.210"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1530\/jrf.0.0460025"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0303-7207(95)03583-S"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(82)90085-6"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.6281886"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(86)90589-5"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)52451-6"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1159\/000126439"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2826.1993.tb00363.x"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/0361-9230(79)90013-3"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-6147(91)90484-A"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1989.tb12029.x"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1006\/pulp.1994.1001"},{"key":"e_1_2_5_42_1","first-page":"124P","article-title":"The effect of caffeine on plasma corticosterone and pituitary adrenocorticotrophin (ACTH) release in the rat is antagonised by adenosine","volume":"39","author":"Nicholson S.A.","year":"1987","journal-title":"J. Physiol."},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1220535"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/0091-6749(86)90086-2"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1159\/000125183"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-116-2-633"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-89-1-254"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.07-04-01093.1987"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02245738"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1210\/mend-2-12-1311"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/0303-7207(94)90282-8"},{"key":"e_1_2_5_52_1","first-page":"58","article-title":"Effects of caffeine on anterior pituitary and thyroid function in the rat","volume":"214","author":"Spindel E.R.","year":"1980","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_5_53_1","volume-title":"Lack of endocrine effects of a low dose of caffeine in man","author":"Spindel E.R.","year":"1980"},{"key":"e_1_2_5_54_1","first-page":"346","article-title":"Neuroendocrine effects of caffeine. II. Effects on thyrotropin and corticosterone secretion","volume":"225","author":"Spindel E.R.","year":"1983","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_5_55_1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/978-3-642-69823-1_8","volume-title":"Caffeine\u2010Perspectives from Recent Reasearch","author":"Spindel E.R.","year":"1984"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(85)90181-X"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(94)90127-9"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1159\/000126572"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1159\/000126984"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(88)90451-X"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-124-2-583"},{"key":"e_1_2_5_62_1","first-page":"665","article-title":"Tissue selective inhibition of cyclic nucleotide phosphodiesterase by denbufylline","volume":"39","author":"Wilke R.","year":"1989","journal-title":"Arzneim-Forsch\/Drug Res."}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Fsj.bjp.0701158","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Fsj.bjp.0701158","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1038\/sj.bjp.0701158","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T08:33:01Z","timestamp":1698395581000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1038\/sj.bjp.0701158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,5]]},"references-count":61,"journal-issue":{"issue":"3","published-print":{"date-parts":[[1997,5]]}},"alternative-id":["10.1038\/sj.bjp.0701158"],"URL":"https:\/\/doi.org\/10.1038\/sj.bjp.0701158","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,5]]},"assertion":[{"value":"2009-02-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}