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At least 19 recordsLinked to original sources
PubMed1990

Pharmacokinetics of (+)-rolipram and (-)-rolipram in healthy volunteers.

Plasma levels of S-(+)-rolipram and R-(-)-rolipram in six healthy male volunteers were measured by radioimmunoassay after intravenous injection of 0.1 mg and oral administration of 1.0 mg of the pure enantiomers. Following i.v. treatment, plasma levels of both isomers declined in three phases, with half-lives of 0.2 h, 0.6-0.9 h and 6-8 h. Total clearance was 6 ml.min-1.kg-1. Oral administration of 1.0 mg gave a peak concentration of 16 ng.ml-1 after 0.5 h. Bioavailability of (+)-rolipram was 77% and of the (-) enantiomer it was 74%. There was no significant difference in Cmax, half-life, total clearance or bioavailability between the two enantiomers.

Administration, Oral↗
PubMed1993

Stereospecificity of rolipram actions on eosinophil cyclic AMP-specific phosphodiesterase.

The stereospecificity of rolipram inhibition of particulate cyclic AMP-specific phosphodiesterase (PDE IV) from guinea-pig eosinophils has been investigated. (-)-Rolipram (IC50 = 0.22 +/- 0.08 microM) was 2.5-fold more potent than (+)-rolipram (IC50 = 0.58 +/- 0.05 microM) in inhibiting membrane-bound PDE IV. Solubilization of PDE IV with deoxycholate (0.5%) and NaCl (100 mM) increased rolipram stereospecificity [IC50 (-)-rolipram = 0.020 +/- 0.002 microM; IC50 (+)-rolipram = 0.33 +/- 0.07 microM]. Partial purification of this solubilized PDE IV by DEAE-trisacryl anion-exchange chromatography reduced the enantiomeric potency difference compared with the pre-chromatographed activity, with (-)-rolipram (IC50 = 0.20 +/- 0.02 microM) being only 2.9-fold more potent than (+)-rolipram (IC50 = 0.57 +/- 0.14 microM). Vanadate-glutathione complex (V-GSH) stimulated membrane-bound PDE IV activity and increased the potency of (-)-rolipram (IC50 = 0.014 +/- 0.006 microM) but not (+)-rolipram (IC50 = 0.32 +/- 0.07 microM). In intact eosinophils, (-)-rolipram (EC50 = 0.19 +/- 0.02 microM) was 10-fold more potent than (+)-rolipram (EC50 = 1.87 +/- 0.09 microM) in enhancing isoprenaline (10 microM)-stimulated cyclic AMP accumulation. Strong correlations were demonstrated for displacement of [3H]rolipram binding to brain membranes by several PDE inhibitors and their inhibition of solubilized PDE IV (r = 0.98, P < 0.001, n = 7) and stimulation of cyclic AMP accumulation in intact cells (r = 0.98, P < 0.001, n = 6). Rolipram was a relatively weak inhibitor of partially purified pig aortic PDE IV and only slight stereospecificity was exhibited [IC50 (-)-rolipram = 1.47 +/- 0.09 microM; IC50 (+)-rolipram = 2.73 +/- 0.38 microM]. The results indicate the presence of a partially concealed stereospecific site (Sr) on eosinophil PDE IV possibly similar to the high-affinity rolipram-binding site in brain through which rolipram can potently inhibit enzyme activity. This site, which apparently is not present on partially purified pig aortic PDE IV, is concealed in freshly prepared eosinophil membranes but is exposed by solubilization or V-GSH treatment and is important in regulating intracellular cyclic AMP accumulation in intact cells.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1988

Influence of rolipram on the cyclic 3',5'-adenosine monophosphate response to histamine and adenosine in slices of guinea-pig cerebral cortex.

The effect of the phosphodiesterase (PDE) inhibitor rolipram on the cyclic AMP responses to adenosine, histamine and combinations of these two agonists, was examined in [3H]adenine-labelled slices of guinea-pig cerebral cortex. Constant levels of [3H]-cyclic AMP were achieved within 10 min of agonist addition, both in the presence and absence of rolipram (0.1 mM). Histamine (1 mM) produced an 8-fold increase in [3H]-cyclic AMP (compared with basal) which was increased 7-fold by rolipram. The responses to adenosine (0.1 mM) and adenosine and histamine in combination were larger than that to histamine alone (46-fold or more compared with basal) but the potentiation by rolipram was much smaller (2.5-fold or less). With both agonists the effect of rolipram was dose-dependent, the steady state [3H]-cyclic AMP levels increasing 1-2-fold for a 10-fold increase in rolipram concentration. Removal of the histamine or adenosine stimulus once steady state had been reached resulted in a rapid fall in [3H]-cyclic AMP levels with a half time of less than 5 min. Rolipram (0.1 mM) did not significantly alter the initial rates of fall in [3H]-cyclic AMP levels but increased the time taken for them to return to basal levels. The findings of higher steady state levels of cyclic AMP in the presence of rolipram, together with an almost unaltered rate of cyclic AMP turnover, are consistent with an interaction of rolipram with PDE which is overcome by an increase in cyclic AMP concentration. However, the relatively smaller effects of rolipram on the higher steady levels of cyclic AMP produced by adenosine and the rather shallow dose-dependence of the PDE inhibitor on the responses to both agonists are inconsistent with a simple competitive inhibition of total PDE activity in responding cells. The results can be explained, however, by the involvement of different forms of PDE, with the rolipram-sensitive, calcium-independent form dominating at low cyclic AMP levels and the rolipram-insensitive, calcium-dependent form becoming more important when cyclic AMP levels are higher.

2-Chloroadenosine↗
PubMed1992

Coexpression of human cAMP-specific phosphodiesterase activity and high affinity rolipram binding in yeast.

Studies by various investigators have demonstrated that the low Km, cAMP-specific phosphodiesterase (PDE IV) is selectively inhibited by a group of compounds typified by rolipram and Ro 20-1724. In addition to inhibiting the catalytic activity of PDE IV, rolipram binds to a high affinity binding site present in brain homogenates. Although it has been assumed that the high affinity rolipram-binding site is PDE IV, no direct evidence has been produced to support this assumption. The present studies were undertaken to determine whether the rolipram-binding site is coexpressed with PDE IV catalytic activity in Saccharomyces cerevisiae genetically engineered to express human recombinant monocytic PDE IV (hPDE IV). Expressing hPDE IV cDNA in yeast resulted in a 20-fold increase in PDE activity that was evident within 1 h of induction and reached a maximum by 3-6 h. The recombinant protein represented hPDE IV as judged by its immunoreactivity, molecular mass (approximately 88 kDa), kinetic characteristics (cAMP Km = 3.1 microM; cGMP Km greater than 100 microM), sensitivity to rolipram (Ki = 0.06 microM), and insensitivity to siguazodan (PDE III inhibitor) and zaprinast (PDE V inhibitor). Saturable, high affinity [3H] (R)-rolipram-binding sites (Kd = 1.0 nM) were coexpressed with PDE activity, indicating that both binding activity and catalytic activity are properties of the same protein. A limited number of compounds were tested for their ability to inhibit hPDE IV catalytic activity and compete for [3H](R)-rolipram binding. Analysis of the data revealed little correlation (r2 = 0.35) in the structure-activity relationships for hPDE IV inhibition versus competition for [3H] (R)-rolipram binding. In fact, certain compounds (e.g. (R)-rolipram Ro 20-1724) possessed a 10-100-fold selectivity for inhibition of [3H] (R)-rolipram binding over hPDE IV inhibition, whereas others (e.g. dipyridamole, trequinsin) possessed a 10-fold selectivity for PDE inhibition. Thus, although the results of these studies demonstrate that hPDE IV activity and high affinity [3H](R)-rolipram binding are properties of the same protein, they do not provide clear cut evidence linking the binding site with the PDE inhibitory activity of rolipram and related compounds.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Rolipram, a stereospecific inhibitor of calmodulin-independent phosphodiesterase, causes beta-adrenoceptor subsensitivity in rat cerebral cortex.

Prolonged pretreatment of rats with the atypical antidepressant rolipram attenuates noradrenaline (NA) sensitivity of the cerebral cortical cAMP generating system. The development of this down-regulation is time (7 d treatment required) and dose dependent (EC50 = 0.35 mg/kg). Density of beta-adrenoceptor as measured by (-)-3H-dihydroalprenolol [(-)-3H-DHA] binding is also reduced by rolipram pretreatment. The effect of rolipram is absolutely stereospecific for the (-)-enantiomer (ED50 = 0.18 mg/kg). In addition, only with this isomer, a reduction in daily weight gain was found compared to sham treated controls. Presynaptic denervation using intracerebroventricular (i.c.v.) injections of 6-hydroxydopamine (6-OHDA) prior to or during rolipram treatment did not completely block the effect of a rolipram treatment on down-regulation of cerebral cortical beta-adrenoceptors. The data favor a pre- and postsynaptic action of rolipram different from all other antidepressants studied so far in this experimental setting. Rolipram is known as inhibitor of brain phosphodiesterase. Using partially purified calmodulin-independent phosphodiesterase from brain it is shown that exclusively the (-)-enantiomer of rolipram inhibits phosphodiesterase with an IC50 of 1.25 mumol/l whereas the (+)-isomer possesses little potency. Since a marked stereospecificity for the (-)-isomer of rolipram was displayed in all pharmacological parameters tested so far with (+)- and (-)-rolipram, it is suggested that stereospecific and isozyme specific inhibition of cAMP-phosphodiesterase is, at least in part, related to the mechanism of action of the potential antidepressant drug rolipram and possibly of other antidepressants as well.

Adenylyl Cyclases↗
PubMed1989

Autoradiographic mapping of a selective cyclic adenosine monophosphate phosphodiesterase in rat brain with the antidepressant [3H]rolipram.

Rolipram is a clinically effective antidepressant with selective cAMP phosphodiesterase (PDE) inhibiting properties. (+/-)-[3H]Rolipram binds with high affinity (Kd = 2.52 +/- 0.47 nM) to sections of rat brain (Hill number = 0.90 +/- 0.05). Binding is stereospecific. Association of (+/-) [3H]rolipram to sections is rapid (47% of specific binding in the first minute, kobs = 0.52 min-1). Dissociation of (+/-)-[3H]rolipram exhibits non first order kinetics (3 component model; t1/2 = 2.5 min, 50 min and 6 h, respectively). A number of PDE inhibitors reduce (+/-)-[3H]rolipram binding to the level of nonspecific binding ((-)-rolipram, IC50 = 0.9 nM; (+/-)-rolipram, IC50 = 1.5 nM; Ro 20-1724, IC50 = 11 nM; ICI 63.197, IC50 = 35 nM; medazepam, IC50 = 240 nM; diazepam, IC50 = 1200 nM; IBMX, IC50 = 3800 nM). In vitro autoradiography reveals high binding site densities in the cerebellum, olfactory bulb, lateral septal nucleus, frontal cortex, subiculum and CA1 of hippocampus. Most of the labeled structures are part of the limbic system. In vivo autoradiography of (+/-)-[3H]rolipram binding shows much more nonspecific binding than in vitro, nevertheless the distribution pattern of (+/-)-[3H]rolipram binding sites is similar. A comparison of the distribution pattern of (+/-)-[3H]rolipram binding sites with that of an antidepressant (monoamine oxidase inhibitor, monoamine uptake inhibitor) reveals no overlap. Limited, though significant correlations exist with the distribution of beta 1-adrenergic, adenosine1 and glutamate/quisqualate receptors as well as protein kinase C, but not with beta 2-adrenergic receptors and forskolin binding sites.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Stereospecific binding of the antidepressant rolipram to brain protein structures.

The characteristics for the binding of the selective cAMP phosphodiesterase inhibitor and antidepressant agent rolipram to brain and peripheral organs were investigated. (+/-)-[3H]Rolipram equilibrium binding and Scatchard analysis revealed saturable, reversible, stereospecific, Mg2+-dependent and heat-sensitive binding with an apparent Hill number of 1. Binding was detected both to membrane-bound and soluble sites, with dissociation constants Kd of 1.2 and 2.4 nM, respectively, and binding site concentrations (Bmax) of 19.3 and 23.6 pmol/g rat forebrain. The (-)-enantiomer of rolipram was ca. 20 times more effective than the (+)-enantiomer in displacing (+/-)-[3H]rolipram from membranes. Rolipram bound to brain tissue of all mammalian species tested including man, while tissue from bird and fish showed less binding. Organs other than brain exhibited only negligible binding. Only specific cAMP phosphodiesterase inhibitors (ICI 63.197, Ro 20-1724) were potent competitors, while rolipram itself was inactive in a variety of receptor binding assays of neuroactive ligands. The kinetics of (-)-[3H]rolipram binding to the particulate fraction revealed a complex association and dissociation behaviour. The nature of the rolipram binding protein(s) is not clear, but the low affinity binding site evident from binding kinetics may represent a rolipram-sensitive phosphodiesterase isoenzyme also common to some peripheral organs, while the high affinity binding site(s) may be related to PDE isoenzymes more confined to the central nervous system.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Characterization of cAMP-dependent inhibition of LPS-induced TNF alpha production by rolipram, a specific phosphodiesterase IV (PDE IV) inhibitor.

Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tissue injury by eliciting the release of toxic factors from reticuloendothelial cells. One of the principal endogenous factors involved in this process is tumor necrosis factor alpha (TNF alpha). In this study, inhibitors selective for different classes of phosphodiesterases (PDE), were examined for their effects on LPS-induced TNF alpha production by human monocytes. The selective cAMP-PDE IV inhibitors, rolipram and RO-20-1724 were capable of inhibiting LPS-induced TNF alpha production by human monocytes in a concentration-dependent manner. Rolipram was used to examine further the cellular pharmacology of PDE IV inhibitors on cytokine production. The IC50 for inhibition of LPS-induced TNF alpha production by rolipram was 0.1 microM, whereas production of IL-1 beta or IL-6 was unaffected. Furthermore, rolipram was equally effective in inhibiting TNF alpha production by a number of other stimuli. Inhibition of TNF alpha production by rolipram was associated with an elevation of intracellular cAMP, consistent with a mechanism involving phosphodiesterase inhibition. Rolipram was efficacious in suppressing LPS-induced TNF alpha mRNA expression, and at the protein level was also active when added to cultures post-stimulated with LPS. This indicates that rolipram may act at both the transcriptional and translational levels. Rolipram inhibited TNF alpha production in vivo in a rat endotoxemia model. Collectively, these data suggest that the prototypic inhibitor of PDE IV isozyme, rolipram, can effectively and selectively inhibit LPS-induced TNF alpha production through elevation of intracellular cAMP.

Animals↗
PubMed1990

Effects of lithium and rolipram enantiomers on locomotor activity in inbred mice.

Rolipram is a racemic drug that increases brain cAMP availability by inhibiting phosphodiesterase. Lithium, on the other hand, reduces cAMP levels in brain by inhibiting adenylate cyclase and by increasing phosphodiesterase activity. Inbred strains of mice were used in the present study to determine whether the opposite effects of lithium and rolipram on cAMP levels were evident from behavioural effects of the drugs. In the first experiment, locomotor activity was measured in strains of male and female mice given an injection of either vehicle, (+)- or (-)-rolipram in order to find appropriate test conditions for studying interactions with lithium. (-)-Rolipram was more potent than its antipode in inducing hypokinesia, and the effects of (+)- and (-)-rolipram depended on mouse strain. In the second experiment, mice received lithium in their food for 3-4 weeks prior to testing, and they were then given an injection of vehicle, (+)- or (-)-rolipram before behaviour tests. Lithium reduced locomotor activity in mice given the vehicle, whereas it counteracted activity-suppressant effects of rolipram. The behavioural findings are consistent with the opposite pharmacological effects of lithium and rolipram on cAMP, and support the notion that cAMP availability in brain may play a role in behavioural effects of lithium and rolipram.

Animals↗
PubMed1994

The inotropic mechanism of the phosphodiesterase inhibitor OPC 3911 alone and in combination with rolipram, studied in papillary muscles of ferret and guinea-pig and isolated myocytes of guinea-pig ventricular muscle.

OPC 3911 is a potent inhibitor and PDE III is a specific inhibitor in cardiac muscle. The effects of the drug alone and in combination with the non-inotropic PDE IV inhibitor rolipram were analysed using hearts from guinea-pigs and ferrets. OPC 3911 had an EC50 value of 0.1 microM. At 0.1 microM peak force was increased by 50.7 +/- 7.6% (n = 6, P < 0.001), time to peak tension (TPT) reduced by 18.7 +/- 5.6% (n = 6, P < 0.05). Time to half relaxation (THR) was prolonged by 19 +/- 4.2% (n = 6, P < 0.001). After addition of rolipram (30 microM), there was a potentiation of peak force at all concentrations of OPC 3911. At 0.1 microM OPC rolipram increased peak force by 82.8 +/- 8.9% (n = 6, P < 0.001), reduced TPT by 73 +/- 6% (n = 6, P < 0.005) and increased THR by 27 +/- 5% (P < 0.01). OPC 3911 shortened action potential duration (APD) at 50% repolarization by 5.3 +/- 2.5% (n = 6, P < 0.05). Addition of rolipram prolonged APD by 3.7 +/- 2.5% (n = 6, P < 0.05). Second inward current (Isi) was increased at 3 microM OPC 3911 by 46 +/- 6% (n = 6, P < 0.05). The combination of OPC 3911 and rolipram intensified the Isi to 101 +/- 5% (n = 3). Rolipram slowed the rate of restitution and the onset of restitution was prolonged. Relative maximum post-extrasystolic potentiation was reduced in the presence of OPC 3911 from 67 +/- 5% to 45 +/- 6%. Adding rolipram caused potentiation of 55 +/- 6%. OPC 3911 increased the recirculation fraction of activator calcium from 0.36 to 0.42 (n = 10, P < 0.05). After addition of rolipram the recirculation fraction was 0.41 +/- 0.04 (n = 10, P < 0.05). The results suggest that rolipram exerts its potentiating effect on OPC 3911 via an increased Isi.

Action Potentials↗
PubMed1994

Reversal of pulmonary capillary ischemia-reperfusion injury by rolipram, a cAMP phosphodiesterase inhibitor.

Isoproterenol (ISO) and forskolin, agents that increase adenosine 3',5'-cyclic monophosphate (cAMP) via adenylyl cyclase activation, reverse lung injury associated with increased microvascular permeability. We studied the role of rolipram, a relatively isozyme-selective cAMP phosphodiesterase (PDE) inhibitor, in reversing increased capillary permeability due to ischemia-reperfusion (I/R), a form of oxidant injury in the lung, by using the isolated perfused rat lung model. Rolipram (2 microM) administered after 45 min of ischemia and 45 min of reperfusion reduced I/R-increased permeability as measured by the capillary filtration coefficient to control lung values. Computer image analysis of air space edema and perivascular cuffing, as well as wet-to-dry weight ratios, confirms the permeability reversal by rolipram administration. Rolipram inhibition of cAMP PDE in the lung was assessed by using [3H]adenine prelabeling adapted for the whole lung and perfusate [3H]cAMP accumulation. Rolipram failed to increase perfusate cAMP alone but dramatically increased perfusate cAMP above ISO alone. Dose-response relationships of ISO or rolipram show a close correlation of the half-maximal effective dose (ED50) for injury reversal and perfusate cAMP production. The combination of rolipram and ISO produced synergistic reversal of I/R injury. We conclude that reversal of I/R-induced increased microvascular permeability can be achieved with rolipram and that the mechanism of action of rolipram is probably through PDE isozyme-selective inhibition. The similarity of the ED50 values for cAMP efflux and reversal of permeability increases also supports a close coupling between cAMP accumulation and endothelial cell permeability.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Effects of rolipram on responses to acute and chronic antigen exposure in monkeys.

The following study was performed to test the hypothesis that treatment with rolipram, a specific inhibitor of phosphodiesterase (PDE) IV, should inhibit many pulmonary responses to acute and chronic antigen challenge in atopic monkeys by elevating intracellular cAMP and subsequently inhibiting leukocyte function. Monkeys received subcutaneous injections of either vehicle (2% DMSO) or 10 mg/kg of rolipram 1 h before exposure to Ascaris suum antigen (Ag). Acute responses to Ag, including bronchoconstriction, pulmonary leukocyte infiltration, and cytokine production, were monitored before and 4 h after single Ag aerosol administration. To monitor the effects of rolipram on chronic Ag exposure, a 10-d, multiple-Ag protocol, previously demonstrated to induce airway hyperresponsiveness (AHR) to methacholine (MCh), was performed. Ag exposure increased respiratory system resistance (Rrs) 221.7 +/- 31.88% (n = 5). This increase in Rrs was not significantly altered by rolipram. Rolipram significantly (p < 0.002) increased cAMP levels in bronchoalveolar lavage (BAL) leukocytes 1 h after administration (n = 5). Ag-induced increases in BAL IL-8 and TNF were significantly reduced by rolipram, but IL-1 beta and IL-6 increases were unaffected (n = 9). Ag-induced increases in BAL eosinophils and neutrophils were significantly reduced by rolipram (n = 9). In the multiple-Ag protocol (n = 7), rolipram significantly reduced both the number of BAL eosinophils (p < 0.02) and the development of AHR (p < 0.002). Despite its inability to inhibit acute Ag-induced bronchoconstriction, rolipram was protective against acute and chronic inflammatory responses to Ag and prevented the development of AHR, suggesting that selective PDE-IV inhibition is a relevant target for asthma therapy.

Animals↗
PubMed1985

Effects of rolipram, a novel antidepressant, on monoamine metabolism in rat brain.

The phosphodiesterase inhibitor and putative antidepressant rolipram (0.3-30 mg/kg i.p.) stimulated the accumulation of dopa following inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl dose-dependently in all brain regions investigated, suggesting that both dopamine and noradrenaline synthesis was enhanced. The stimulatory effect of rolipram on dopa accumulation in dopamine rich regions persisted even after pretreatment with gamma-butyrolactone which by itself increased dopa accumulation three fold. Following inhibition of catecholamine synthesis with alpha-amethyl-p-tyrosine rolipram accelerated the disappearance of noradrenaline and slowed the disappearance of dopamine. At low doses rolipram tended to reduce the pargyline-induced accumulation of 3-methoxytyramine. Rolipram attenuated the accumulation of 5-hydroxytryptophan in the neocortex and the diencephalon of 3-hydroxybenzylhydrazine HCl pretreated rats. The data suggest that rolipram enhances noradrenergic transmission by direct stimulation of tyrosine hydroxylase and by an increase of neuronal activity. Despite a stimulatory effect on tyrosine hydroxylase rolipram does not appear to alter dopamine release and metabolism to a large extent. In view of the occurrence of head-twitches the rolipram-induced reduction of 5-hydroxytryptamine metabolism may be due to feedback inhibition.

Animals↗
PubMed1993

Rolipram enhances the development of voltage-dependent Ca2+ current and serotonin-induced current in rat pheochromocytoma cells.

The effects of chronic treatment (6-8 days) with a phosphodiesterase inhibitor, rolipram, on the expression of voltage-dependent Ca2+ channels, nicotinic acetylcholine (ACh) receptors and 5-hydroxytryptamine (5-HT) receptors were investigated in PC12 cells. The results were compared with the effects of nerve growth factor (NGF), 8-bromo-cyclic AMP (8-Br-cAMP) and phorbol 12-myristate 13-acetate (PMA). In the morphological study rolipram, at a high concentration (100 microM) induced the extension of neurites. A similar result was obtained in 8-Br-cAMP (1 mM)-treated cells. Rolipram, at a low concentration (10 microM) or PMA (10(-7) M) did not induce obvious morphological change. NGF (100 ng/ml) induced the extension of long neurites and the formation of neural networks. Rolipram (100 microM) increased the current density (pA/pF) of voltage dependent Ca2+ current (ICa). Both NGF and 8-Br-cAMP also increased the current density of ICa, whereas PMA did not. NGF increased the current density of the nicotinic ACh response whereas rolipram, 8-Br-cAMP and PMA decreased. Rolipram (100 microM), NGF (100 ng/ml), and 8-Br-cAMP (1 mM) increased the current density of the 5-HT response whereas the effect of PMA (100 nM) was slight. The results suggest that rolipram is able to contribute to the neuronal development by increasing intracellular cAMP as well as 8-Br-cAMP. Consequently, rolipram behaves like a neurotrophic factor in cultured PC12 cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

Multiple second messenger systems act sequentially to mediate rolipram-induced prolongation of prostaglandin E2-induced mechanical hyperalgesia in the rat.

In this study we have evaluated the mechanisms mediating the prolonged hyperalgesia induced by administration of prostaglandin E2 plus rolipram, an inhibitor of type IV phosphodiesterase. The Randall-Selitto paw pressure device was employed to measure the effect of intradermal injection of test agents on the time course of the decrease in mechanical nociceptive threshold produced by prostaglandin E2 plus rolipram in the hairy skin of the hindpaw of the rat. The intradermal injection of prostaglandin E2 produced a dose-dependent decrease in the nociceptive threshold which lasted approximately 2 h. While rolipram alone had no significant effect on nociceptive threshold, it enhanced and prolonged (> 72 h) prostaglandin E2-induced hyperalgesia. WIPTIDE, a protein kinase A inhibitor, when administered 30 min after prostaglandin E2, or with prostaglandin E2 plus rolipram, a time when prostaglandin E2-induced hyperalgesia was at its peak, produced a significant reduction in hyperalgesia. However, at 90 or at 180 min after injection of prostaglandin E2 plus rolipram, WIPTIDE was found to be without effect. H-8, a protein kinase G inhibitor, and okadaic acid, a protein phosphatase inhibitor, when administered 30 min after prostaglandin E2, or 180 min after prostaglandin E2 plus rolipram, produced no significant effect. However, when administered 90 min after prostaglandin E2 plus rolipram, each produced a significant reduction in the hyperalgesia induced by prostaglandin E2 plus rolipram.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

Inhibition of granulocyte cAMP-phosphodiesterase by rolipram in vivo is not sufficient to protect the canine myocardium from reperfusion injury.

The purpose of this study was to determine whether the selective type IV cAMP-phosphodiesterase inhibitor rolipram could reduce the reperfusion injury that occurs during myocardial infarction in the anesthetized dog. This question was tested in pentobarbital-anesthetized dogs subject to 90 min of regional myocardial ischemia and 5 h of reperfusion. Dogs were treated with 1 mg/kg of rolipram (i.v., 15 min before reperfusion) followed by a 1 mg/kg/h infusion over the duration of the 5 h of reperfusion. Rolipram was tested in vitro for efficacy in inhibition of isolated human neutrophil superoxide generation. Rolipram produced significant inhibition of superoxide production over the concentration range of 0.1-100 microM rolipram when neutrophils were stimulated with a 10(-7) M concentration of the chemotactic peptide f-Met-Leu-Phe. Rolipram significantly inhibited superoxide generation from human and canine granulocytes in whole blood stimulated by zymosan. Therapeutic concentrations of rolipram in the blood of dogs were achieved during the course of the experiments with a plasma concentration of 0.761 +/- 0.095 micrograms/ml (2.76 +/- 0.34 microM) at the time of reperfusion, and 0.574 +/- 0.098 micrograms/ml (2.08 +/- 0.36 microM) at the end of the reperfusion period. The relative severity of myocardial ischemia between the two treatment groups was similar as assessed with radiolabeled microsphere measurement of myocardial blood flow. Transmural myocardial blood flows were not significantly different between the two groups after coronary occlusion (control, 0.05 +/- 0.01 ml/min/g, n = 6, vs. rolipram, 0.18 +/- 0.07 ml/min/g, n = 6; p = 0.48).(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1991

[Electroencephalographic study with rolipram (ME 3167), a selective inhibitor of adenosine 3',5'-monophosphate phosphodiesterase, in rabbits].

The electroencephalographic (EEG) effects of rolipram were investigated in rabbits with chronic electrode implants. Intravenous administration of rolipram at 10 to 100 micrograms/kg evoked an increase in the arousal EEG pattern period (low amplitude fast waves) in the cortical EEG and synchronization of the hippocampal theta waves with increased voltages. Rolipram at higher doses caused behavioral excitation in rabbits. Rolipram did not affect EEG arousal responses to both auditory stimulation (2000 Hz, monotone) and electrical stimulation (100 Hz, 0.1 msec, 3-6 V) of the midbrain reticular formation or the posterior hypothalamus. The recruiting response induced by centromedian thalamic stimulation at a low frequency (7 Hz, 0.1 msec, 4-8 V) was not altered by rolipram. Rolipram was without effect on the photic driving response to flash light (2 Hz) in the occipital cortex. Rolipram caused a slight increase in the duration of after discharges induced by electrical stimulation (50 Hz, 0.5 msec, 4-20 V) of the dorsal hippocampus. These results suggest that rolipram is a drug that causes the EEG arousal pattern.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Rolipram forms a potent discriminative stimulus in drug discrimination experiments in rats.

Long Evans rats were trained to discriminate 0.2 mg/kg IP (+/-)-rolipram from vehicle injection in a food-motivated two-lever operant task. Eight out of nine rats acquired the discrimination after an average of 91 sessions (min 65, max 137). The ED50 of (+/-)-rolipram was 0.06 mg/kg IP. Generalization tests with (-)- and (+)-rolipram showed that the (-)-isomer was 8 times more active than (+)-rolipram with an ED50 of 0.06 and 0.4 mg/kg IP respectively. The phosphodiesterase inhibitor RO 20-1724 partially (83%) generalized to (+/-)-rolipram in doses of 0.6 and 1.0 mg/kg IP. IBMX 5 mg/kg IP showed 63% generalization. Tests with imipramine and the (+)- and (-)-isomer of the noradrenaline uptake inhibitor oxaprotiline suggest that NA-uptake inhibiting drugs do not form an interoceptive cue which is (+/-)-rolipram-like. dbcAMP 12.5 mg/kg SC and 100 mg/kg SC dbcGMP did not generalize to the training drug. The nature of the discriminative stimulus produced by this dose of (+/-)-rolipram in rats remains to be elucidated.

Animals↗