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Michael Artman - One of the best experts on this subject based on the ideXlab platform.
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Inotropic Responses to Selective (RO 20–1724 and SQ 65, 442) and Nonselective (Trequinsin) Inhibitors of Cyclic AMP-Specific Class IV Phosphodiesterase in Newborn, Immature, and Adult Rabbit Myocardium
Pediatric Research, 1992Co-Authors: Niki L Oquist, Samuel J Strada, Michael ArtmanAbstract:ABSTRACT: In contrast to myocardium from adult rabbits, myocardium from newborns is insensitive to the inotropic effects of selective inhibitors (e. g. amrinone, milrinone, and indolidan) of the cGMP-inhibited high-affinity cAMP phosphodiesterase (PDE) localized in the sarcoplasmic reticulum. This difference may be explained at least partially by our recent observation that this camp PDE activity is low in sarcoplasmic reticulum from newborns. Furthermore, because the predominant cytosolic high-affinity cAMP PDE activity in newborns is a cGMP-insensitive form, we postulated that selective inhibitors of this form of cAMP-specific PDE may increase cardiac contractility in newborns. Therefore, the inotropic effects of RO 20–1724 and SQ 65, 442 (selective inhibitors of cGMP-insensitive, high-affinity cAMP PDE) were compared with Trequinsin (a potent, less selective PDE inhibitor) in right ventricular papillary muscles isolated from newborn (NB; 24–48 h), immature (14–16 d), and adult New Zealand White rabbits. At a drug concentration of 100 $mUm, RO 20–1724 and SQ 65, 442 depressed maximal rate of tension development to 67 ± 4 and 70 ± 2% of control, respectively, in NB papillary muscles. The NB response to RO 20–1724 differed significantly from the immature (127 ± 2%) and adult (115 ± 3%) groups (p < 0.05), but the effects of SQ 65, 442 were comparable among the three age groups. In contrast, Trequinsin exerted a positive inotropic effect in the NB group (355 ± 22% of control) that was substantially greater than the maximal response obtained in the immature (139 ± 6% of control) or adult (131 ± 5% of control) groups (p < 0.01). These differences in inotropic responsiveness could not be ex- plained by differences in sensitivity to drug-induced inhibition of cAMP or cGMP hydrolysis in cytosolic fractions from the three age groups. Thus, selective inhibitors of the predominant form of high-affinity cAMP PDE in NB myocardium do not exert a positive inotropic response in NB papillary muscles. The age-specific cardiotonic effects of Trequinsin suggest that other PDE isozymes could contribute to the modulation of contractility during postnatal maturation.
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Inotropic responses to selective (RO 20-1724 and SQ 65,442) and nonselective (Trequinsin) inhibitors of cyclic AMP-specific class IV phosphodiesterase in newborn, immature, and adult rabbit myocardium.
Pediatric research, 1992Co-Authors: Niki L Oquist, Samuel J Strada, Michael ArtmanAbstract:ABSTRACT: In contrast to myocardium from adult rabbits, myocardium from newborns is insensitive to the inotropic effects of selective inhibitors (e. g. amrinone, milrinone, and indolidan) of the cGMP-inhibited high-affinity cAMP phosphodiesterase (PDE) localized in the sarcoplasmic reticulum. This difference may be explained at least partially by our recent observation that this camp PDE activity is low in sarcoplasmic reticulum from newborns. Furthermore, because the predominant cytosolic high-affinity cAMP PDE activity in newborns is a cGMP-insensitive form, we postulated that selective inhibitors of this form of cAMP-specific PDE may increase cardiac contractility in newborns. Therefore, the inotropic effects of RO 20–1724 and SQ 65, 442 (selective inhibitors of cGMP-insensitive, high-affinity cAMP PDE) were compared with Trequinsin (a potent, less selective PDE inhibitor) in right ventricular papillary muscles isolated from newborn (NB; 24–48 h), immature (14–16 d), and adult New Zealand White rabbits. At a drug concentration of 100 $mUm, RO 20–1724 and SQ 65, 442 depressed maximal rate of tension development to 67 ± 4 and 70 ± 2% of control, respectively, in NB papillary muscles. The NB response to RO 20–1724 differed significantly from the immature (127 ± 2%) and adult (115 ± 3%) groups (p < 0.05), but the effects of SQ 65, 442 were comparable among the three age groups. In contrast, Trequinsin exerted a positive inotropic effect in the NB group (355 ± 22% of control) that was substantially greater than the maximal response obtained in the immature (139 ± 6% of control) or adult (131 ± 5% of control) groups (p < 0.01). These differences in inotropic responsiveness could not be ex- plained by differences in sensitivity to drug-induced inhibition of cAMP or cGMP hydrolysis in cytosolic fractions from the three age groups. Thus, selective inhibitors of the predominant form of high-affinity cAMP PDE in NB myocardium do not exert a positive inotropic response in NB papillary muscles. The age-specific cardiotonic effects of Trequinsin suggest that other PDE isozymes could contribute to the modulation of contractility during postnatal maturation.
Paul O. Madsen - One of the best experts on this subject based on the ideXlab platform.
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Prevention of contrast medium-induced renal vasospasm by phosphodiesterase inhibition
Investigative radiology, 1998Co-Authors: Peter Drescher, Jane M. Knes, Paul O. MadsenAbstract:Rationale and objectives This study investigated the involvement of cyclic adenosine monophosphate (cAMP) in contrast medium-induced renal vasomotor effects and the efficacy of selective phosphodiesterase (PDE) inhibitors influencing cAMP in preventing contrast medium-induced renal vasospasm. Methods Isometric contractions of rabbit renal artery rings were subjected to increasing concentrations of the ionic contrast medium sodium/meglumine diatrizoate (DIA) and the nonionic contrast media iopamidol (IOP) and iodixanol (IOD) and compared with a potassium chloride control. Subsequently increasing concentrations of the nonselective phosphodiesterase inhibitors theophylline and papaverine and the following selective phosphodiesterase inhibitors were applied: vinpocetine, Trequinsin, zardaverine, rolipram, and dipyridamole (subtypes I-V) before restimulation of the arterial tissue with contrast medium. Results Diatrizoate, iopamidol, and iodixanol induced contractions up to 30%, 15%, and 3.5% of the potassium chloride control, respectively. All phosphodiesterase inhibitors markedly inhibited the contrast medium-induced contractions in a dose-dependent manner. The selective phosphodiesterase inhibitors rolipram and Trequinsin attenuated these contractions significantly more (92% and 94%) than did zardaverine, dipyridamole, and vinpocetine, with an inhibitory potency of 37%, 41%, and 62%, respectively. Conclusions Nonionic contrast media induced renal vasoconstriction less potently than ionic contrast media. Significant differences in the ability to prevent contrast medium-induced vasoconstriction were observed among the various phosphodiesterase subtypes studied. selective phosphodiesterase inhibition with inhibitor subtypes II and IV showed the most promising results in specifically preventing contrast medium-induced renal vasospasm.
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smooth muscle tone regulation in rabbit cavernosal and spongiosae tissue by cyclic amp and cyclic gmp dependent mechanisms
The Journal of Urology, 1994Co-Authors: Christoph Sparwasser, P Drescher, J A Will, Paul O. MadsenAbstract:AbstractThe relaxing effects of several specific and nonspecific inhibitors of phosphodiesterases (PDE) on rabbit isolated corpus cavernosum (CC) and spongiosum (CS) were investigated. Preparations were mounted in organ baths, and isometric tension was recorded. The results were compared with the effects of direct administration of analogs of the second messenger cyclic nucleotides and the effects of forskolin, a direct stimulator of adenylate cyclase, and the nitric oxide donor 3-morpholinosydnonimine (SIN 1). All drugs relaxed the phenylephrine-induced contractions in CC and CS in a dose-dependent fashion. In CC and CS, type III (SK&F 95654) and type V (zaprinast and dipyramidole) PDE inhibitors, as well as the nonspecific inhibitors papaverine and Trequinsin, showed no differences in IC50. The type IV inhibitor rolipram relaxed CC and CS at significantly lower concentrations (p <0.005) than any other PDE inhibitor, and in CC the type III and IV inhibitor zardaverine was more potent (p <0.05) than SK&F ...
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Smooth Muscle Tone Regulation in Rabbit Cavernosal and Spongiosae Tissue by Cyclic AMP- and Cyclic GMP-Dependent Mechanisms
The Journal of Urology, 1994Co-Authors: Christoph Sparwasser, P Drescher, J A Will, Paul O. MadsenAbstract:AbstractThe relaxing effects of several specific and nonspecific inhibitors of phosphodiesterases (PDE) on rabbit isolated corpus cavernosum (CC) and spongiosum (CS) were investigated. Preparations were mounted in organ baths, and isometric tension was recorded. The results were compared with the effects of direct administration of analogs of the second messenger cyclic nucleotides and the effects of forskolin, a direct stimulator of adenylate cyclase, and the nitric oxide donor 3-morpholinosydnonimine (SIN 1). All drugs relaxed the phenylephrine-induced contractions in CC and CS in a dose-dependent fashion. In CC and CS, type III (SK&F 95654) and type V (zaprinast and dipyramidole) PDE inhibitors, as well as the nonspecific inhibitors papaverine and Trequinsin, showed no differences in IC50. The type IV inhibitor rolipram relaxed CC and CS at significantly lower concentrations (p
Niki L Oquist - One of the best experts on this subject based on the ideXlab platform.
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Inotropic Responses to Selective (RO 20–1724 and SQ 65, 442) and Nonselective (Trequinsin) Inhibitors of Cyclic AMP-Specific Class IV Phosphodiesterase in Newborn, Immature, and Adult Rabbit Myocardium
Pediatric Research, 1992Co-Authors: Niki L Oquist, Samuel J Strada, Michael ArtmanAbstract:ABSTRACT: In contrast to myocardium from adult rabbits, myocardium from newborns is insensitive to the inotropic effects of selective inhibitors (e. g. amrinone, milrinone, and indolidan) of the cGMP-inhibited high-affinity cAMP phosphodiesterase (PDE) localized in the sarcoplasmic reticulum. This difference may be explained at least partially by our recent observation that this camp PDE activity is low in sarcoplasmic reticulum from newborns. Furthermore, because the predominant cytosolic high-affinity cAMP PDE activity in newborns is a cGMP-insensitive form, we postulated that selective inhibitors of this form of cAMP-specific PDE may increase cardiac contractility in newborns. Therefore, the inotropic effects of RO 20–1724 and SQ 65, 442 (selective inhibitors of cGMP-insensitive, high-affinity cAMP PDE) were compared with Trequinsin (a potent, less selective PDE inhibitor) in right ventricular papillary muscles isolated from newborn (NB; 24–48 h), immature (14–16 d), and adult New Zealand White rabbits. At a drug concentration of 100 $mUm, RO 20–1724 and SQ 65, 442 depressed maximal rate of tension development to 67 ± 4 and 70 ± 2% of control, respectively, in NB papillary muscles. The NB response to RO 20–1724 differed significantly from the immature (127 ± 2%) and adult (115 ± 3%) groups (p < 0.05), but the effects of SQ 65, 442 were comparable among the three age groups. In contrast, Trequinsin exerted a positive inotropic effect in the NB group (355 ± 22% of control) that was substantially greater than the maximal response obtained in the immature (139 ± 6% of control) or adult (131 ± 5% of control) groups (p < 0.01). These differences in inotropic responsiveness could not be ex- plained by differences in sensitivity to drug-induced inhibition of cAMP or cGMP hydrolysis in cytosolic fractions from the three age groups. Thus, selective inhibitors of the predominant form of high-affinity cAMP PDE in NB myocardium do not exert a positive inotropic response in NB papillary muscles. The age-specific cardiotonic effects of Trequinsin suggest that other PDE isozymes could contribute to the modulation of contractility during postnatal maturation.
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Inotropic responses to selective (RO 20-1724 and SQ 65,442) and nonselective (Trequinsin) inhibitors of cyclic AMP-specific class IV phosphodiesterase in newborn, immature, and adult rabbit myocardium.
Pediatric research, 1992Co-Authors: Niki L Oquist, Samuel J Strada, Michael ArtmanAbstract:ABSTRACT: In contrast to myocardium from adult rabbits, myocardium from newborns is insensitive to the inotropic effects of selective inhibitors (e. g. amrinone, milrinone, and indolidan) of the cGMP-inhibited high-affinity cAMP phosphodiesterase (PDE) localized in the sarcoplasmic reticulum. This difference may be explained at least partially by our recent observation that this camp PDE activity is low in sarcoplasmic reticulum from newborns. Furthermore, because the predominant cytosolic high-affinity cAMP PDE activity in newborns is a cGMP-insensitive form, we postulated that selective inhibitors of this form of cAMP-specific PDE may increase cardiac contractility in newborns. Therefore, the inotropic effects of RO 20–1724 and SQ 65, 442 (selective inhibitors of cGMP-insensitive, high-affinity cAMP PDE) were compared with Trequinsin (a potent, less selective PDE inhibitor) in right ventricular papillary muscles isolated from newborn (NB; 24–48 h), immature (14–16 d), and adult New Zealand White rabbits. At a drug concentration of 100 $mUm, RO 20–1724 and SQ 65, 442 depressed maximal rate of tension development to 67 ± 4 and 70 ± 2% of control, respectively, in NB papillary muscles. The NB response to RO 20–1724 differed significantly from the immature (127 ± 2%) and adult (115 ± 3%) groups (p < 0.05), but the effects of SQ 65, 442 were comparable among the three age groups. In contrast, Trequinsin exerted a positive inotropic effect in the NB group (355 ± 22% of control) that was substantially greater than the maximal response obtained in the immature (139 ± 6% of control) or adult (131 ± 5% of control) groups (p < 0.01). These differences in inotropic responsiveness could not be ex- plained by differences in sensitivity to drug-induced inhibition of cAMP or cGMP hydrolysis in cytosolic fractions from the three age groups. Thus, selective inhibitors of the predominant form of high-affinity cAMP PDE in NB myocardium do not exert a positive inotropic response in NB papillary muscles. The age-specific cardiotonic effects of Trequinsin suggest that other PDE isozymes could contribute to the modulation of contractility during postnatal maturation.
Clive P. Page - One of the best experts on this subject based on the ideXlab platform.
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the pharmacology of two novel long acting phosphodiesterase 3 4 inhibitors rpl554 9 10 dimethoxy 2 2 4 6 trimethylphenylimino 3 n carbamoyl 2 aminoethyl 3 4 6 7 tetrahydro 2h pyrimido 6 1 a isoquinolin 4 one and rpl565 6 7 dihydro 2 2 6 diisopropylph
Journal of Pharmacology and Experimental Therapeutics, 2006Co-Authors: Victoria Boswellsmith, Domenico Spina, Alec W Oxford, Mike B Comer, E A M Seeds, Clive P. PageAbstract:The pharmacology of two novel, Trequinsin-like PDE3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido-[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one], has been investigated in a number of in vitro and in vivo assays. Electrical field stimulation-induced contraction of guinea pig superfused isolated tracheal preparations was significantly inhibited by RPL554 (10 microM) and RPL565 (10 microM) (percentage control; 93 +/- 1.2 and 84.4 +/- 2.7, respectively). Contractile responses were suppressed for up to 12 h after termination of superfusion with RPL554 demonstrating a long duration of action. RPL554 and RPL565 inhibited, in a concentration-dependent manner, lipopolysaccharide-induced tumor necrosis factor alpha release from human monocytes [IC50; 0.52 microM (0.38-0.69) and 0.25 microM (0.18-0.35), respectively] and proliferation of human mononuclear cells to phytohemagglutinin [IC50; 0.46 microM (0.24-0.9) and 2.90 microM (1.6-5.4), respectively]. The inhibitory effect of these drugs in vitro was translated into anti-inflammatory activity in vivo. RPL554 (10 mg/kg) and RPL565 (10 mg/kg) administered orally significantly inhibited eosinophil recruitment following antigen challenge in ovalbumin-sensitized guinea pigs. Likewise, inhalation of dry powder containing RPL554 by conscious guinea pigs (25% in micronized lactose) 1.5 h before antigen exposure significantly inhibited the recruitment of eosinophils to the airways. Exposure of conscious guinea pigs to inhalation of dry powder containing RPL554 (2.5%) and RPL565 (25%) in micronized lactose significantly inhibited histamine-induced plasma protein extravasation in the trachea and histamine-induced bronchoconstriction over a 5.5-h period. Thus, RPL554 and RPL565 are novel, long-acting PDE 3/4 inhibitors exhibiting a broad range of both bronchoprotective and anti-inflammatory activities.
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The effect duration of selective phosphodiesterase inhibitors in the guinea pig
Life sciences, 1998Co-Authors: Domenico Spina, Pierpaolo Ferlenga, Ivano Biasini, Ermanno Moriggi, Francesco Marchini, Claudio Semeraro, Clive P. PageAbstract:Abstract The beta-adrenoceptor agonists, isoprenaline, salbutamol and salmeterol, the non-selective phosphodiesterase (PDE) isoenzyme inhibitors, theophylline, Trequinsin; the PDE3 isoenzyme inhibitor, milrinone; the PDE3/4 isoenzyme inhibitor, benzafentrine; and the PDE4 isoenzyme inhibitors, denbufylline, nitraquazone, RP 73401, Ro-20-1724, rolipram and tibenelast all induced concentration-dependent reversal of prostaglandin F2α-induced contraction of guinea-pig supervised trachea in vitro . The relaxant response of the non-selective PDE isoenzyme inhibitor Trequinsin was slow in onset and demonstrated very slow recovery, similar to that observed with the long-acting beta 2 -adrenoceptor agonist, salmeterol and the PDE4 inhibitor, RP 73401. The relaxant agonists also significantly reversed bombesin-induced bronchospasm in anaesthetised guinea-pigs and there was a highly significant correlation between the ability of drugs to reverse PGF2α-induced contraction of guinea-pig isolated trachea in vitro and bombesin-induced bronchoconstriction in vivo . Furthermore, both salmeterol and Trequinsin demonstrated long lasting bronchodilator responses consistent with the in vitro data. These results show that PDE isoenzyme inhibitors demonstrate different pharmacodynamic profiles that is not determined by PDE4 inhibitory potency and indicate that other factors may be important in this regard.
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The Effect of Selective Phosphodiesterase Inhibitors in Comparison with other Anti-asthma Drugs on Allergen-induced Eosinophilia in Guinea-pig Airways
Pulmonary pharmacology, 1995Co-Authors: Katharine H. Banner, F. Marchini, A. Buschi, E. Moriggi, C. Semeraro, Clive P. PageAbstract:Abstract Summary: The effects of isoenzyme selective phosphodiesterase (PDE) inhibitors and other anti-asthma drugs on antigen-induced eosinophil recruitment and activation in guinea-pig airways was studied. Guinea-pigs were sensitized and subsequently challenged with aerosolized ovalbumin (OVA). Bronchoalveolar lavage (BAL) was performed 24 h later. A significant increase in eosinophils and eosinophil peroxidase (EPO) was detected in BAL fluid and BAL fluid supernatant respectively from OVA immunized guinea-pigs compared with sham treated animals. Guinea-pigs were treated for 7 days prior to antigen challenge with either the following drugs or the appropriate vehicle (i.p.). The selective β 2 agonist, salbutamol (0.3 mg/kg), the PDE III inhibitor, milrinone (15 mg/kg) and the non-selective PDE inhibitor, Trequinsin (1 mg/kg) had no effect on eosinophil number or EPO levels. The PDE IV inhibitor, rolipram (15 mg/kg), the mixed type III/IV PDE inhibitor, benzafentrine (15 mg/kg) and the nonselective PDE inhibitor, aminophylline (31.5 mg/kg) had no effect on eosinophil number but reduced the amount of EPO detected. The anti-inflammatory glucocorticosteroids, beclomethasone (10 mg/kg) and betamethasone (4 mg/kg) and the type IV PDE inhibitor, RP 73401 (5 mg/kg) reduced both eosinophil numbers and EPO levels. These results suggest a role for the type IV PDE isoenzyme in the control of eosinophil recruitment and possibly activation in the airways.
Gabriele Jedlitschky - One of the best experts on this subject based on the ideXlab platform.
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immunolocalization of multidrug resistance protein 5 in the human genitourinary system
The Journal of Urology, 2002Co-Authors: Anne T Nies, Walter F Thon, Dietrich Keppler, Herbert Spring, Gabriele JedlitschkyAbstract:Purpose: The intracellular messenger cyclic guanosine monophosphate (cGMP) has an important role in regulating smooth muscle tone. An increase in intracellular cGMP levels is a prerequisite for penile erection. Inhibition of cGMP degradation by cGMP specific phosphodiesterase 5 has been used for treating erectile dysfunction. In addition to degradation by phosphodiesterase, cGMP is exported from cells by multidrug resistance protein 5 (MRP5), also called ABCC5, which we recently identified as an adenosine triphosphate dependent export pump for cGMP. MRP5 is potently inhibited by substances known as phosphodiesterase inhibitors, including sildenafil and Trequinsin. Therefore, we analyzed whether MRP5 is expressed in tissues of the human genitourinary system and whether MRP5 and phosphodiesterase 5 proteins are localized in the same cell types.Materials and Methods: Localization of MRP5 and phosphodiesterase 5 was analyzed by immunofluorescence microscopy in cryosections of various tissues of the human geni...
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The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides.
Journal of Biological Chemistry, 2000Co-Authors: Gabriele Jedlitschky, Brian Burchell, Dietrich KepplerAbstract:Abstract Cellular export of cyclic nucleotides has been observed in various tissues and may represent an elimination pathway for these signaling molecules, in addition to degradation by phosphodiesterases. In the present study we provide evidence that this export is mediated by the multidrug resistance protein isoform MRP5 (gene symbol ABCC5). The transport function of MRP5 was studied in V79 hamster lung fibroblasts transfected with a humanMRP5 cDNA. An MRP5-specific antibody detected an overexpression of the glycoprotein of 185 ± 15 kDa in membranes from MRP5-transfected cells and a low basal expression of hamster Mrp5 in control membranes. ATP-dependent transport of 3′,5′-cyclic GMP at a substrate concentration of 1 μmwas 4-fold higher in membrane vesicles fromMRP5-transfected cells than in control membranes. This transport was saturable with a K m value of 2.1 μm. MRP5-mediated transport was also detected for 3′,5′-cyclic AMP at a lower affinity, with a K mvalue of 379 μm. A potent inhibition of MRP5-mediated transport was observed by several compounds, known as phosphodiesterase modulators, including Trequinsin, with a K i of 240 nm, and sildenafil, with a K i value of 267 nm. Thus, cyclic nucleotides are physiological substrates for MRP5; moreover, MRP5 may represent a novel pharmacological target for the enhancement of tissue levels of cGMP.
