bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of the cAMP system by medorinone correlates with positive inotropy or vasorelaxation
Authors: Silver Paul J. , Lepore Rhonda E. , Canniff Paul C. , O'Connor Bernard , Lemp Bernhard , Harris Alex L. 
Published: January 2005

AbstractMedorinone is a structurally novel positive inotropic/vasodilator agent that selectively inhibits cardiovascular low Km cAMP phosphodiesterase (PDE). As inhibitors of this PDE isozyme would be expected to activate the cAMP system, the objectives of the present study were to quantitate changes in cAMP content, activation of cAMP protein kinase (cAPK), and positive inotropy in isolated guinea pig papillary muscles or vasorelaxation in aortic smooth muscle by medorinone. In papillary muscles, positive and significant correlations were evident between isometric force development as a function of cAMP content (r = 0.92; P <0.01) or cAPK activity ratio, an index of activation of cAPK (r = 0.78, P <0.05) for concentrations of medorinone from 1 to 300 μM. Similar correlations were evident in aortic smooth muscles frozen during medorinone‐mediated relaxation of phenylephrine contractions (r = 0.89, P <0.05). These correlations and lines of regression were similar to those obtained for milrinone, papaverine, and isoproterenol; the correlation was similar for forskolin while the slope of the regression line was less. The temporal sequence of these events was also quantitated for a concentration of medorinone (100 μM) that produced approximately a 100% increase in papillary muscle isometric force and 90% vasorelaxation. Significant increases in either cAMP content or cAPK activity ratio paralleled increases in force development (papillary muscle) or vasorelaxation (aortic smooth muscle). In summary, these results show that significant increases in cAMP content or cAPK activation are correlated with modulation of cardiac or vascular force by medorinone and thus support the hypothesis that inhibition of the low Km cAMP PDE is a mechanism by which medorinone effects positive inotropy and vasodilation.
Effects of novel catechol ether imidazolidinones on calcium‐independent phosphodiesterase activity, [3H]rolipram binding, and reserpine‐induced hypothermia in mice
Authors: Koe B. Kenneth , Lebel Lorraine A. , Nielsen Jann A. , Russo Lorena L. , Saccomano Nicholas A. , Vinick Fredric J. , Williams Ian H. 
Published: January 2005

AbstractA series of new catechol ether imidazolidinones incorporating structural features of rolipram and Ro 20‐1724 were synthesized as inhibitors of the calcium‐independent phosphodiesterase (IPDE) from rat cerebral cortex. Several compounds were found to be more potent than rolipram as IPDE inhibitors; all of the compounds studied were more potent than Ro 20‐1724. The new imidazolidinones also showed affinity for the [3H]rolipram binding site in mouse brain membranes and reversed reserpine‐induced hypothermia in mice at relatively low doses. In vitro, the potency of these compounds as IPDE inhibitors did not correlate with their affinity for the [3H]rolipram binding site. Reversal of reserpine hypothermia by the imidazolidinones (“antidepressant effect”) could not be linked definitively to either in vitro activity.
Dose‐response analysis of the effects of fenoldopam, dopamine‐1 receptor agonist, on renal function
Authors: Dlewati Abdallah , Lokhandwala Mustafa F. 
Published: January 2005

AbstractThe present study was carried out to perform a dose‐response analysis of the effect of fenoldopam, a DA‐1 receptor agonist, on renal sodium excretion. Infusions of fenoldopam for 30 min at doses of 0.125, 0.25, 0.5, and 1.0 μ/kg/min in four separate groups of pentobarbital‐anesthetized dogs cused dose‐dependent hypotension and renal vasodilation. The reflex tachycardic response was not dose‐dependent and seen only with the three higher doses. There was no change in glomerular filtration with any of the four doses of fenoldopam. At the doses of 0.25 and 0.5 μ/kg/min fenoldopam caused significant increases in urine volume, urinary sodium excretion, and fractional excretion of sodium during the infusion as well as during the first recovery period of 30 min. At the highest dose of 1 μ/kg/min no diuresis or natriuresis was seen during the infusion; however, significant increases in urine volume and sodium excretion were seen during the two recovery periods. At the lowest dose (0.125 μ/kg/min) fenoldopam caused minimal hemodynamic changes but produced maximum increases in urine volume and urinary sodium excretion. These effects of fenoldopam were antagonized by the DA‐1 receptor antagonist, SCH 23390. The results of our study show that the tublar effects of fenoldopam leading to increased renal sodium excretion are evident at doses lower than those required to cause changes in systemic and renal hemodynamics. In addition, at higher doses when the magnitude of hypotension is very pronounced, this effect may limit the increase in sodium excretion produced by fenoldopam.
Cork gnawing in the rat as a screening method for buspirone‐like anxiolytics
Authors: Pollard Gerald T. , Howard James L. 
Published: January 2005

AbstractMale Long‐Evans rats were individually allowed access to No. 11 corks for 30 min per day. After 30 sessions, the mean amount gnawed away, 0.10 g per session, was stable enough to allow drug testing; it reached asymptote at 0.03 g after 140 sessions. Drugs were injected PO 30 min before testing, except as noted. On the asymptotic baseline, the novel anxiolytic buspirone (8–32 mg/kg) and its congener gepirone (8–32 mg/kg) produced large, doserelated increases in cork gnawing. The standard anxiolytics chlordiazepoxide (16–32 mg/kg) and meprobamate (128 mg/kg, 60 min pretreatment) and the new sedative zopiclone (4–32 mg/kg) also produced substantial increases. Diazepam, oxazepam, and alprazolam produced marginal increases, and pentobarbital had no effect at behaviorally relevant doses. The non‐anxiolytics d‐amphetamine, chlorpromazine, acute imipramine, morphine (IP), and valproic acid either decreased or did not change cork gnawing. Phencyclidine (IP) and scopolamine produced marginal increases. Apomorphine (5 mg/kg SC) produced intense stereotyped gnawing of cage mesh but abolished gnawing of cork. Cork gnawing is proposed as a simple, economical behavioral method to identify buspirone‐like anxiolytics.
Pharmacology and safety of phenylpropanolamine
Authors: Johnson David A. 
Published: January 2005

AbstractPhenylpropanolamine (PPA) is a phenylethylamine found commonly in cough medicines, nasal decongestants, and over‐the‐counter (OTC) diet aids. Since its discovery more than 70 years ago, the pharmacology of this drug has periodically been reexamined as the result of advances in the understanding of the sympathetic nervous system and adrenergic receptor function. This review presents a brief overview of the pharmacology of PPA, with an emphasis on how the drug effects smooth muscle tissues. Additionally, since the safety of PPA has recently been called into question, research pertaining to its toxicity is also reviewed.
Unusual binding of [3H] MDL 72222 in guinea pig hippocampus
Authors: Meyerson Laurence R. , Park Hyoungsup 
Published: January 2005

Abstract[3H] MDL 72222 labeled a non‐homogeneous population of sites in guinea pig hippocampal membranes (Kd1 = 1 nM; Kd2 = 60 nM). The binding was not sodium dependent. Competition studies with a variety of characterizing agents showed displacement of [3H] MDL 72222 binding by 5‐HT uptake inhibitors. [3H] MDL 72222 binding was not effectively displaced by established 5‐HT3 antagonists. MDL 72222, fluoxetine, fluvoxamine and citalopram competitively inhibited the uptake of [3H] 5‐HT into guinea pig hippocampal synaptosomes with Ki values of 1.97, 0.02, 0.023, 0.049 μM, respectively. The results demonstrate that [3H] MDL 72222 labels a non‐homogeneous population of sites in guinea pig brain, as well as inhibiting 5‐HT uptake into synaptosomal preparations.
Vasoactive properties of phenylpropanolamine (d, I‐norephedrine) and its enantiomers in isolated rat caudal artery
Authors: Johnson David A. , Maher Timothy J. 
Published: January 2005

AbstractThe sympathomimetic properties of PPA and its individual component enantiomers d‐ and l‐norephedrine (NOR) were examined in isolated perfused/superfused caudal arteries from Sprague‐Dawley (SD) rats. Segments of caudal artery were cannulated, mounted in a tissue bath, and perfused with a modified Kreb's solution. PPA, d‐ and I‐NOR were alternately injected into the perfusion stream, and vasoconstriction was measured as the rise in perfusion pressure. Various drugs were added to the perfusion buffer to determine the activity of PPA, d‐, and I‐NOR at specific adrenoceptor subtypes and to determine whether the actions of these vasoconstrictors were influenced by calcium channel antagonists, cocaine, or reserpine. The results demonstrated that the norephedrines acted as partial agonists primarily via direct stimulation of postjunctional alpha1‐adrenoceptors with relatively low potency; however, I‐NOR did have significant activity at beta‐adrenoceptors with relatively low potency; however, I‐NOR did have significant activity at beta‐adrenoceptors as well. When the enantiomers of PPA were compared, d‐NOR had only minor vasoconstrictor activity, relative to I‐NOR, which was well over 100 times less potent than the endogenous.
Reversal of both QNX‐induced locomotion and habituation decrement is indicative of M1 agonist properties
Authors: Carlezon William A. , Cornfeldt Michael L. , Szewczak Mark R. , Fielding Stuart , Dunn Robert W. 
Published: January 2005

AbstractScopolamine, a non‐selective muscarinic antagonist at M1 and M2 receptors, has been shown to cause hyperactivity and memory deficits in rodents. However, the relative role of activation at M1 and M2 receptors is unclear. The effects in rats of a putative M1 antagonist 3‐quinuclidinyl‐xanthene‐9‐carboxylate hemioxalate hydrate (QNX) were assessed in a paradigm that measures locomotion and habituation, a form of non‐associative learning, to a locomotor activity box. On day 1, subcutaneous administration of QNX (1.0 mg/kg) elicited a large (370%) increase in locomotion. On day 2, control animals demonstrated habituation 24 hr after their first exposure to the locomotor box, as shown by significant decreases (−47%) in locomotor activity, while on day 2 the locomotor activity scores of animals that had been treated on the previous day with QNX did not differ from the day 1 scores of control animals. The selective M1 agonist 4‐(m‐chlorophenylcarbamoyloxy)‐2‐butynyl‐trimethyl ammonium chloride (McN‐A‐343, 10.0 mg/kg) significantly attenuated both the QNX‐induced locomotion and habituation deficit, while neither the non‐selective muscarinic agonist oxotremorine (0.125 mg/kg) nor the acetylcholinesterase inhibitor physostigmine (0.06 mg/kg) had a significant effect on these behaviors. These data suggest that, in this model, the M1 cholinergic receptor mediates both locomotion and habituation. Furthermore, M1 agonists can be identified by reversal of both QNX‐induced locomotion and memory decrement in this paradigm.
Review of chirality and its importance in pharmacology
Authors: Maher Timothy J. , Johnson David A. 
Published: January 2005

AbstractWhile many pharmacologists have become increasingly aware of the importance of chirality and the role it plays in accounting for the oftentimes dramatic differences in the pharmacodynamics and pharmacokinetics of pure enantiomeric forms of therapeutic agents, there continues to be a significant lack of diligence regarding the need for properly identified stereochemicals in the scientific literature. All too frequently published reports and textbooks fail to adequately identify the stereochemical nature of the drugs utilized in a study Since the individual components of an enantiomeric pair typically have significant differences in their pharmacologic activities, the need for unambiguous descriptive nomenclature is evident. This review presents a summary of the various types of nomenclature utilized in the pharmacologic literature and their chemical bases. Several examples are described which illustrate the significant differences between enantiomeric forms of drugs and suggest possible theoretical bases for such differences. The need for continued awareness on the part of pharmacologists and the proper, unambiguous identification of stereolsomers in the scientific literature and labeling is stressed.
Anticonflict and discriminative stimulus effects of the 5‐HT1A compounds WY‐47,846 and WY‐48,723 and the mixed 5‐HT1A agonist/5‐HT2 antagonist WY‐50,324 in pigeons
Authors: Barrett James E. , Zhang Lei 
Published: January 2005

AbstractThe effects of the pyrimidinylpiperazinyl imide WY‐47,846 (zalospirone), the substituted arylpiperazine WY‐48,723, and the adamantyl piperazine derivative WY‐50,324 were studied under punishment (conflict) procedures with pigeons to evaluate potential anxiolytic activity. These compounds were also studied in pigeons trained to discriminate administration of the serotonin (5‐HT)1A agonist 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin [8‐OH‐DPAT] (0.3 mg/kg) or buspirone (1.0 mg/kg), both administered i.m., from saline. All three compounds have high affinity for the 5‐HT1A receptor site and WY‐50,324 also has high affinity for 5‐HT2 receptors, with activity as an antagonist at this site. Increases in punished responding occurred with all three drugs, with the magnitude of the increases in the order WY‐50,324 > WY‐48,723; > WY‐48,846; increases with WY‐50,324 reached almost 15,000% of control levels. Increases in punished responding occurred at doses that did not affect unpunished responding. Doses producing maximal effects of the three drugs were comparable (1.0 mg/kg), although WY‐48,723 and WY‐50,324 also produced large increases at doses as low as 0.1 mg/kg. All three drugs also substituted for 8‐OH‐DPAT and buspirone, with WY‐48,723 and WY‐50,324 producing complete substitution at 0.1–0.3 mg/kg, whereas WY‐47,846 did not substitute in 8‐OD‐DPAT‐trained pigeons until a dose of 10 mg/kg; in pigeons trained with buspirone, a dose of 1.0 mg/kg WY‐47,846 resulted in complete substitution. All three drugs appear to have potential anxiolytic and/or antidepressant activity through actions mediated at the 5‐HT1A receptor. The unique combination of 5‐HT1A agonist activity with 5‐HT2 antagonist activity appears to confer potent anxiolytic‐like actions on WY‐50,324 that prompt additional exploration of the interactions between these receptor subtypes and their role in anxiety and other disorders.
Use of a metabolic inhibitor to reduce dapsone‐dependent haematological toxicity
Authors: Coleman Michael Damian , Tingle Malcolm Drummond 
Published: January 2005

AbstractAside from its established use as an antileprotic and anti‐inflammatory drug, dapsone is also effective in the therapy of Pneurnocystis carinii pneumonia. Unfortunately, its use is often limited by its dose‐dependent toxicity, such as methaemoglobinaemia and haemolysis; the latter condition occurs most frequently in gIucose‐6‐dehydrogenase deficient individuals. It is also responsible for occasional life‐threatening disorders such as agranulocytosis. Dapsone may undergo acetylation, but its toxicity is due to the product of its oxidative metabolism, dapsone hydroxylamine. This is generated in man by the constitutive hepatic cytochrome P450 enzyme IIIA4. Studies in the rat revealed that dapsone‐dependent methaemoglobinaemia could be greatly diminished by the co‐administration of metabolic inhibitors. In the isolated perfused rat liver, dapsone hydroxylamine levels and hence methaemoglobin formation fell significantly in the presence of cimetidine. In addition, the clearance of the parent drug was retarded, and perfusate concentrations of monoacetyl dapsone increased. The protective effect of cimetidine also reduced methaemoglobin formation in the whole rat during the chronic administration of dapsone. Incubation of dapsone in a two‐compartment in vitro system using human tissues in the presence of cimetidine or ketoconazole resulted in a decrease in methaemoglobin formation in all the human livers tested. Although cimetidine was only effective if incubated with microsomes and NADPH prior to the addition of dapsone. Administration of cimetidine (3 × 400 mg daily) to volunteers 3 days prior to and 4 days post administration of a single dose of 100 mg dapsone caused drug concentrations to increase by almost 30%. There was a marked fall in peak methaemoglobin levels and the percentage of the dose excreted in urine as dapsone hydroxylamine N‐glucuronide was reduced by almost one third. During high dose dapsone therapy it may be possible that the co‐administration of cimetidine might reduce toxicity while maintaining drug efficacy.
Age‐ and pathology‐dependent alterations in the efficacy of phenylephrine‐ and 5‐hydroxytryptamine‐induced contractions in isolated rat aorta
Authors: Christ George J. 
Published: January 2005

AbstractMale Fischer 344 rats were made diabetic for 8–9 weeks by a single intraperitoneal injection of streptozotocin. Steady‐state contractile responses elicited by 5‐hydroxytryptamine (5‐HT) and phenylephrine (PE) activation of the 5‐HT2‐ and α1‐adrenergic receptors, respectively, were studied in aortic rings from diabetic, age‐matched control and 24‐month‐old (senescent) F‐344 rats. Concentration‐response curves (CRCs) for PE and 5‐HT were analyzed by the Black and Leff operational model of pharmacological agonism to determine efficacy (τ) and slope factor values. Efficacy estimates obtained with the operational model were compared to two commonly used model‐independent estimates of agonist efficacy; (1) Stephenson's efficacy estimate (e), and (2) the estimation of agonist receptor reserves. The estimated τ for PE in aortic rings from age‐matched control animals (12.38) was significantly reduced by both experimental diabetes (4.52) and senescence (7.12), and these findings were in agreement with results obtained using the model‐independent efficacy estimates. However, with respect to 5‐HT‐induced contractions, the estimated τ in age‐matched control animals (2.46) was also significantly reduced by both diabetes (1.58) and senescence (1.69), but these alterations were not detected by the model‐independent efficacy estimates. In all cases, a decrease in operational efficacy,τ, was associated with a decrease in the asymptote of the PE or 5‐HT CRC expressed as the agonist maximal effect (Emax)/tissue maximal effect (Tmax) and/or alterations in the fractional occupancy/response relationship. In addition, τ was sensitive to small changes in agonist efficacy that occurred in the absence of any apparent alterations in the occupancy/response relationship. As such, these studies extend our previous observations in rat aorta to highlight the advantages of using the Black and Leff efficacy estimate, τ, rather than other commonly used model‐independent estimates of agonist efficacy. © 1992 Wiley‐Liss, Inc.
Mianserin‐induced 5‐HT2 receptor downregulation results in anxiolytic effects in the elevated plus‐maze test
Authors: Benjamin D. , Saiff E. I. , Nevins T. , Lal H. 
Published: January 2005

AbstractSeveral agents that downregulate 5‐HT2 receptors produce anxiolytic effects in humans, but the role of 5‐HT2 receptor downregulation has been difficult to assess because of their other actions. To test the effects of pharmacological downregulation of 5‐HT2 receptors on exploratory behavior in the mouse, mianserin, a drug known to downregulate 5‐HT2 receptors after a single dose, was administered 30 min, 48 hr, or 18 days prior to testing in the elevated plus‐maze. Following testing in the elevated maze, the head‐shake response to 4‐iodo‐R‐(—)‐2,5‐dimethoxyphenylisopropylamine (DOI), a selective 5‐HT2/5‐HT1C agonist was assessed, and in a separate group of animals 5‐HT1A, 5‐HT1B, 5‐HT1C, β1,β2, and 5‐HT2 agonist and antagonist binding was quantified autoradiographically. Mianserin pretreatment resulted in a significant dose‐related anxiolytic effect in the elevated plus maze evidenced by increases in the percentage of entries to, and time spent on the open arms. Head‐shakes induced by DOI were also dose‐dependently decreased as a result of mianserin pretreatment. At this time, the binding of the 5‐HT2 receptor antagonist, 7‐amino‐8[125I]ketanserin was decreased by 50%. Binding of DOI to 5‐HT2 receptors was decreased by 46%, and to 5‐HT1C receptors was decreased by 53%, but no other changes were found in any of the other receptor types examined. These findings demonstrate that the 5‐HT2 receptor plays at least a permissive role in anxiety‐like behaviors, since an intact 5‐HT2 system is necessary for the full expression of the anxiety‐like response, but the role of 5‐HT1C receptor downregulation in the effects of mianserin cannot be ruled out at this time. © 1992 Wiley‐Liss, Inc.
Use of tissue plasminogen activator for rapid dissolution of fibrin and blood clots in the eye after surgery for glaucoma and cataract in humans
Authors: Tripathi Ramesh C. , Tripathi Brenda J. , Bornstein Scott , Gabianelli Eugene , Ernest J. Terry 
Published: January 2005

AbstractWe treated 10 patients with tissue plasminogen activator (tPA) for complications that threatened the successful outcome of anterior segment surgery for glaucoma and/or cataract, and that endangered the structural and functional integrity of the eye. Eight patients who had developed massive fibrin or blood clots in the anterior chamber each received 10–20 μg of tPA intracamerally, and two patients who had and extensive subconjunctival blood clot that blocked the filtration site received 25 or 30 μg of tPA subconjunctivally. The clots dissolved within 30 min to a few hours in all patients. Except in one patient who developed a 10% hyphema after the tPA injection, we observed no ocular complications in any of our patients during a follow‐up period that ranged from 2–22 months. Our preliminary investigations show that intracameral injection of tPA is highly effective and safe for the rapid dissolution of fibrin and blood clots in the anterior chamber that obstruct the visual axis, obscure the view of the fundus, or cause failure of filtering blebs, and for lysis of synechiae of 2 to 3 days duration. Optimal results were obtained with intracameral injection of ≥ 10 μg tPA at 4 to 10 days after surgery. However, tPA should be regarded as an acute therapy and adjunctive modality for the treatment of fibrin and blood clots in the anterior segment of the eye. To avoid possible drug‐induced complications, we advocate titration of the dose and repeat injection rather than a single large bolus of the drug. © 1992 Wiley‐Liss, Inc.