bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of BRL38227, salbutamol, and aminophylline, alone and in combination, on plasma potassium and on the heart
Authors: Clapham John C. , Hamilton Thomas C.
Published: January 2005

The present study was undertaken in order to examine the effects of the potassium channel activator BRL38227 and of aminophylline on hypokalaemia, cardiac stimulation (increased heart rate and contractility, dQ/dt), and electrocardiogram (ECG) changes induced by the β2‐adrenoceptor agonist, salbutamol in the anaesthetised cat. Salbutamol (1.25 μg.kg−1min−1), but not BRL38227 (0.1–1.0 μg.kg−1 min−1), infusion elicited a marked hypokalaemia (plasma K+ >2.5 mmolliter −1). This dose of salbutamol also elicited an immediate cardiac stimulation which appeared to be maximal and changes in ECG were evident as a reduction in QTc interval (20%) and T‐wave height (80%). Cardiac stimulation following either BRL38227 or aminophylline was more gradual in onset, the maximum response being about 50–80% of the salbutamol effect. No ECG changes were observed in cats receiving BRL38227 whilst T‐wave amplitude was reduced (50–60%) following aminophylline. Combination of salbutamol with aminophylline resulted in a greater degree of hypokalaemia, cardiac stimulation, and T‐wave depression. The salbutamol‐induced reduction in QTc was converted to a slight prolongation after infusion for 75 min. The ECG changes observed were not indicative of arrhythmia. Conversely, BRL38227 had no effect on salbutamol‐induced hypokalaemia, cardiac stimulation, or T‐wave depression, though the degree of QTc interval shortening was reduced. When BRL38227 was administered in conjunction with aminophylline, plasma potassium and QTc were unchanged. Depression of T‐wave amplitude by aminophylline was slightly reduced in the combination group. Effects on heart rate and dQ/dt were similar to those seen for BRL38227 alone. Salbutamol‐induced hypokalaemia was reversed by the nonselective β‐adrenoceptor antagonist, propranolol, but not by the β1‐adrenoceptor selective antagonist, atenolol, confirming a β2‐adrenoceptor selective effect. Cardiac stimulation was reversed by both propranolol and atenolol. In conclusion, salbutamol‐induced hypokalaemia, cardiac stimulation, and ECG changes, as well as the additive effect of aminophylline, were demonstrated in the anaesthetised cat, but were unchanged by BRL38227. Furthermore, combination of BRL38227 with aminophylline did not result in any adverse effects on the parameters measured. Thus, on the basis of these results in the cat, combination of BRL38227 with the bronchodilator drugs, salbutamol or aminophylline, would not be expected to exacerbate the cardiovascular effects of these drugs. © 1992 Wiley‐Liss, Inc.
Diuretic and hypotensive actions of torasemide in hypertensive models of rat
Authors: Uchida Takeshi , Ohtaki Yutaka , Kido Hideaki , Shinyama Hiroshi , Hayashi Kazutaka , Yamanaga Katsumi , Watanabe Masahiro
Published: January 2005

The diuretic and the antihypertensive actions of torasemide were examined in renal and genetic hypertensive rats and compared to the effects of furosemide. Oral administration of torasemide (1 and 3 mg/kg) elicited a dose‐dependent increase in the excretion of urine and electrolytes and elevated the urinary Na/K ratio in both renal and genetic hypertensive rats. Torasemide and furosemide had a similar maximum diuretic effect in the normotensive Wistar rat and the spontaneously hypertensive rat (SHR). However, the diuretic activity of furosemide was weaker in the renal hypertensive rat (RHR). Torasemide showed approximately 30 times greater diuretic potency than furosemide. Torasemide and furosemide demonstrated hypotensive action in hypertensive rat models, but not in the normotensive Wistar rat. Especially in the RHR, torasemide exhibited a more potent hypotensive action than furosemide. These results show that the diuretic and antihypertensive activities of torasemide are effective in various rat models of hypertension, while the diuretic activity of furosemide is weak in certain hypertensive rat models. © 1992 Wiley‐Liss, Inc.
Molecular biology of the 5‐HT1 receptor subfamily
Authors: Hartig Paul R. , Adham Nika , Zgombick John , Weinshank Richard , Branchek Theresa
Published: January 2005

Four serotonin receptor clones have now been isolated and characterized. They encode the serotonin 5‐HT1A, 5‐HT1C, 5‐HT1D, and 5‐HT2 receptors. The serotonin 5‐HT1C receptor, which was originally classified as a 5‐HT1 receptor, is now seen to be a member of the 5‐HT2 receptor subfamily. Within the current 5‐HT1 receptor subfamily, the two clones that have been described (5‐HT1A and 5‐HT1D) show similarities in amino acid sequence and function but are not as closely related as might have been expected. The human 5‐HT1D receptor clone, when expressed in mouse fibroblast cells, displays pharmacological binding properties in agreement with human cortical membrane preparations. Sumatriptan, a new antimigraine medication, exhibits an apparent dissociation constant of 3.4 nM at this human receptor site. This represents the highest affinity interaction yet identified for this drug, and suggests that significant species differences may exist in the binding of this compound to 5‐HT1D receptors. Similar species differences in ergot drug affinities have been described for the 5‐HT2 receptor. Deduced amino acid sequence homologies between serotonin and other monoamine receptor clones are discussed, leading to a classification scheme for serotonin receptors involving superfamily, family, and subfamily relationships. © 1992 Wiley‐Liss, Inc.
Novel high‐affinity 3H‐serotonin binding sites in rat and bovine brain tissue
Authors: Weisberg Ellen , Teitler Milt
Published: January 2005

Five sites (5HT1A, 5HT1B, 5HT1C, 5HT1D, and 5HT1E) have been detected using 3H‐5HT radioligand methodology and mammalian brain tissue. We report herein that high‐affinity 3H‐5HT binding to homogenates of bovine and rat caudate and cortical tissues cannot be interpreted without including at least one additional 5HT receptor. Competition studies were performed in rat frontal cortex tissues, using pharmacological blockade of 5HT1A, 5HT1B, and 5HT1C receptors to facilitate examination of other possible sites. Ergotamine, under these conditions, produced a low‐affinity competition K1 = 1.2 1μM with a Hill coefficient of 1.0. 5‐carboxyamidotryptamine (5CT), under these conditions, produced a complex competition curve, with an overall K1 value of 101 nM and a Hill coefficient of 0.55. Computer‐assisted analysis of the 5CT competition curve revealed a high‐affinity site (K1 = 16nM) and a low‐affinity site (K1 = 802 nM). Therefore, competition curves produced using ergotamine and 5‐CT indicate that there is a site in rat frontal cortical tissue with high affinity for 5HT, 5CT, and low affinity for ergotamine as well as a site with high affinity for 5HT and low affinity for 5CT and ergotamine. The site with high affinity for 5HT, and low affinity for 5CT and ergotamine resembles the 5HT1E receptor, insofar as these three drugs are concerned. There is no reported site with high affinity for 5HT and 5CT and low affinity for ergotamine (heretofore referred to as 5HT1F). The lack of a high‐affinity ergotamine competition for 3H‐5HT binding to non‐5HT1A, 5HT1B, and 5HT1C sites indicates that there is no detectable 5HT1D binding in this tissue. In rat striatal tissue both 5CT and ergotamine produced complex competition curves with Hill coefficients less than unity (0.6 and 0.65, respectively). Computer‐assisted analysis indicated that a minority of sites (approximately 35%) displayed high affinity for both ergotamine and 5CT, while 65% of the sites displayed low affinity for both 5CT and ergotamine. The site labeled with 3H‐5HT displaying high affinity for 5CT and ergotamine coincides with the pharmacological profile of a 5HT1D site. The site labeled with 3H‐5HT displaying low affinity for 5CT and ergotamine coincides with the pharmacological profile of the 5HT1E site. Results from bovine cortical and striatal tissues reinforce the conclusions drawn from the rat brain data. In summary, detailed studies of specific 3H‐5HT binding to non 5HT1A‐1C sites indicate that (1) there are detectable 5HT1D sites in rat striatal tissue but not in rat cortical tissue, (2) there are detectable 5HT1E sites in rat brain tissue, and (c) a novel high‐affinity 3H‐5HT binding site possessing high affinity for 5CT and low affinity for ergotamine has been detected in rat and bovine brain tissues. © 1992 Wiley‐Liss, Inc.
Studies on the effects of 5‐HT1A drugs in the pigeon
Authors: Barrett J. E.
Published: January 2005

A number of compounds with high receptor binding affinity for the 5‐hydroxytryptamine (5‐HT) receptor subtype designated as 5‐HT1A can produce anxiolytic and/or antidepressant effects in humans. In contrast to the traditional benzodiazepine anxiolytics, many of the clinically efficacious 5‐HT1A drugs are either ineffective or produce inconsistent results in traditional preclinical anxiolytic screens using behavioral procedures with rodents. In preclinical antidepressant models with these animals, however, effects of the 5‐HT1A drugs, as well as those of traditional antidepressant compounds, are predictive of their antidepressant activity in humans. In contrast, 5‐HT1A drugs are quite effective in pigeons studied under a rather conventional punishment or conflict‐type procedure that is also sensitive to the benzodiazepine anxiolytics. However, traditional antidepressant compounds, such as the tricyclic drugs amitriptyline and imipramine, as well as the 5‐HT reuptake blockers such as fluoxetine, do not show effects similar to the newer 5‐HT1A drugs in this procedure. Thus, in rodents, current antidepressant models are sensitive to drugs that appear to function through different mechanisms, whereas conflict‐type procedures typically do not reveal anxiolytic‐like effects with 5‐HT1A drugs. The pigeon conflict procedure, however, discriminates between the 5‐HT1A antidepressants and antidepressant drugs functioning through other systems, whereas the effects of known anxiolytics in this procedure are quite similar. Increases in punished responding with 5‐HT1A drugs correlates highly (r= +0.83) with affinity for the 5‐HT1A receptor in pigeons. This paper reviews behavioral studies conducted with the pigeon in which the focus has been on the analysis of 5‐HT1A compounds and addresses additional work that is required to answer many of the outstanding questions about this new class of anxiolytic and/or antidepressant drugs. © 1992 Wiley‐Liss, Inc.
Effects of gepirone on ethanol consumption, exploratory behavior, and motor performance in rats
Authors: Knapp Darin J. , Benjamin Dan , Pohorecky Larissa A.
Published: January 2005

Activation of 5‐HT receptors via reuptake inhibition, precursor loading, or inhibition of catabolism have consistently resulted in decreases in ethanol preference in rats. The objective of the present studies was to determine whether activation of the 5‐HT1A receptor with gepirone, a selective agonist, decreases ethanol preference. Preference was first evaluated for ethanol solutions from 3 to 11%, in a free‐choice situation with ethanol solution or tapwater available in the home cage. Male Sprague‐Dawley rats consumed the most ethanol solution relative to water at a concentration of 6%. When ethanol (6% solution) was available to ethanol‐habituated rats in a 1‐hr restricted access situation, subjects consumed 5.9 ± 0.4 ml. Pretreatment with gepirone (0.46–4.6 mg/kg IP) resulted in a dose‐dependent reduction in ethanol consumption in the restricted‐access paradigm. The 5‐HT reuptake inhibitor fluoxetine also resulted in dose‐related decreases in ethanol consumption in restricted access. A subsequent experiment using a lower dose of fluoxetine also found a suppressive effect on ethanol intake. A single daily dose of gepirone failed to decrease the consumption of 6% ethanol when it was continuously available in the home cage. The short half‐life of gepirone might explain its lack of effect in continuous access with only one daily dose. Gepirone decreased open‐field activity at higher (2.3 to 4.6‐mg/kg) doses, but did not affect rotorod performance at any dose (4.6–9.2 mg/kg) tested, whereas haloperidol (0.025–1.0 mg/kg) significantly decreased time on the rotorod. These results suggest that 5‐HT1A receptor activation decreases ethanol intake in limited access and that the motorically disrupting effects of gepirone are not manifest under these conditions. © 1992 Wiley‐Liss, Inc.
Gastrointestinal motility responses to the S and R enantiomers of zacopride, a 5‐HT4 agonist and 5‐HT3 antagonist
Authors: Gullikson Gary W. , Virina Maida A. , Loeffler Richard F. , Yang Dai‐Chang , Goldstin Bela , Flynn Daniel L. , Moormann Alan E.
Published: January 2005

Zacopride is an antiemetic agent whose (S) and (R) stereoisomers demonstrate differential pharmacology at 5‐HT3 receptors, emphasizing the importance of pharmacologic profiling of each enantiomer of a racemic drug mixture. Characterization of the gastrointestinal motility‐enhancing activities of the enantiomers relative to their 5‐HT3 antagonist properties was done both in vivo and in vitro. In dogs at a dose of 0.3 mg/kg, IV, the (S) antipode was more active in stimulating gastric antral contractions and gastric emptying of a solid meal than (R) zacopride. The (S) enantiomer was also at least 10 times more potent in enhancing gastric emptying in rats. The potency of (S) zacopride at the putative prokinetic receptor (5‐HT4) was 3.3 times greater than that of (R) zacopride in rat esophageal tunica muscularis mucosae strips. The greater potency of (S) zacopride over the (R) antipode for motility stimulation was also observed for its 5‐HT3 antagonism in dogs. (S) zacopride almost completely blocked cisplatin emesis at 0.01 mg/kg, IV, while (R) zacopride was inactive. However, both enantiomers were more active as antiemetics than as prokinetics in the dog. More potent activity at the 5‐HT3 than the 5‐HT4 receptor was also demonstrated for both enantiomers in vitro. Additionally, in antagonizing 2‐methyl‐5‐HT contractions in guinea pig ileum, the (S) antipode was again more potent than the (R). In summary, (S) zacopride is more potent than the (R) enantiomer for both 5‐HT3 antagonism and prokinetic activity, with 5‐HT3 antagonism, rather than motility enhancement (5‐HT4 agonism), being the primary activity of both zacopride stereoisomers. © 1992 Wiley‐Liss, Inc.
Free radicals, glutamate, dopamine, and serotonin after ischemia reperfusion insult in aging gerbil brain
Authors: Delbarre R. Bernard , Delbarre Gisèle , Calinon François
Published: January 2005

The study of cerebral ischemia in animals is not easy, because cerebral circulation is not the same as in humans. Indeed, in most animals, there is a collateral circulation between the vertebral and carotid arteries before these arteries enter the brain. On the other hand, in gerbils, unilateral ligation produces ischemia in the ipsilateral forebrain and leads to death in 40–60% of the animals. Because the cerebral ischemia so produced is not effective in all gerbils, it is important to select “sensitive” gerbils by funduscopic examination. Only sensitive gerbils are retained for further experimentation. The nature of the aging process is the subject of some speculation. One hypothesis is referred to as the free radical theory. This theory postulates that free radicals are involved in aging and age‐related disorders of the brain. Therefore, we have determined levels of neuromediators involved in cerebral ischemia and memory, including catecholamines (dopamine [DA], dihydroxyphenylacetic acid [DOPAC], hydroxyvanillic acid [HVA]) and indolamines (5‐hydroxyindolacetic acid [5HIAA], serotonin [5‐HT]), amino acids (aspartate, glutamate and GABA), and free radicals (.OH). We have chosen for study the caudate nucleus, hippocampus, and retina, where changes after ischemia/reperfusion insult are well documented. In gerbil brain, levels of .OH and neurotransmitters are low at birth, reach a plateau, and then decrease with aging. After cerebral ischemia (60 min) induced by left carotid occlusion, the reperfusion (30 min) symptoms are classified using a behavioral score (Stroke Index). Moreover, after ischemia/reperfusion insult (IRI), increases in Stroke Index, .OH, glutamate, aspartate, GABA, monoamines, and indolamines are more pronounced in older gerbils. © 1992 Wiley‐Liss, Inc.
Nicotine suppresses the proliferative response of peripheral blood lymphocytes in rats
Authors: Caggiula Anthony R. , McAllister Cathy G. , Epstein Leonard H. , Antelman Seymour M. , Knopf Steven , Saylor Saundra , Perkins Kenneth A.
Published: January 2005

Nicotine, the psychoactive ingredient of cigarette smoke, alters lymphocyte function in vitro. However, unlike tobacco smoke, the immunologic effects of nicotine in vivo have not been determined. In the present study a single SC administration of 0.33, 0.66, or 1.32 mg/kg (free base) of nicotine bitartrate to male rats produced a dose‐dependent decrease in the in vitro proliferative response of blood lymphocytes to the T‐cell mitogen Con A when sampled 1 hr after nicotine administration. These results strongly suggest that acute nicotine exposure can induce immune perturbation in vivo. Nicotine also increased plasma corticosterone (CORT) and there was a substantial negative correlation (r = −.52) between CORT levels and the extent of proliferation (DPM) for the optimal Con A dose. The correlation between nicotine's immunologic and CORT effects is discussed within the context of several other potential mediators of nicotine's effects. © 1992 Wiley‐Liss, Inc.
Low molecular weight analogs of trolox with potent antioxidant activity in vitro and in vivo
Authors: Silver Paul J. , Gordon Robert J. , Horan Patrick J. , Bushover Cynthia R. , Gorczyca William P. , Etzler John R. , Buchholz R. Allan , Schlegel Donald , Ellames George J. , Smith David I. , Ezrin Alan M.
Published: January 2005

Alpha‐tocopherol and its water‐soluble derivative, Trolox, are capable of terminating free radical chain reactions and limiting reperfusion‐induced cell damage. In the present study, we have quantitated the effects of two relatively potent analogs of alpha‐tocopherol/Trolox, WIN 62079 and U‐78517F, which attenuated exogenously generated free radical damage in cultured cells and reperfusion injury in vivo. In a cultured rat renal tubular epithelial cell line (NRK‐52E), millimolar concentrations of ascorbate or the combination of Trolox plus ascorbate reduced cellular damage (quantitated as lactate dehydrogenase [LDH] release) induced by radicals generated by hypoxanthine/xanthine oxidase. In contrast, WIN 62079 and U‐78517F attenuated damage at micromolar concentrations. Similarly, intravenous administration of WIN 62079 (three hourly doses of 3 mg/kg) and U‐78517F (10 mg/kg infused over 5 min) reduced reperfusion‐induced myocardial damage in rabbit coronary‐occulded hearts: Trolox (three hourly doses of 100 mg/kg) was less potent and required ascorbate (three hourly doses of 150 mg/kg) as a cofactor. These data demonstrate that is feasible to design potent, water‐soluble analogs of Trolox which are efficacious against free radical‐mediated cell death and which do not require ascorbate as a cofactor. Moreover, since U‐78517F and WIN 62079 are two to three orders of magnitude more potent than Trolox, and since they contain different amino side chains, these data further support the concept that side chain modifications of the chromane ring nucleus of alpha‐tocopherol derivatives significantly affect activity, possibly by providing additional activity or by enhancing availability to the cellular site of action. © 1992 Wiley‐Liss, Inc.
Neurokinin A‐induced guinea pig gallbladder contraction: Potential mechanism of action
Authors: Moummi Chafiq
Published: January 2005

The present study was performed to examine the mechanism of action of neurokinin A (NKA) on guinea pig gallbaldder smooth muscle. Muscle strips were prepared and mounted in 10 mL tissue bath containing Krebs' solution under 1 g tension. NKA induced a concentration‐dependent increase in gallbladder muscle tension and reached a maximal response at 1 μM. The EC50 value was approximately 30nM. Preincubation of the muscle strips with neurotoxins, tetrodotoxin (1 μM), or omega‐conotoxin (0.1 μM) had no effect on the NKA contractile response. NKA‐induced gallbladder contractions were insensitive to cyclooxygenase inhibitors (5 μM) piroxicam and indomethacin. In contrast, the calcium channel blockers verapamil and diltiazem (0.1–1 μM) significantly blocked the contractile response to NKA. The intracellular calcium chelator BAPTA/AM had no significant effect on NKA activity. The removal of extracellular calcium, however, completely abolished the contractile response of NKA. These data suggest that NKA has a direct contractile effect on guinea pig gallbladder smooth muscle, which is independent of prostaglandin release. The primary source of calcium involved in mediating the NKA contractile response is the extracellular pool, suggesting that NKA might act via activation of L‐type voltage‐operated calcium channels to mediate its action. © 1992 Wiley‐Liss, Inc.
Protective effects of zinc L‐carnosine (Z‐103) on reserpine‐induced gastric ulceration in rats
Authors: Cho C. H.
Published: January 2005

The present study examined the gastric protective effects of zinc L‐carnosine (Z‐103) in reserpinized rats. We also studied whether this antiulcer effect is related to the preservation of mast cells degranulation in the glandular mucosa. Reserpine administration (5 mg/kg, intraperitoneally [i.p.]) produced severe hemorrhagic glandular ulcers which were accompained with a marked decrease in mucosal mast cell counts. The severity of ulcers and mast cell degranulation were reduced by Z‐103 when given orally 30 min before and 6 hr after reserpinization. However, this protection was not observed when the drug was administered as a single dose 30 min beforehand. The present findings extended the antiulcer action of Z‐103 from stress‐ and ethanol‐induced gastric damage to those on reserpine‐provoked gastric ulcers. It also indicates that the protective action on reserpine ulceration is likely to be due to the stabilization on mast cell membrane in the glandular mucosa. © 1992 Wiley‐Liss, Inc.
Potentiation of atropine‐induced retardation of small intestine transit in mice by a pulsed magnetic field
Authors: Santini R. , Seigne M.
Published: January 2005

The interaction of a pulsed (100 and 50 Hz) magnetic field (90 μT) with the effect of atropine on small intestine transit was studied in mice. Both frequencies of the magnetic field significantly potentiated the atropine‐induced delay in intestinal transit but did not affect intestinal transit per se. This result further strengthens previous observations on interactions between electromagnetic fields and the actions of drugs. © 1992 Wiley‐Liss, Inc.
Role of receptors in the trabecular meshwork of the eye as targeted to the development of antiglaucoma therapy
Authors: Tripathi Ramesh C. , Yang Charles , Tripathi Brenda J. , Borisuth Navaneet S. C.
Published: January 2005

The major pathway for the outflow of aqueous humor from the anterior chamber of the eye is the trabecular meshwork/Schlemm's canal system. The meshwork is composed of connective tissue beams that are ensheathed by trabecular cells; these cells derive their nutrition from the aqueous humor and thus are uniquely susceptible to morphologic and biochemical regulation by bioactive substances that are present or released in this fluid and to pharmacologic agents that are targeted to act on the tissue. The receptors that have been detected on trabecular cells include those for growth modulatory peptides (bFGF, TGF‐βI, transferrin, IGF‐1, and EGF), epinephrine, dopamine, glucocorticoids, benzodiazepines, prostanoids, biogenic amines, the Fc portion of IgGs, and probably those for molecules of the extracellular matrix (integrins). Selective up‐ or down‐regulation of the receptors on the trabecular cells would facilitate an effective control of the intraocular pressure in diseased conditions of the eye. We discuss the prospects and hurdles in the utilization of receptor targeting as a therapeutic modality for trabecular cell regeneration in glaucoma as well as for pharmacologic trabeculectomy and as a treatment for hypotony after glaucoma filtration surgery. We believe that regulation of receptor expression is a novel method for the development of new antiglaucoma agents and for minimizing the side effects of drugs that are administered topically and systemically for the control of the intraocular pressure. © 1992 Wiley‐Liss, Inc.
Potential cognition‐enhancing properties of S 9977 in three moenls of amnesia in the mouse
Authors: Porsolt Roger D. , Lenègre Antoine , Rettori Marie‐Claire , Mocaër Elisabeth
Published: January 2005

The effects of S 9977 (1,3,7‐trimethyl 8‐[3‐(4‐diethylaminocarbonyl‐l‐piperazinyl) 1‐propyl]‐3,7‐dihydro(1H)2,6‐purinedione hydrochloride) on the amnesias induced by scopolamine, diazepam, and electroconvulsive shock (ECS) were studied in a passive avoidance procedure in the mouse. Amnesia was induced by injecting scopolamine or diazepam (1 mg/kg i.p.) 30 min before or ECS administered immediately after the first session (S1) of the passive avoidance task. S 9977 was studied in a dose range of 0.0312–16 mg/kg administered p.o. 60 min before S1. Retention was measured 24 hr later (S2) in the absence of any treatment. S 9977 was also investigated after repeated administration (twice daily for 3 days and then 60 min before acquisition on the 4th day) using the scopolamine‐induced amnesia model. Additional experiments investigated the interactions of the compound with the major behavioral effects of the amnesic treatments, namely scopolamine‐induced hyperactivity (activity meter test), diazepam‐induced release of punished behavior (four plates test), and ECS‐induced convulsion. S 9977 at low doses (0.0312–0.5 mg/kg p.o.) clearly attenuated the memory deficits induced by the three amnesic treatments after acute treatment and no tolerance was observed after repeated treatment in the scopolamine model. S 9977 did not affect either scopolamine‐induced hyperactivity, diazepam‐induced release of punished behavior, or ECS‐induced convulsions. These results point to the specificity of S 9977's antiamnesic activity and suggest that it might be a useful agent for the treatment of memory deficits of different origins in humans. © 1992 Wiley‐Liss, Inc.
Myocardial salvage by trolox and ascorbic acid, but not ascorbic acid alone, in anesthetized dogs and rabbits
Authors: Lee King C. , Horan Patrick J. , Canniff Paul C. , Silver Paul J. , Ezrin Alan M.
Published: January 2005

The myocardial salvaging properties of Trolox (Trix; a water‐ and lipid‐soluble vitamin E analog with antioxidant properties) and ascorbic acid (Asc; a water‐soluble antioxidant) were evaluated in anesthetized male dogs and rabbits. Myocardial infarction (MI) was induced by occlusion and reperfusion of the left anterior descending coronary artery: a 2‐hr occlusion and 4‐hr reperfusion in dogs, and a 15‐min occlusion and 3‐hr reperfusion in rabbits. This occlusion/reperfusion protocol induced %MI (MI normalized to area at risk) of approximately 20% beyond that induced by occlusion alone in both species. Trlx, Asc (100 and 150 mg/kg/injection, respectively, by injection; or 100 and 150 mg/kg/min, respectively, by continuous infusion), or vehicle (Veh) were administered into the ascending aorta in dogs and into the left atrium in rabbits. In severely ischemic dogs (myocardial collateral blood flow < 0.1 ml/min/g), a single injection of Trlx plus Asc, but not Asc alone, at the onset of reperfusion reduced %MI (Trlx + Asc = 24.3 ± 5.4%, n = 7; Asc = 50.1 ± 9.6%, n = 4; Veh = 45.0 ± 5.0%, n = 5). In rabbits, %MI was reduced (or tended to be reduced) by either 3 hourly injections (Trlx + Asc = 33.3 ± 4.0%, n = 19; Asc = 48.3 ± 6.3%, n = 11; Veh = 43.7 ± 3.3%, n = 8) or an injection followed by continuous infusion (Trlx + Asc = 36.0 ± 4.0%, n = 9; Veh = 49.0 ± 3.0%, n = 8), beginning at the onset of reperfusion. %MI in rabbits was not affected by either hourly injections beginning from 1 hr after, or a single injection at 1–3 × the dosages (i.e., 100–300 and 150–450 mg/kg for Trlx and Asc, respectively), during onset of reperfusion. Hemodynamic variables (arterial pressure, heartrate, rate‐pressure‐product and left ventricular contractility) were similar among all treat‐ ment groups in both species. In conclusion, Trlx/Asc combination, but not Asc alone, re‐ duces %MI in dogs and rabbits. The salvaging effects of Trlx/Asc are unrelated to any changes in hemodynamics. These results are consistent with the hypothesis that lipid peroxidation is involved in myocardial reperfusion injury. © 1992 Wiley‐Liss, Inc.
Chemical and enzymatic modification of the platelet binding site for two antidepressant drugs
Authors: Chudzik Jerzy , Helmeste Daiga M. , Tang Siu Wa
Published: January 2005

Isolated human platelet membranes were subjected to chemical and enzymatic modification using a range of protein and lipid‐modifying agents. We studied the binding properties of two antidepressant drugs (imipramine and paroxetine) for the serotonin uptake protein under these conditions, with the premise that if the binding sites had different topographical requirements, then their binding properties may be differentially modulated. The results show differential modulation of binding of these two drugs by thiol/disulfide bond modifying reagents. This suggests the presence of two different mechanisms of recognition and binding for IMI and paroxetine. Additionally, the binding of both drugs to the serotonin transporter was found to be extremely sensitive to lipid‐modifying reagents, but susceptible to proteolytic cleavage only under certain environmental conditions. © 1992 Wiley‐Liss, Inc.
Preclinical toxicology of the GABA uptake inhibitor CI‐966
Authors: Walker Robin M. , Houston Barry J. , Macallum G. Eileen , Clarke David W. , Smith Graham S. , Cox Raymond H. , Hawkins Kathleen L. , Radulovic Louis L.
Published: January 2005

Cl‐966 (1‐[2‐[bis[4‐(trifluoromethyl)phenyl]methoxy]]‐1,2,5,6‐tetr5ahydro‐3‐pyridinecarboxylic acid, HCl salt) is an anticonvulsant agent that blocks the re‐uptake of gammaaminobutyric acid (GABA) into presynaptic nerve terminals and glial cells. The preclinical toxicology of Cl‐996 was evaluated in male and female B6C3F1 mice, Wistar rats, and beagle dogs. Doses were administered orally and are expressed as free acid equivalents. Acute (gavage) toxicity was characterized principally by CNS signs (hypoactivity, atasia, tremors, convulsions, and prostration); diarrhea and urine scald; and delayed mortality (2–3 days in mice and 2–11 days in rats) with 14 day median lethal doses of 653 and 825 mg/kg in male and female mice and 1,019 and 830 mg/kg in male and female rats, respectively. In a 4‐week rat study in which Cl‐966 was given in the diet, the high dose of 500 mg/kg/day was not tolerated, with marked decreases in body weight and food consumption necessitating sacrifice during the second week. The 150 mg/kg/day dose caused reduced body weight gain, lower food consumption, and hyperactivity, while 50 mg/kg/day was clearly a no‐effect level. In dogs, Cl‐966 was given in gelatin capsules at doses of 2 to 25mg/kg/day in an exploratory study and at 2,6, and 15 mg/kg/day in a 4‐week study. Prostration, ataxia, disorientation, and other mainly CNS‐related clinical signs occurred at 5 to 25mg/kg. Aspartate and/or alanine aminotransferase activities were elevated at 20 and 25 mg/kg in the exploratory dog study. However, there were no histopathologic findings in either species directly attributable to Cl‐966 treatment. Enhanced GABAergic activity was considered to be the cause of most of the clinical signs elicited by Cl‐966 in rodents and dogs. Blood Cl‐966 levels were dose‐dependent, but higher in females than males for both rats and dogs. These results were used to support initial clinical trials of Cl‐966 in humans. © 1993 Wiley‐Liss, Inc.
Identification of multiple nitrobenzylthioinosine binding sites in guinea pig platelets: Comparison with binding in guinea pig erythrocytes
Authors: Williams Evan F.
Published: January 2005

The novel existence of multiple binding sites for the potent nucleoside transporter Probe, [3H]nitrobenzylthioinosine, was identified in guinea pig platelet membranes and the binding characteristics compared to those of guinea pig erythrocyte membranes. Scatchard analysis of the binding in platelets reveled two high affinity binding sites with affinity constant (KD) of 0.94 ± 0.07 nM and 83 ± 13 nM with corresponding maximal binding capacities (Bmax) of 21 ± 7 and 110 ± 25 fmol/mg protein, respectively. In comparison, guinea pig erythrocyte membranes revealed a homogeneous population of the binding sites with KD of 0.17 ± 0.04 nM and a Bmax value of 73 ± 11 fmol/mg protein. Biphasic semi‐log plots of the binding site heterogeneity in erythrocytes not reveled by Scatchard plots. Determination of the potencies of selected drugs in inhibiting the binding showed evidence of differential interacitons with the binding sites by various agents which may be exploited pharmacologically. © 1993 Wiley‐Liss, Inc.
WAY 100289: Pharmacological profile of a novel 5‐HT3 receptor antagonist
Authors: Rhodes Keith F. , Middlefell Vicki C. , Lattimer Norman , Brammer Neil T. , Coleman James , Taylor Anne P. , Saville Valerie L. , Ward Terence J.
Published: January 2005

WAY 100289, endo‐N‐[8‐methyl‐8‐azabicyclo [3.2.1.] octan‐3‐yl) aminocarbonyl]‐2‐cyclopropylmethoxybenzamide, was an antagonist of 5‐HT evoked depolarization (5‐HT3 receptor‐mediated) of the rat isolated cervical vagus nerve (pA2 value 8.9). Schild‐plot analysis was consistent with a competitive antagonist mechanism (slope 0.8), though antagonism was not fully surmountable. WAY 100289 was a relatively weak antagonist of 5‐HT3 receptor‐mediated contractions of the guinea‐pig isolated ileum longitudinal muscle‐myenteric plexus preparation (pA2 value 6.2). In 5‐HT3 receptor binding studies in rat entorhinal cortex membranes WAY 100289 displaced [3H]‐zacopride with a pK1 value of 8.4, in good agreement with results in the vagus nerve. In urethane anaesthetised rats the 5‐HT evoked Bezold‐Jarisch reflex was blocked by WAY 100289 with an ED50 of 1.3 μg/kg i.v., consistent with 5‐HT3 receptor antagonism. In the conscious rat WAY 100289 was approximately 30‐fold more potent by the i.v. than by the p.o. route. Following a dose of 1 mg/kg of WAY 100289 the Bezold‐Jarisch reflex was reduced by more than 50% for in excess of 6 h. In a series of in vitro functional and ligand binding assays WAY 100289 showed good selectivity for the 5‐HT3 receptor with the only notable additional activity that of non‐competitive antagonism of nicotinic receptor mediated depolarization of the rat vagus nerve (−log IC50 value 6.7). The compound was without significant effect as an inhibitor of the uptake of 5‐hydroxytryptamine, noradrenaline or dopamine by rat brain synaptasomes. In general, WAY 100289 is a novel, achiral 5‐HT3 receptor antagonist with good in vitro potency and selectivity and good in vivo activity, oral bio‐availability, and duration of action. © 1993 Wiley‐Liss, Inc.
Cardiovascular effects of apraclonidine in the conscious dog
Authors: Jones Carl E. , Sallee Verney , DeSantis Louis , Gayheart Pamela A. , Hamrick Melissa L. , Bravenec J. Stanley , Longlet Nancy A.
Published: January 2005

Apraclonidine (p‐aminoclonidine) a recognized α2‐adrenergic agonist, has been approved for use with ocular laser surgery and is under consideration for use as a chronic treatment for glaucoma. The potential cardiovascular actions of apraclonidine in conscious animals has yet to be fully explored. The present studies were performed in conscious, chronically instrumented dogs to evaluate these possible cardiovascular effects. In a first study, apraclonidine was administered iv in dosages ranging from 5 to 200 μg. When administered by this route, apraclonidine elicited profound, but transient, cardiovascular actions. Mean arterial pressure (MAP) and left ventricular systolic pressure (LVSP) showed significant increases at dosages of 50–100 μg or higher, while heart rate (HR) showed a significant reduction. No variables had values significantly different from control values 60 min after administration. In a second study, apraclonidine was applied topically to either one or both eyes in total dosages of 125–1,000 μg. In contrast to iv administration, even with doses of up to 1,000 μg, topical apraclonidine administered in the eye elicited no significant change in cardiovascular variables. In the third set of studies, the neurotransmitters acetylcholine (1–10 μg/kg) and norepinephrine (0.2–2 μg/kg) were administered iv both before and 45 min after 500 μg apraclonidine was applied to the eye. Topical apraclonidine enhanced the mean AP response to norepinephrine by as much as 18% and the LVSP response to norepinephrine by as much as 17% No effect on the response to acetylcholine was seen. We conclude that all cardiovascular changes following iv apraclonidine can be attributed to its vasoconstrictor action with the consequent rise in MAP. The absence of measurable effects after topical application was likely due to a much slower entry into the circulation, although the vasoconstrictor action of apraclonidine after topical applications seemed to be additive to that of iv norepinephrine. © 1993 Wiley‐Liss, Inc.
Self‐Medication: A survey of nonprescription drug use
Authors: Buckalew Louis W. , Buckalew Nancy M.
Published: January 2005

A sample of adults (n = 148) which reflected age, gender, and race characteristics of the 1980 U.S. Census was surveyed on the incidence of obtaining over the counter (OTC) drugs during the previous year and the nature of the drugs used. Most (78%) reported obtaining OTC drugs, and of 15 categories, headache or pain remedies, cold or flu remedies, and vitamins were most frequently (>50%) reported as used. No gender or race effects were found for obtaining OTC drugs or for the nature of OTC drugs used. Identified patterns of OTC drug use were related to previous research and have implications for drug development, health care, and marketing concerns. © 1993 Wiley‐Liss, Inc.
Molecular characterization of A1 and A2a adenosine receptors
Authors: Jacobson Kenneth A. , van Galen Philip J. M. , Ji Xiao‐Duo , Ramkumar Vickram , Olah Mark E. , Stiles Gary L.
Published: January 2005

Detailed amino acid sequence analyses of A1 and A2a adenosine receptors were assembled by analogy to other G‐protein‐coupled receptors and correlated with pharmacological observations. Sites for phosphorylation, palmitoylation, and sodium binding have been proposed. Striatal A2a receptors from human and other species were photoaffinity‐labeled using the selective, radioiodinated agonist PAPA‐APEC. Selective chemical affinity labels for A1 and A2a receptors have been introduced. For example, an isothiocyanate, ρ‐DITC‐APEC (100 nM), irreversibly diminished the Bmax for [3H]CGS 21680 (2‐[4‐[(2‐carboxyethyl) phenyl] ethylamino]‐5′‐N‐ethylcarboxamido‐adenosine) binding in rabbit striatal membranes by 71% (Kd unaffected), suggesting a direct modification of the ligand binding site. Novel trifunctional affinity labels have been designed. Rabbit and human A2a receptors were characterized using [3H]XAC binding in the presence of 50 or 25 nM CPX (8‐cyclopentyl‐1,3‐dipropylxanthine), respectively. The inhibition of A2 radioligand binding by the histidyl‐modifying reagent diethylpyrocarbonate suggested the involvement of His residues in interactions with adenosine agonists and antagonists. Properties of transiently expressed mutants of bovine A1 receptors in which either His251 or His278 residues have been substituted with Leu suggest that both histidines are important in binding. © 1993 Wiley‐Liss, Inc.
Inotropic actions of adenosine derivatives in the mammalian heart
Authors: Scholz H. , Kohl C. , Neumann J. , Schmitz W. , Seeland C. , Stein B.
Published: January 2005

The effects of adenosine receptor (AR) stimulation on contractile parameters as well as inositol phosphates, cAMP content, and phospholamban‐phosphorylation was studied in cardiac preparations. In guinea‐pig papillary muscles adenosine increased inositol trisphosphate formation and also slightly elevated force of contraction. In the presence of isoprenaline, however, adenosine still enhanced inositol trisphosphate formation but reduced force of contraction. In isolated electrically driven guinea‐pig ventricular cardiomyocytes the A1‐AR agonist R‐PIA and the A1/A2‐AR agonist NECA reduced isoprenaline‐stimulated contractility but only R‐PIA decreased isoprenaline‐enhanced cAMP content. The selective A2‐AR agonist CGS 21680 increased isoprenaline‐stimulated cAMP content. This effect of CGS 21680 was antagonized by the A2‐AR antagonist CGS 15943A and was increased after pertussis toxin‐pretreatment. Furthermore, R‐PIA and NECA decreased via A1‐ARs the isoprenaline‐stimulated phospholamban‐phosphorylation in guinea‐pig ventricular cardiomyocytes. © 1993 Wiley‐Liss, Inc.
Clinical cardiac electrophysiologic effects of adenosine
Authors: Griffith Michael J.
Published: January 2005

Adenosine is very useful for the acute diagnosis and treatment of tachycardias in humans. Adenosine's major cardiac effect, when given as a bolus, is to produce transient atrioventricular block. It can be used either to terminate tachycardias that involve the atrioventricular node or to transiently reveal an atrial tachycardia by slowing the ventricular response, and so to allow the diagnosis to be made. Adenosine is effective in the diagnosis of broad complex tachycardias, revealing and terminating supraventricular tachycardias, with usually no effect on ventricular tachycardia. Adenosine's great advantages over verapamil are its safety, especially in haemodynamically unstable patients, and its short half‐life. Is major disadvantage is the somatic side effects it produces: chest pain, deep breathing, flushing, and a variety of other sensations. Adenosine's effects on other tachycardias also gives an insight into their mechanisms. Right ventricular outflow tachycardia is terminated by adenosine, which supports the thesis that it is due to triggered afterdepolarizations. This may be the explanation for the termination of some atrial tachycardias by adenosine. Sinus node reentry tachycardia is slowed and terminated by adenosine, suggesting that at least part of the tachycardia circuit is in the sinus node. To conclude, the ability of adenosine to selectively block atrioventricular conduction, combined with its very short half‐life, make it a very useful drug both clinically and in the electrophysiology laboratory. © 1993 Wiley‐Liss, Inc.
Adenosine and the vascular tissue renin‐angiotensin system in the forearm of essential hypertensive patients
Authors: Taddei Stefano , Virdis Agostino , Mattei Paola , Favilla Stefania , Salvetti Antonio
Published: January 2005

The present study was designed to evaluate whether adenosine can activate a vascular tissue renin‐angiotensin system in the forearm of essential hypertensive patients. In a group of 6 patients, we infused adenosine at cumulative increasing doses into the brachial artery and collected simultaneous arterovenous samples for angiotensin II determinations (by radioimmunoassay). Forearm blood flow was evaluated by strain‐gauge plethysmography. Adenosine caused a dose‐dependent increment in forearm blood flow and in venous angiotensin II, whereas it did not affect arterial angiotensin II. When repeated in the presence of the antagonist, theophylline, the adenosine effect was blunted. Moreover, in the forearm of another group of 6 hypertensives ischemia was applied for 7 min to induce the production of endogenous adenosine while active renin (by radioimmunometric assay) and angiotensin II were measured. During the reactive hyperemia, venous active renin and angiotensin II increased, while arterial values did not change. This effect was also blunted by theophylline. Taken together these data indicate that either exogenous or endogenous adenosine can activate a vascular tissue renin‐angiotensin system in the forearm of essential hypertensive patients. © 1993 Wiley‐Liss, Inc.
Adenosine myocardial perfusion imaging in the noninvasive diagnosis and prognosis of coronary artery disease
Authors: Verani Mario S.
Published: January 2005

Adenosine is a purine base compound which is of fundamental importance in many physiologic processes in the body, including vasodilation in most arterial vascular beds. Adenosine produces maximal or near‐maximal coronary vasodilation by interacting with the adenosine A2 receptors in the cell wall, on a dose dependent fashion. The mechanism of thallium‐201 myocardial perfusion defects induced by adenosine scintigraphy is a heterogeneity of myocardial blood flow due to a greater coronary flow increase in the normal arteries and a lesser increase in the stenotic arteries. The ultra‐short half‐life of adenosine (< 10 sec) necessitates continuous intravenous administration at a dose of 140 μg/kg/min for six min. The excellent safety record of this regimen has been demonstrated in several thousand patients in the United States. Side effects occur in most patients during adenosine infusion. Chest pain occurs often and in some cases may be due to a true coronary steal phenomenon. In the author's experience, first degree AV block occurs in approximately 10% and second or third degree AV block in approximately 4% of the patients, and are due to the negative dromotropic effect of adenosine on the AV node. On the positive side, these untoward effects are very short‐lived and typically disappear within one or two minutes after discontinuing the adenosine infusion. No serious complications or fatalities have been observed to date with this test. The cumulative experience with adenosine thallium‐201 scintigraphy indicates high sensitivity and specificity in the diagnosis of coronary artery disease. Recent data also suggest it may be an excellent technique to assess a patient's prognosis early after a myocardial infarction. Adenosine‐induced coronary vasodilation, in combination with thallium‐201 or the new technetium‐99m perfusion agents, holds great promise in the assessment of patients with coronary artery disease. © 1993 Wiley‐Liss, Inc.
Mechanism of adenosine‐induced bronchoconstriction: An animal model
Authors: Pauwels Romain , Joos Guy F. , Kips Johan C. , Peleman Renaat A.
Published: January 2005

A rat model of adenosine‐induced bronchoconstriction has been used to study the mechanism involved in the adenosine‐induced airway narrowing. A remarkable difference in bronchial responsiveness to adenosine between various inbred rat strains was observed. The BDE strain was the most responsive strain and was used for further characterization of the adenosine response in the airways. Tachyphylaxis to a second challenge was a constant phenomenon. The order of potency of adenosine analogues was 5′N‐ethoxycarboxy‐adenosine (NECA) > adenosine > N6‐(2‐phenylisopropl)‐adenosine (R‐PIA). The adenosine‐induced bronchoconstriction was mainly caused by the activation of mast cells and postganglionic vagal neurons. The direct effect of adenosine of bronchial smooth muscle was rather limited. Adenosine challenge induced the release of histamine and 5‐hydroxytryptamine in the airways. Cromoglycate, nedocromil, theophylline, and enprofylline inhibited the adenosine‐induced bronchoconstriction. Adenosine and neurokinin A had an additive and possibly a synergistic effect in causing bronchoconstriction and mast cell activation. © 1993 Wiley‐Liss, Inc.