bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulation of myocardial function after brief regional ischemia by glucagon
Authors: Jolly Stanley R. , Jordan Joseph C. , Rose Gregory C.
Published: January 2005

Glucagon (1.5 to 45 μg/kg, i.v.) has been examined in open‐chest anesthetized dogs subjected to 15 minutes of occlusion of the left circumflex coronary artery (LCCA) and reperfusion. Regional segment lengths in myocardium supplied by the LCCA and left anterior descending (LAD) coronary arteries were measured by sonomicrometry. Occlusion of the LCCA produced paradoxical bulging. At 2.5 hours after reperfusion, segmental shortening in the LCCA area remained significantly reduced at 33 ± 11% of baseline. Regional shortening in the LAD area increased upon LCCA occlusion but was not significantly different from baseline at 2.5 hours. Glucagon increased heart rate and peak positive dP/dt while decreasing systemic pressure. After glucagon 15 μg/kg i. v., LCCA regional shortening was 71 ± 10% of baseline, a significant increase compared with the 2.5 hours reperfusion value. For comparison, isoproterenol 0.3 mg/kg increased segment shortening to 119 ± 19% of baseline. Glucagon reduced end‐diastolic segment length in both LCCA and LAD regions. In conclusion, glucagon significantly improved regional function in myocardium recovering from an episode of regional ischemia.
Uricosuric property of a new diuretic compound, S‐8666‐S‐(‐)‐enantiomer in rats
Authors: Shinosaki Toshihiro , Harada Hiroshi , Yonetani Yukio
Published: January 2005

The uricosuric property of S‐8666‐S‐(‐)‐enantiomer (S), which is the diuretic component of the uricosuric diuretic agent S‐8666, was studied using rats. S markedly increased the tubular fractional excretion of uric acid in a stop‐flow analysis using rats treated with pyrazinoic acid (PZO), an inhibitor of tubular urate secretion, but did not affect the tubular urate transport in animals not treated with PZO. On the other hand, S was hypouricosuric and hyperuricemic in a clearance study using rats treated with oxonate, a uricase inhibitor, and also in an experiment using eviscerated rats with functional hepatectomy. The diuretic property of S was comparable to that of furosemide in rats. However, furosemide under an equivalent diuretic response was more potently hypouricosuric in oxonate‐treated rats and eviscerated rats with functional hepatectomy and even in the stop‐flow experiments, and more hyperuricemic in eviscerated rats with functional hepatectomy. The hypouricosuric effect of S in oxonate‐treated rats could be canceled by administration together with the R‐(+)‐enantiomer. These results led to the conclusion that S is less hypouricosuric and hyperuricemic than furosemide at an equivalent diuretic dose owing to its dual effects on tubular urate transport, and the hypouricosuric property can be canceled by administration together with the R‐(+)‐enantiomer.
Evaluation of the morphine reversal actions and antinociceptive activity of a new class of opiate antagonists structurally related to fentanyl
Authors: Wynn Richard L. , Bagley Jerome R. , Spencer H. Kenneth , Spaulding Theodore C.
Published: January 2005

Structural changes to the fentanyl molecule based on heterocyclic modifications at the sector distal to the piperidine nitrogen results in morphine reversal activity. A series of such compounds known as 4‐(heteroanilido) piperidines were tested for reversal of morphine antinociception and depressed respiration rate per minute (RPM) using a rabbit tooth pulp model. Nine compounds were tested and all reversed morphine depressed RPM with doses ranging from 0.007 mg/kg to 1.55 mg/kg. Four of the nine compounds also significantly reversed antinociception at doses ranging from 0.005 mg/kg to 0.6 mg/kg. All but one compound elicited significant antinociception in non‐morphine rabbits. Maximum possible effect (MPE) ranged from 21% to 57% and cumulative doses to achieve antinociception ranged from 0.16 mg/kg to 7.7 mg/kg. These compounds increased RPM in non‐morphine rabbits with a range from 9% to 49% over control values. A furan ring at the distal site was found to be important in selective reversal of RPM. When a methylated 2‐pyridine was combined with a 2‐furan, reversal of both morphine antinociception and depressed RPM was achieved. One compound in this series compared favorably to the mixed agonist‐antagonist nalbuphine and a second compared favorably to the pure antagonist naloxone.
General approach leading to the development of imidazoquinoline and imidazopyrimidine benzodiazepine receptor ligands
Authors: Tully W. Roger , Gardner Colin R. , Westwood Robert
Published: January 2005

The observation that the imidazoquinoxaline ethyl ester RU32180 possessed an affinity of 175 nM for benzodiazepine (BDZ) receptors led to the discovery of several series of potent receptor ligands such as esters ofimidazoquinolines and imidazobenzothiazoles. The lack of oral activity shown by these esters was rectified in the benzoyl imidazoquinolne RU31719, which possessed nearly all the properties of a classical BDZ agonist but with reduced muscle relaxant activity. Structure‐activity studies led to the benzoyl imidazoquinazoline RU32514 and from there to the imidazopyrimidine RU32698, which has robust anxiolytic activity, but induces little sedation and no muscle relaxation in a range of animal models. Further studies yielded the oxadiazolyl imidazopyrimidines such as RU33203, a potent partial agonist, and the thiazolyl imidazopyrimidine RU33356, the first member of the series to possess antagonist/inverse agonist properties.
Effects of selected imidazopyrimidine ligands for benzodiazepine receptors in rodent models of anxiety and behavioural impairment
Authors: Deacon Robert M. J. , Guy Andrew P. , Gardner Colin R.
Published: January 2005

A group of imidazopyrimidine ligands of benzodiazepine receptors has been shown to produce anti‐conflict effects in a punished rat operant task, at comparable doses to classical benzodiazepine agonists such as diazepam. Most were able to attenuate the convulsant effects of pentylenetetrazole and electroshock in the mouse, although with reduced potency compared with the reference classical benzodiazepines. Their activity in tests of functional central nervous system impairment (rotating drum and potentiation of phenobarbitone in the mouse, potentiation of chloral hydrate and pull‐up test in the rat) was also markedly less than the classical agonists. These data are consistent with these imidazopyrimidines being partial agonists at the benzodiazepine receptor.
Hemodynamic profile of the new cardiotonic agent CK‐2289 compared to milrinone and enoximone in the anesthetized dog
Authors: Greenberg Stanley S. , Paul Jeff , Touhey Beatrix
Published: January 2005

We examined the hemodynamic profile of CK‐2289, a new imidazolone developed for the treatment of congestive heart failure, in the normal pentobarbital‐anesthetized dog. Mongrel dogs (10–18 kg) of either sex were anesthetized with pentobarbital sodium (35 mg/kg, intravenously [i.v.]) and instrumented for routine hemodynamic measurements using an open‐chest, artificially ventilated preparation. Intravenous administration of CK‐2289 (3, 10, 30, and 100 μ/kg) to pentobarbital‐anesthetized dogs increased left ventricular (LV) dP/dTmax by 9, 26, 73, and 80%, respectively, and decreased mean arterial pressure (MAP) by 2, 6, 18, and 34%. CK‐2289 was 2.7 times more potent as a positive inotropic agent than as a vasodilator. Heart rate (HR) increased by 2, 10, 18, and 28% after these doses of CK‐2289, while left ventricular end diastolic pressure (LVEDP) decreased by 4.5 mmHg after the highest dose of compound. CK‐2289 increased coronary blood flow (CBF) after each dose of compound. However, the increased CBF was less than that produced by milrinone for equivalent increases in LV dP/dTmax. Renal blood flow increased while vertebral blood flow was reduced after administration of the two highest doses of CK‐2289. However, vertebral vascular resistance decreased slightly from control values. Milrinone and enoximone behaved qualitatively similar to, but were 6 and 27 times less potent than CK‐2289 as cardiotonic agents. Thus, CK‐2289 is a mixed positive inotrope and vasodilator with a hemodynamic profile similar to milrinone and enoximone, which sugests it may have utility in the treatment of heart failure.
Atrial natriuretic peptide modulators: Dissociation of receptor binding and particulate guanylate cyclase activity
Authors: Horng Jong S. , Wyss Virginia L. , Schirmer Elmer W. , McCowan Jefferson R. , Yu Melvin J.
Published: January 2005

Prazosin stimulated 125l‐rANP(102–126) binding to bovine adrenal zona glomerulosa membranes (BAZGM) allosterically by converting the lower‐affinity state binding sites into the higher‐affinity state. The modulatory effect could be mimicked by guanabenz and LY193422, and was concentration‐dependent. SC50 (concentration required to stimulate binding by 50%) values for guanabenz, prazosin, and LY193422 were 13, 25, and 1.8 μM, respectively. Prazosin (30 μM) enhanced 125l‐ANP(102–126) binding by decreasing the KD from 251 ± 24 to 97.4 ± 8.3 pM without affecting the Bmax. Competitive inhibition of 125l‐ANP binding by ANP analogs was potentiated by prazosin (30 μM) and LY193422 (50 μM). The modulator‐stimulated 125l‐rANP(102–126) binding was reversible by the addition of unlabelled ANP analogs during incubation. Previously, we also demonstrated that these modulators potentiated the ANP‐mediated inhibition of ACTH‐induced aldosterone synthesis in rat adrenal zona glomerulosa cells [Horng, J. S., Steinberg, M. I., Wyss, V. L., Wiest, S. A., Schirmer, E. W., McCowan, J. R., and Yu, M. J.: Atrial natriuretic peptide (ANP) receptor modulators: Effects of prazosin and guanabenz analogs on ANP receptor binding and in vitro biological activity. FASEB Journal 3:A733, 1989; Yu, M. J., McCowan, J. R., Steinberg, M. I., Wiest, S. A. Wyss, V. L., and Horng, J. S.: Atrial natriuretic peptide receptor modulators: Effect of disubstituted quinazolines on receptor binding and in vitro biological activity. Journal of Medicinal Chemistry 33:348–353, 1990]. However, neither prazosin nor LY193422 affected basal or ANP‐induced particulate guanylate cyclase activity in rabbit glomeruli. This is the first study to our knowledge in which ANP modulators were demonstrated to potentiate ANP‐mediated response independent of cGMP. Our studies suggest that potentiation of ANP‐mediated inhibition of aldosterone synthesis by these analogs does not involve particulate guanylate cyclase and that these modulators induce a cyclase‐uncoupled, high affinity ANP receptor in the adrenal gland, which might be different from cyclase‐uncoupled ANP clearance receptor.
Pelanserin inhibition of serotonin‐induced phosphatidylinositol turnover and contraction in rabbit aorta
Authors: Villalobos‐Molina Rafael , Castillo Carlos , Hong Enrique
Published: January 2005

Stimulation of rabbit aortic rings with serotonin or quipazine increased the incorporation of [32P]Pi into phosphatidylinositol (Pl) and induced a dose‐related contraction. The effects of serotonin and quipazine were blocked by 5‐HT2 antagonists with the following order of potency: pelanserin = ketanserin ≫ methysergide. Indorenate, a 5‐HT1 agonist, failed to modify phosphatidylinositol labeling in rabbit aorta but elicited a very weak contraction at high concentrations. Pelanserin blocked epinephrine‐stimulated phosphatidylinositol labeling, being two orders of magnitude less potent than prazosin. The results demonstrate that pelanserin is a potent antagonist of the stimulation of Pl labeling and vasoconstrictor effects of 5‐hydroxytryptamine and suggest that 5‐HT2 blockade is involved as its major pharmacologic action.
Antisecretory, mucosal‐protective, and diarrheagenic activity of a novel synthetic prostaglandin, SC‐46275, in the rat
Authors: Perkins William E. , Collins Paul W. , Bianchi Robert G. , Gasiecki Alan F. , Bauer Raymond F. , Jones Peter H. , Gaginella Timothy S.
Published: January 2005

The synthetic prostaglandin SC‐46275, an omega‐chain cyclopentenyl analogue of enisoprost, has been studied in the rat to determine its suitability for development as an anticulcer agent. In the pylorus ligated (Shay) model, SC‐46275 exhibited more potent antisecretory activity when administered intragastrically than when administered intraduodenally, the minimal effective doses (M.E.D.) being, respectively, 10 and 100 μg/kg. Intragastric administration of SC‐46275 significantly (P ≤ 0.05) reduced the number (M.E.D. 2.5 μg/kg) and length (M.E.D. 5 μg/kg) of ethanol‐induced gastric lesions. It was also active intragastrically (M.E.D. 0.3 μg/kg) against indomethacin‐induced intestinal damage. Interestingly, SC‐46275 had no effect on the incidence of indomethacin‐induced intestinal damage when given intragastrically and significantly reduced the severity of damage only at the highest dose tested, 300 μg/kg. SC‐46275, was less diarrheagenic than misoprostol when given intraduodenally; it was even less diarrheagenic when given intragastrically, being virtually devoid of diarrheagenic activity at a dose 300 times greater than the antisecretory dose. These data indicate that SC‐46275, a potent, possibly locally active gastric antisecretory, mucosal‐protective prostaglandin possessing minimal diarrheagenic activity, may be useful in the treatment of gastric/duodenal ulcer disease.
Aminopyridazine muscarinic agonist, SR 95639A, is a functional M2 receptor antagonist in rat brain
Authors: Anderson David J. , Decker Michael W. , Arneric Stephen P. , Cadman Evelyn , Buckley Michael J. , Vella‐Rountree Lorraine , Williams Michael
Published: January 2005

The minaprine analog SR 95639A (morpholinoethylamino‐3‐benzocylohepta‐(5,6‐c)pyridazine dihydrochloride), a putative muscarinic M1 receptor agonist, was evaluated for muscarinic activity in a number of biochemical and behavioral tests. Binding studies indicated that SR 95639A was 4‐fold selective for the M1 receptor. In contrast, both carbachol and the Merck “super agonist,” L 670,207, were 50‐fold selective for the M2 receptor, with Ki values of 47 μM and 100nM at the M1 receptor and 1 μM and 2nM at the M2 receptor, respectively. At concentrations up to 1 mM, SR 95639A had no effect on M1 receptor‐evoked phosphatidyl inositol (Pl) hydrolysis, while carbachol and L 670,207 had EC50 values of 116±10 μM and 0.60±0.12 μM respectively. SR 95639A (100 μM) did not inhibit the Pl response elicited by carbachol. At striatal M2 receptors linked to inhibition of forskolin‐mediated cyclic AMP production, SR 95639A at concentrations up to 100 μM had no agonist activity, while carbachol and L 670,207 had respective EC50 values of 540±31 nM and 2.9±0.5 nM. However, SR 95639A was an effective antagonist (K app = 3.50±0.45 μM; n = 5) of the carbachol response. In a rat radial arm maze paradigm, SR 95639A did not enhance cognitive performance and was unable to reverse deficits induced by scopolamine. The compound produced a dose‐dependent increase in mouse locomotor activity and did not attenuate the effects of scopolamine on habituation, but did potentiate oxotremorineinduced hypothermia.
Antihypertensive activity of himbacine in anesthetized cats
Authors: Gilani Anwar‐Ul‐Hassan
Published: January 2005

Himbacine is a plant alkaloid isolated from Galbulimima baccata. Intravenous administration of himbacine produced a fall in blood pressure and heart rate in anesthetized normotensive cats. These effects were similar in areflexic and normal cats, suggesting direct peripheral action with no central component involvement. Presence of himbacine did not alter the preganglionic stimulation of cat nictitating membrane, ruling out the possibility of ganglion blockade. In isolated rabbit aorta, himbacine inhibited K+‐induced contraction, an effect similar to that of papaverine. These data indicate that antihypertensive and bradycardiac actions of himbacine are mediated through its direct depressant action on myocardium and blood vessels, and that the compound is relatively safe with i.p. LD50 in mice of 230 mg/kg.
Pharmacology and physiology of metabotropic glutamate receptors in mammalian central nervous system
Authors: Conn P. Jeffrey , Desai Manisha A.
Published: January 2005

Until recently, all receptors for glutamate and other excitatory amino acids (EAAs) were thought to be ligand‐regulated cation channels which, when activated, lead directly to cell depolarization. This family of glutamate receptors is referred as the ionotropic glutamate receptor family and is involved in transmission of fast synaptic responses. It is now clear that glutamate also acts on a distinct family of metabotropic receptors. These glutamate receptors are not cation channels but are linked to effector systems via guanine nucleotide binding proteins (G‐proteins). To date, the best‐characterized G protein‐coupled glutamate receptor is linked to phospholipase C and stimulation of phosphoinositide hydrolysis. The pharmacology of this receptor subclass has been thoroughly investigated and is clearly distinct from that of the ionotropic glutamate receptors. Until recently, little was known about the physiological roles of the metabotropic glutamate receptors. However, the recent discovery of selective metabotropic glutamate receptor agonists has made it possible to begin to investigate the physiological effects of activation of this novel class of glutamate receptor.
Lophotoxins: Irreversible active‐site‐directed inhibitors of nicotinic acetylcholine receptors
Authors: Abramson Stewart N. , Fenical William , Taylor Palmer
Published: January 2005

The lophotoxins are a family of structurally‐related neurotoxins that can be isolated from various species of marine soft coral. Like many other naturally occurring neurotoxins, they inhibit nicotinic acetylcholine receptors, resulting in neuromuscular paralysis. However, they are unlike other nicotinic acetylcholine receptor antagonists in several respects. For instance, they do not contain a positive charge common to most cholinergic antagonists; they are conformationally constrained; they react covalently with a specific amino acid (Tyr190) in the a‐subunit of the receptor; and they inhibit both neuronal and muscle subtypes of the receptor. These features make the lophotoxins useful probes for understanding the structure and function of neuronal and muscle nicotinic acetylcholine receptors. Their unique activity may also prove to be useful in a variety of clinical applications.
Dextran metabolism following infusion of 7.5% NaCl/6% dextran‐70 to euvolemic and hemorrhaged rabbits
Authors: Dubick Michael A. , Ryan Barbara A. , Summary James J. , Wade Charles E.
Published: January 2005

Dextran metabolism was evaluated in euvolemic and hemorrhaged rabbits following administration of a 7.5%NaCl/6% Dextran‐70 (HSD) solution. Control rabbits and those bled 8 ml/kg body weight were infused i.v. with 4 ml/kg of HSD or HSD containing 14C‐Dextran‐70. Blood samples were withdrawn prior to and at times up to 96 hr after HSD infusion. Peak serum dextran concentrations were about 29% higher in hemorrhaged rabbits than in controls, yet serum dextran t1/2 was similar in both groups. Molecular weight (MW) distribution of dextran in serum showed a slight shift toward a MW >70,000, consistent with excretion of lower MW forms in the urine. After 96 hr concentrations of 14C‐Dextran were 20‐fold higher in liver from both groups of rabbits, in comparison to spleen, lung, and kidney. In addition, dextranase activity in liver was markedly higher than in the other tissues assayed. These studies indicate that dextran infused as HSD does not associate with any protein fractions, is found only in low concentrations in tissue, and has a serum half‐life adequate to serve as a useful plasma volume expander.
Ritanserin, a new therapeutic approach for drug abuse. Part 3: Effects on fentanyl and sucrose
Authors: Meert T. F. , Janssen P. A. J.
Published: January 2005

Rats given the choice between fentanyl and water will develop a preference for fentanyl after a first period of exposure to fentanyl alone. Chronic treatment with the 5‐HT2 antagonist ritanserin reduced the fentanyl intake and fentanyl preference. The effects of ritanserin were present from the first day and activity started at doses ≥0.04 mg/kg when given subcutaneously once daily. At 2.5 mg/kg ritanserin, the highest dose tested, fentanyl intake and fentanyl preference was reduced by 50 and 33%, respectively. The reductions in fentanyl intake were compensated by an increase in water drinking. At no time was there a systematic interference of ritanserin with consumatory physiological processes nor did ristanserin create aversion for fentanyl. Furthermore, ritanserin did not interact with the discriminative stimulus properties of fentanyl. In a similar experiment and in contrast to its activity on fentanyl intake, ritanserin was unable to reduce sucrose intake and sucrose preference. These results are discussed in terms of a global and specific mechanism of action of ritanserin on the need for drug reinforcement after chronic exposure to drugs of abuse.
Thiazide diuretics and male sexual dysfunction
Authors: Rockhold Robin William
Published: January 2005

The associations that have been noted between the clinical use of the thiazide diuretics and impairment of male sexual performance remain enigmatic. Recent studies are reviewed, in which aspects of the male sexual dysfunction in hypertensive men following treatment with thiazide diuretics were examined. The data are interpreted in light of previously published studies on the subject to suggest that penile erectile defects and decrements in sexual activities are specifically related to thiazide administration. A rodent model of thiazideinduced male sexual dysfunction is introduced that documents dose‐related impairment, by hydrochlorothiazide, of penile erectile reflexes and male copulatory performance. The etiology of thiazide‐induced male sexual dysfunction is hypothesized to result from alterations in sodium excretion that alter afferent renal nerve input to hypothalamic areas regulating male sexual responses.
Venoconstrictor responses to ergosine and ergosinine: Evidence for the isomerization of ergosinine
Authors: Müller‐Schweinitzer Else , Ellis Philip , Ziegler René
Published: January 2005

Ergosine and its D‐isolysergic acid derivative ergosinine were investigated on canine saphenous veins both in vivo and in vitro. Following local i.v. infusion in vivo, about 5 times higher doses of ergosinine were necessary to produce the same venoconstrictor response as induced by ergosine. When administered orally, however, both ergot alkaloids were equi‐effective. In vitro methiothepin, a 5‐HT receptor blocker with high affinity for 5‐HT1 receptors, antagonized venoconstrictor responses to 5‐HT and ergosine within the same concentration range, being significantly less potent when tested against norepinephrine. The reverse was true for the α2‐selective adrenoceptor blocker yohimbine, which was significantly more potent against norepinephrine and ergosine than against 5‐HT, suggesting that ergosine has affinity to both 5‐HT1‐like receptors and α2‐adrenoceptors. Concentration‐response curves to norepinephrine were shifted to the right in a parallel fashion when ergosine or ergosinine were present in the organ baths, suggesting competitive antagonism. The blocking potency of ergosinine increased with increasing incubation times in Krebs‐Henseleit solution becoming similar to that of ergosine when an incubation time of 2 hr was applied. It is suggested that the pharmacological activity of ergosinine is the consequence of an isomerization into its natural stereoisomer ergosine, which may occur both in vivo and in vitro.
Mechanism of monoamine oxidase‐A inhibition by BW 1370U87
Authors: White Helen L. , Scates Philip W.
Published: January 2005

BW 1370U87 is a potent, selective inhibitor of rat and human MAO‐A with a competitive mechanism of action. Ki = 0.01 μM with either serotonin or tyramine as substrate. After preincubation of BW 1370U87 with mitochondrial MAO, full enzyme activity was restored by dialysis. Following oral administration to rats, BW 1370U87 inhibited brain MAO‐A in a dose‐dependent manner, with a duration greater than 6 hr, but less than 24 hr. No significant inhibition of MAO‐B by BW 1370U87 was observed either in vitro or ex vivo. The selectivity, reversibility, and competitive kinetics of the inhibition by BW 1370U87 may contribute to an improved safety profile with this novel MAO‐A inhibitor.
Metabolism of BW 1370U87 by crude liver homogenates from several species: An in vitro method for preliminary investigation of species differences in metabolism
Authors: Norton Ronald M. , White Helen L. , Cooper Barrett R.
Published: January 2005

We employed broken cell liver preparations in order to investigate potential species‐specific differences in the metabolism of BW 1370U87, a new selective and reversible MAO‐A inhibitor. The drug metabolizing capacity of crude liver homogenates from rat, dog, cat, monkey, and man was assessed based on the utilization of BW 1370U87 and the appearance of suspected metabolites. When incubated with liver homogenates (37° C) in the presence of a cofactor preparation designed to generate TPNH, BW 1370U87 (1 or 10 μM) was metabolized in a species and time dependent manner. The rate of disappearence of BW 1370U87 was more rapid in dog and cat preparations than those of rat, monkey and man. The appearance of metabolites coincided with the disappearance of BW 1370U87. Three metabolites, identified and synthesized as BW 183U88, BW 380U88, and BW 330U88 appeared in all five species. These metabolites were also found to be selective MAO‐A inhibitors both in vitro and ex vivo and may contribute to the overall activity exhibited by the parent molecule.
Inhibition of rat cardiac calcium pump activity by cationic amphiphilic drugs
Authors: Kodavanti Prasada Rao S. , Pentyala Srinivas N. , Yallapragada Prabhakara R. , Cameron Joseph A. , Desaiah Durisala
Published: January 2005

Cationic amphiphilic drugs such as imipramine, chlorimipramine, chlorpromazine, chlorphentermine, and chloroquine have been shown to cause myocardial toxicity including arrhythmia, cardiomyopathy, and myocarditis. Since calcium transport by sarcoplasmic reticulum (SR) plays a critical role in contraction‐relaxation coupling of myocardium, the toxicity exhibited by these drugs could be due to their effects on this phenomenon. Hence, we have studied the effects in vitro and in vivo of imipramine, chlorimipramine, chlorpromazine, chloroquine, and chlorphentermine on cardiac SR 45Ca‐uptake and Ca2+‐ATPase in male Fisher‐344 rats. For in vitro studies, cardiac SR was prepared from normal rat hearts. For in vivo studies, rats were treated with drugs by oral gavage (p.o) at a dose of 20 pair‐fed. All these drugs in vitro inhibited the cardiac SR 45Ca‐uptake to a varying extent.

The order of potency is chlorimipramine > chlorpromazine > imipramine > chlorphentermine > chloroquine. The inhibitory pattern of these drugs on cardiac SR Ca2+‐ATPase also followed the same trend. The chlorinated analogs of these drugs are more potent in inhibiting 45Ca‐uptake as well as Ca2+‐ATPase as compared to their nonchlorinated con‐geners. In vivo, all the drugs except chloroquine inhibited the 45Ca‐uptake and Ca2+‐ATPase activity to a different extent. The inhibition of cardiac SR calcium pump activity was seen as early as 7 days of treatment with chlorimipramine whereas all the other drugs (imipramine, chlorpromazine, and chlorphentermine) inhibited this calcium pump only at 21 days of treatment. Although in vivo chloroquine‐induced inhibition of calcium pump activity did not reach significant level, it seems that there may be an effect at higher concentrations. In summary, the present results indicate that these cationic amphiphilic drugs might be exerting myocardial toxicity due to changes in cellular Ca2+ homeostasis because of their effects on cardiac SR calcium transport phenomenon. © 1992 Wiley‐Liss, Inc.
Macrofilaricidal activity of the stembark of Streblus asper and its major active constituents
Authors: Chatterjee Ranjit Kumar , Fatma Nigar , Murthy Puvvada Kalpana , Sinha Preeti , Kulshrestha Dinesh Kumar , Dhawan Bhola Nath
Published: January 2005

The crude extract of the stembark of Streblus asper, a traditionally used medicinal plant of India, revealed significant macrofilaricidal activity against Litomosoides carinii and Brugia malayi in rodents. The study revealed two cardiac glycosides, K029 (asperoside) and K030 (strebloside) of the extract to be responsible for antifilarial activity. Of the two glycosides, the more effective macrofilaricide was K029 which was active at 50 mg/kg orally against L. carinii (>90%), B. malayi (>70%), and Acanthocheilonema viteae (>70%) in their respective hosts. The glycosides were also active in vitro against all the three filarial species. Significantly weak activity was detected in glycon and aglycon portions of the parent glycosides (K029 and K030). Several cardiac glycosides of other origins did not show any comparable antifilarial efficacy. The aglycosidic portion of the extract, however, showed poor adulticidal activity (44.5% activity at 1 g/kg against L. carinii). The present finding, thus, opens up the possibility of generating new leads in the development of novel macrofilaricides. © 1992 Wiley‐Liss, Inc.
Effects of S 9977‐2 on the guinea pig isolated trachea and the human isolated bronchus
Authors: Advenier Charles , Kiniffo Francis , Molimard Mathieu , Blanc Marie , Naline Emmanuel , Mocaër Elisabeth
Published: January 2005

The effects of S 9977‐2, a new compound which belongs to the trimethylxanthine family and has shown in vivo promnesic activity and in vitro acetylcholinesterase activities inhibition, were studied on the guinea pig isolated trachea and on human isolated bronchi. On the guinea pig isolated trachea, S 9977‐2 in concentrations of 10−7–10−4 M potentiated the contractile effect of acetylcholine. The potency of acetylcholine was increased 3.39, 4.26, 9.54, and 13.18 fold with concentrations of 10−7, 10−6, 10−5, and 10−4M, respectively. The maximum effect of acetylcholine was not modified. S 9977‐2 did not potentiate the effects of carbachol or pilocarpine. Under similar conditions, eserine (10−8 and 10−6M) and tacrine (10−8–10−6M) also potentiated the effects of acetylcholine. The potentiating effect of these two substances was stronger than that of S 9977‐2, with a 44.7 fold increase for eserine (10−7M) and a 64.6 fold increase for tacrine (10−6M). However, both eserine and tacrine had a contractile effect of their own on the guinea pig isolated trachea, whereas S 9977‐2 had no such effect. On the human isolated bronchus, S 9977‐2 at a concentration of 10−5M produced a 19.1 fold increase of acetylcholine effects. On the guinea pig isolated trachea, the effects of S 9977‐2 vs. acetylcholine were not modified by epithelium removal. They were increased by pretreatment with indomethacin 10−6M. In very high concentrations (10−4 and/or 10−3M), S 9977‐2 reduced the effects of histamine and those of serotonin on the guinea pig isolated trachea. S 9977‐2 had no effect on the contractile action of potassium chloride or on the relaxant action of adenosine. The results suggest that in the airway smooth muscle S 9977‐2 partially inhibits acetylcholinesterase and/or pseudocholinesterase activity. © 1992 Wiley‐Liss, Inc.
Electrophysiology of 5‐HT1A receptors in the rat hippocampus and cortex
Authors: Andrade Rodrigo
Published: January 2005

Electrophysiological recordings from hippocampus and cortex have demonstrated that one of the most prominent effects of serotonin in these regions is a membrane hyperpolarization that effectively inhibits neuronal activity. The use of the in vitro brain slice preparation has allowed for detailed pharmacological and physiological studies of this response. Pharmacological analysis using agonists and antagonists indicates that these responses are mediated by activation of receptors of the 5‐HT1A subtype. Buspirone, ipsapirone and 8‐OHDPAT are all partial agonists at this receptor with 8‐OHDPAT exhibiting an intrinsic activity approximately one‐fourth that of serotonin. The ability of 5‐HT1A receptor agonists to elicit a hyperpolarization is dependent on intracellular GTP, suggesting the involvement of a G protein in the transmembrane signalling mechanism. In agreement with this idea, injection of the stable GTP analog GTPγS renders the serotonin induced hyperpolarization irreversible, while GDPβS blunts its effects and pertussis toxin pretreatment blocks it. The 5‐HT1A receptor induced hyperpolarization is mediated by an increase in potassium conductance. While the identity of the potassium channel remains to be determined, its basic characteristics identify it as belonging to a general class of inwardly rectifying G protein activated potassium channels ubiquitously distributed in neuronal and cardiac muscle tissues. In the rat hippocampus and cortex, most pyramidal cells co‐express 5‐HT1A with either 5‐HT4 or 5‐HT2 receptors, respectively, which in turn act to increase the ability of strong stimuli to excite these cells. As a result the net effect of serotonin on membrane excitability is dependent on the strength of incoming stimuli. Weak stimuli are depressed by the coactivation of these receptor subtypes while strong stimuli are enhanced. Thus the effects of selective 5‐HT1A ligands are likely to depend not only on their direct effect on membrane excitability but also on how they alter ongoing serotonergic neurotransmission. © 1992 Wiley‐Liss, Inc.
Treatment of Alzheimer's disease by zinc compounds
Authors: Constantinidis Jean
Published: January 2005

At the onset of Alzheimer's disease (AD), specific lesions occur in the hippocampus, i.e., neuropile‐capillary amyloid (AM) plaques and neuronal paired‐helical filaments (PHF)‐neurofibrillary tangles (NFT). The hippocampus is the area of brain with the highest zinc content. Chemical investigations demonstrated that in AD, the cerebral zinc decreases, especially in the hippocampus. The mechanism may be the following: The primary, genetically determined, microvascular AM (asymptomatic) disturbs the blood‐brain barrier, and metals (calcium, iron, aluminium, silicon, mercury, etc.( reach the cerebral cortex, where their levels increase and displace the zinc (whose level decreases) in some enzymes which become nonfunctional. The secondary production of PHF‐NFT and the neuronal dysfunction responsible of the clinical symptoms of dementia may be related to the functional deficiency of the following zinc‐enzymes: (1) those of DNA metabolism giving rise to abnormal DNA and therefore synthesis of abnormal proteins, constituting the NFT; (2) those involved in phosphorylating mechanisms at a post‐transcriptional (ribosomal‐mitochondrial) level, producing the abnormally phosphorylated tau protein, constituting the PHF; 3) that of glutamate (GLU) catabolism, resulting in a neurotoxic increase of GLU, producing PHF by abnormal phosphorylation of the neurofilaments; 4) those of neuronal detoxification contributing to the neuronal dysfunction. In regard to potential for therapeutic intervention, the timing needed for the AM‐induced production of NFT, in the various areas of the brain, has been estimated to be about 14–67 months. During this time it may be possible to influence the AM‐induced production of NFT: The chronic administration of neuroleptics enhances it, and the chronic administration of other drugs may reduce it. Such drugs may be zinc compounds, which will give an excess of zinc in the brain, will inhibit the above‐mentioned AM induced by zinc deficiency, mechanisms producing the NFT related to the clinical symptoms of dementia, and therefore, may prevent, stop, delay, and even improve them. Preliminary trials with zinc‐aspartate give promising results. Research is in progress to consolidate this zinc theory and to find more appropriate zinc compounds for this treatment. © 1992 Wiley‐Liss, Inc.
Effect of calcium channel antagonists on the cardiac vagal tone response to submaximal exercise
Authors: Billman George E. , Halliwill John R. , Avendano Christopher E.
Published: January 2005

Reductions in cardiac vagal tone have been shown to correlate with a greater susceptibility to ventricular fibrillation. Calcium antagonists have been shown to protect against malignant arrhythmias probably as the result of direct actions on cardiac muscle. However, these drugs could also reflexively alter cardiac vagal tone as a consequence of reductions in arterial pressure. Therefore, the effects of various calcium channel antagonists on cardiac vagal tone, both at rest and during exercise, were investigated. The R‐R interval was recorded in chronically instrumented mongrel dogs (n = 39) and the amplitude of the respiratory sinus arrhythmia (0.24–1.04 Hz) was calculated using time‐series analysis techniques. Before exercise, verapamil (n = 17, 250 μg/kg), nifedipine (n = 5, 10 μg/kg; n = 9, 100 μg/kg), diltiazem (n = 10, 100 mg/kg), Ro 40‐5967 (n = 14, 1,000 μg/kg), and magnesium sulfate (n = 10, 100 mg/kg) significantly increased heart rate, while flunarizine (n = 11, 2.5 mg/kg) and a lower dose of Ro 40‐5967 (n = 5, 250 μg/kg) did not affect heart rate. During exercise, nifedipine (high dose) increased heart rate, while Ro 40‐5967 (high dose) decreased heart rate. All six drugs reduced vagal tone before exercise; magnesium and nifedipine (high dose) elicited the greatest reduction, while flunarizine produced the smallest decrease. The vagal tone response to exercise was not affected by flunarizine and Ro 40‐5967 (low dose), but it was accentuated by magnesium, nifedipine, and verapamil. Intermediate responses were noted for Ro‐40‐5967 (high dose) and diltiazem. Pronounced hemodynamic effects were noted for flunarizine, magnesium, nifedipine, and verapamil, but not for Ro 40‐5967. Thus, calcium antagonists have variable hemodynamic profiles and can elicit pronounced reductions in cardiac vagal tone, presumably due to activation of the baroreceptor reflex. © 1992 Wiley‐Liss, Inc.
Reversal of diazepam‐induced impairment in successive discrimination performance by flumazenil
Authors: Cole Sherwood O.
Published: January 2005

The effects of diazepam (DZ) alone and in combination with flumazenil (Ro 15‐1788) on the performance of a previously learned successive discrimination task were studied in male Sprague‐Dawley rats. DZ 4 mg/kg impaired discrimination performance in five successive sessions, although animals showed some tolerance to the drug's action. The impairment in discrimination performance was due to an increase in responding during no go periods of the task (errors of commission). The benzodiazepine (BDZ) receptor antagonist flumazenil (5 and 10 mg/kg) partially reversed the impairment in discrimination performance and reduced the number of incorrect responses in a generally dose‐dependent manner when coadministered with DZ. These findings suggest that the impairment in discrimination performance by DZ is mediated by central BDZ receptor sites. When administered alone, flumazenil 10 mg/kg (but not 5 mg/kg) produced a mild impairment in discrimination performance which, in contrast to DZ's effects, was due to both small increases in no go period responses (errors of commission) and small decreases in go period responses (errors of omission). These findings suggest that flumazenil is not a neutral antagonist but has some intrinsic action of its own. © 1992 Wiley‐Liss, Inc.
Application of fixed‐interval schedules to intracranial self‐stimulation for assessing psychomotor stimulants
Authors: Schaefer Gerald J. , Michael Richard P.
Published: January 2005

Rats were implanted with stimulating electrodes aimed at the medial forebrain bundlelateral hypothalamus (MFB‐LH) and were trained to lever‐press for brain stimulation on a fixed‐interval 15‐sec schedule of reinforcement. When behavior had stabilized, the animals were tested with graded doses of d‐amphetamine (0.1–1.0 mg/kg), cocaine (3.0–30 mg/kg), and nomifensine (1.0–10 mg/kg). Separate groups of animals were tested in a locomotor activity procedure over the same dose ranges. All three drugs produced graded increases in rates of responding which ranged from 180–295% of saline control levels following the highest dose of each drug. In contrast, there were no significant changes in numbers of reinforcements at any of the doses used. When tested in a locomotor activity device, all three drugs produced similar increases in activity with increasing dosage. Although currently little used, the fixed‐interval schedule of brain self‐stimulation can be helpful in making comparisons of the stimulant properties of abused drugs, such as amphetamine and cocaine, and less well‐known drugs with abuse potential such as nomifensine. © 1992 Wiley‐Liss, Inc.
Calmodulin antagonists bind to sodium‐dependent high‐affinty binding sites for tritiated imipramine
Authors: Helmeste Daiga Maret , Tang Siu Wa
Published: January 2005

Effects of calmodulin antagonists on the binding of tritiated imipramine and inhibition of serotonin uptake were tested in brain and platelet preparations. Naphthalene sulfonamidetype calmodulin antagonists generally inhibited specific [3H]‐Imipramine binding (as well as serotonin uptake) with affinities greater than or equal to those reported for binding to calmodulin itself. The binding inhibition did not require the presence of calcium and was not affected by ethylenediaminetetraacetic acid. Other calmodulin antagonists which do not have naphthalene sulfonamide structures did not inhibit [3H]‐Imipramine binding. These results raise the possibility that the structural similarity between imipramine and the naphthalene sulfonamide cerivatives may be sufficient to allow direct competition at the binding site for [3H]‐Imipramine. This is of great importance for calmodulin biochemistry since at these concentrations, the inhibitors were previously thought to interact virtually exclusively with calmodulin. © 1992 Wiley‐Liss, Inc.
Involvement of nitric oxide formation in the action of ramipril and ramipril‐octil in an inhibitory avoidance task in mice
Authors: Hock Franz J. , Wiemer Gabriele
Published: January 2005

We tested (in an inhibitory avoidance test) ramipril and the n‐octyl‐ester of ramipril (RA‐octil; Hoe 065), which was shown to have no significant influence on plasma‐converting enzyme (CE) activity or blood pressure in spontaneously hypertensive rats. In addition, the influence of the specific NO‐synthase inhibitor NG‐nitro‐L‐arginine (L‐NNA) and the specific B2 antagonist Hoe 140 in combination with ramipril and RA‐octil were tested. Ramipril and RA‐octil showed a significant prolongation of step‐through latencies. L‐NNA and Hoe 140 by themselves showed no effects. The combination of ramipril and of RA‐octil, respectively, with L‐NNA or Hoe 140 did not produce any prolongation of step‐through latencies. © 1992 Wiley‐Liss, Inc. © 1992 Wiley‐Liss, Inc.
Effects of chronic treatment with L‐alpha‐glycerylphosphorylcholine on hippocampal cholinergic transmission in the rat
Authors: Missale Cristina , Sigala Sandra , Rizzonelli Paola , Zanelli Emanuela , Spano PierFranco
Published: January 2005

L‐alpha‐glycerylphosphorylcholine (alpha‐GPC) has been proposed for the treatment of age‐related cognitive disturbances. In the rat the compound prevents the learning impair‐ ment and the retrograde amnesia both induced by scopolamine and this effect appears to be correlated with an increase of hippocampal acetylcholine production and release. Since drugs ameliorating learning and memory are usually administered for long periods of time, here we investigated the effects of chronic treatment with alpha‐GPC on the neurochemical parameters linked to hippocampal cholinergic transmission. The data show that an in‐ creased [3H]acetylcholine (ACh) release was detectable in rats chronically exposed to alpha‐GPC and killed 3 hr after the last administration, suggesting that tolerance did not develop in these experimental conditions. An alpha‐GPC‐induced selective desensitization of hippocampal muscarinic M‐2 receptor function was also found. This event was charac‐ terized by a decreased responsiveness of adenylate cyclase to carbachol inhibition in the absence of changes in M‐2 receptor density. This effect could be relevant in view of M‐2 receptor presynaptic location and function in inhibiting ACh release. In contrast with M‐2 receptor, M‐1 receptor density and function were not significantly changed by the treatment. The present data suggest that alpha‐GPC could be proposed as a useful drug for the chronic treatment of memory deficit. © 1992 Wiley‐Liss, Inc.
Studies on the eleterious effects of free radicals on myocardial contractility and hemodynamics in dogs: Protection by felodipine, a dihydropyridine calcium antagonist
Authors: Chintala Madhu S. , Jacinto Severina M. , Jandhyala Bhagavan S.
Published: January 2005

There is convincing evidence that re‐oxygenation of ischemic organs is associated with the formation of oxygen free radicals and increases in cell calcium that exacerbate the ischemic injury. The objective of the present studies was to determine whether felodipine, a dihydropyridine calcium antagonist, would be effective in preventing cardiovascular toxicity produced by oxygen free radicals. In pentobarbital‐anesthetized dogs, intravenous (i.v.) administration of xanthine plus xanthine oxidase [X + XO] resulted in a rapid fall in arterial blood pressure (by 50–60 mmHg) and heart rate (by 30–40 beats/min). All the indices reflecting cardiac function such as contractility index (max dp/dt/p), cardiac output, stroke volume, left ventricular stroke work, and left ventricular minute work were significantly attenuated during a 120 min observation period. Pretreatment of the animals with felodipine (0.01 μmol/kg, i.v.) provided moderate but significant protection from [X + XO]‐induced deterioration of cardiovascular function, whereas the higher dose (0.05 μmol/kg, i.v.) effectively prevented any adverse alterations in cardiovascular function. The results obtained in the present studies suggest that oxygen free radicals facilitate calcium overload in the ischemic cells and can account for the efficacy of several calcium channel antagonists in preventing ischemic injury such as ischemic renal failure in various experimental models. © 1992 Wiley‐Liss, Inc.
Behavioral effects of RO 41‐9067: A novel D2 dopamine receptor agonist
Authors: Belzung Catherine , Carletti Paola , Angelucci Flavia , Puglisi‐Allegra Stefano , Cabib Simona
Published: January 2005

The behavioral effects of a novel putative D2 dopamine (DA) receptor agonist, RO 41‐9067 (RO), were investigated in the mouse and compared with those of the classic D2 agonist LY 171555 (LY) at equimolar doses. Both RO and LY dose‐dependently increased defensive behavior in naive mice interacting with nonaggressive conspecifics at doses higher than 0.2 and 0.16 mg/kg, respectively. Moreover, low and intermediate doses of RO and LY decreased locomotor activity in mice tested individually in an automated apparatus. Finally, coadministration of the D1 selective agonist SKF 38393 and high doses of RO or LY induced the hyperactive response classically induced by high doses of the mixed D1/D2 agonist apomorphine in the mouse while the inhibitory effects of the lowest doses of RO or LY were not affected by coadministration with SKF. These results indicate that RO induces behavioral effects characteristic of a D2 selective agonist when tested in intact mice and suggest that at high doses this compound activates postsynaptic D2 receptors which also cooperate with D1 receptors in the stimulation of DA‐induced behaviors, while at low doses it selectively activates DA autoreceptors or inhibitory DA receptors of the D2 type. © 1992 Wiley‐Liss, Inc.