bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractPrazosin 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

AbstractStimulation 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

AbstractThe 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

AbstractThe 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

AbstractHimbacine 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

AbstractUntil 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

AbstractThe 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

AbstractDextran 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

AbstractRats 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

AbstractThe 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

AbstractErgosine 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

AbstractBW 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

AbstractWe 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

AbstractCationic 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

AbstractThe 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

AbstractThe 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.