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Dose-dependently Decreased (dose-dependently + decreased)
Selected AbstractsPTH-dependent adenylyl cyclase activation in SaOS-2 cells: Passage dependent effects on G protein interactionsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2002Hong Gao Parathyroid hormone (PTH) sensitive adenylyl cyclase activity (ACA) in SaOS-2 cells varies as a function of cell passage. In early passage (EP) cells (<,6), ACA in response to PTH and forskolin (FOR) was relatively low and equivalent, whereas in late passage (LP) cells (>,22), PTH exceeded FOR dependent ACA. Potential biochemical mechanisms for this passage dependent change in ACA were considered. In EP, prolonged exposure to pertussis toxin (PT) markedly enhanced ACA activity in response to PTH, Isoproterenol and Gpp(NH)p, whereas ACA in response to FOR was decreased. In contrast, the identical treatment of LP with PT diminished all ACA in response to PTH, Gpp(NH)p, and FOR. The dose dependent effects of PT on subsequent [32P]ADP-ribosylation of its substrates, GTPase activity, as well as FOR-dependent ACA, were equivalent in EP and LP. The relative amounts of G,i and G,s proteins, as determined both by Western blot, PT and cholera toxin (CT) dependent [32P]ADP-ribosylation, were quantitatively similar in EP and LP. Western blot levels of G,s and G,i proteins were not influenced by prior exposure to PT. Both PT and CT dependent [32P]ADP-ribosylation were dose-dependently decreased following exposure to PT. However, the PT-dependent decline in CT-dependent [32P]ADP-ribosylation occurred with enhanced sensitivity in LP. The protein synthesis inhibitor cycloheximide partially reversed the PT associated decrease in FOR dependent ACA in EP. In contrast, cycloheximide completely reversed the PT associated decrease in FOR and as well as PTH dependent ACA in LP. G,s activity, revealed by cyc, reconstitution, was not altered either by cell passage or exposure to PT. The results suggest that the coupling between the components of the complex may be pivotally important in the differential responsiveness of early and late passage SaOS-2 cells to PTH. J. Cell. Physiol. 193: 10,18, 2002. © 2002 Wiley-Liss, Inc. [source] Effect of DOV 102,677 on the Volitional Consumption of Ethanol by Myers' High Ethanol-Preferring RatALCOHOLISM, Issue 11 2007Brian A. McMillen Background:, Inhibitors of monoamine neurotransmitter transporters are well established as antidepressants. However, the evidence that single (serotonin) or dual (serotonin,norepinephrine) neurotransmitter uptake inhibitors can treat ethanol abuse, either as a comorbidity with depression or as a separate entity, is inconsistent. Drugs that have, in addition, the ability to inhibit dopamine uptake may have an advantage in the treatment of alcohol abuse. Therefore, the inhibitor of norepinephrine, serotonin and dopamine uptake, DOV 102,677, was tested for its effects on the volitional consumption of ethanol by an ethanol-preferring rat strain. Methods:, Myers' high ethanol-preferring rats were screened by a 10-day, 3 to 30% step-up test and then given free access to the preferred concentration of ethanol in a 3-bottle choice task. Consumption of ethanol (g/kg), water, food, and body weight were measured daily during a 3-day predrug treatment period, a 3-day treatment period, and a 3-day posttreatment period. Additional Sprague,Dawley rats were observed for 24 hours for the behavioral effects of 2.0 mg/kg s.c. reserpine after a 30-minute pretreatment with different doses of DOV 102,677. Results:, The triple monoamine uptake inhibitor DOV 102,677 dose-dependently decreased the volitional consumption of ethanol by as much as 71.2% (20 mg/kg i.p., b.i.d.) over 3 days of administration. This effect carried over into the posttreatment period. Similarly, the proportion of ethanol to total fluids consumed declined by 66.2% (20 mg/kg s.c., b.i.d.), while food consumption and body weight were unaltered. In contrast, amperozide (2 mg/kg i.p., b.i.d.) suppressed the amount of ethanol consumed by 56%, while naltrexone (5 mg/kg i.p., b.i.d.) was without effect. DOV 102,677 (40 mg/kg s.c.) inhibited reserpine-induced akinesia and ptosis, but not hypothermia in Sprague,Dawley rats, consistent with its transient inhibition of serotonin transport, and more long-lived inhibition of norepinephrine and dopamine uptake. Conclusions:, DOV 102,677 significantly decreased the volitional consumption of ethanol with minimal alterations in the intake of food or on body weight in an ethanol-preferring rat strain, suggesting that triple reuptake inhibitors may find utility in treating alcohol abuse. [source] Antitumor activity of chloroform fraction of Scutellaria barbata and its active constituentsPHYTOTHERAPY RESEARCH, Issue 9 2007Jianqing Yu Abstract Scutellaria barbata (SB) is widely used as an antitumor agent in China, but the antitumor components of SB are still unclear. The antitumor activity of various fractions of an ethanol extract of SB was studied in six human malignant cell lines. Bio-based assays showed that non-polar and low-polar solvent fractions of SB had dose-dependent cytotoxicities on six cancer cell lines. The IC50 values of these fractions on the cancer cell lines tested ranged from 16 to 70 µg/mL after 48 h of treatment. Among them, the chloroform fraction (CE-SB) had the strongest cytotoxicity on cancer cell lines with a lower cytotoxic effect on a normal liver cell line. Bel-7402 cell apoptosis induced by CE-SB was examined using Hoechst 33258 staining, agarose gel electrophoresis and flow cytometry. CE-SB dose-dependently decreased the S phase content. Treatment with CE-SB caused cytochrome c release and activation of caspase-9. The antitumor activity of CE-SB in vivo was also evaluated. At 60 mg/kg/day, CE-SB significantly inhibited the solid tumor proliferation and increased the life span of ascites tumor bearing mice (p < 0.01). CE-SB was subjected to bioassay-guided isolation of the active compounds by chromatography on silica gel and Sephadex LH-20. Phytol, wogonin, luteolin and hispidulin were obtained as cytotoxic constituents. Copyright © 2007 John Wiley & Sons, Ltd. [source] Effects of the Non-Competitive NMDA Receptor Antagonist Memantine on the Volitional Consumption of Ethanol by Alcohol-Preferring RatsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2010Gloria E. Malpass This study examined the effects of memantine, a low-affinity, open channel NMDA antagonist, on volitional consumption of ethanol by alcohol-preferring rats and potential locomotor, sedative and hypothermic effects. Volitional consumption of ethanol in a 24-hr two-choice paradigm was determined for male Myers' high-ethanol-preferring (mHEP) rats. Effects of memantine (0.3, 1.0, 3.0 and 10.0 mg/kg, i.p., b.i.d. [twice daily] for 3 days) or vehicle on volitional consumption of ethanol, proportion of ethanol to total fluids consumed, total fluid intake and consumption of food were observed. Potential sedating and locomotor effects of memantine (10.0 mg/kg, i.p., b.i.d.) were determined using an elevated plus maze and an Auto-Track Opto-Varimex activity monitoring system. Rectal temperature was measured to determine if memantine (10.0 mg/kg, i.p.) produces a hypothermic effect. The results indicate that memantine dose-dependently decreased the amount of ethanol and proportion of ethanol to total fluids consumed daily, reaching 48% and 24%, respectively, at the highest dose. These effects did not appear to be anti-caloric. Memantine (10.0 mg/kg) partially reversed both the sedation and the reductions in locomotor activity induced by ethanol. This dose did, however, produce a small, partially reversible hypothermic effect. In conclusion, memantine may decrease ethanol consumption with fewer side effects than other NMDA receptor antagonists, such as phencyclidine (PCP), MK 801 and ketamine. [source] Acute hypertension reveals depressor and vasodilator effects of cannabinoids in conscious ratsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009W-S Vanessa Ho Background and purpose:, The cardiovascular effects of cannabinoids can be influenced by anaesthesia and can differ in chronic hypertension, but the extent to which they are influenced by acute hypertension in conscious animals has not been determined. Experimental approach:, We examined cardiovascular responses to intravenous administration of anandamide and the synthetic cannabinoid, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), in conscious male Wistar rats made acutely hypertensive by infusion of angiotensin II (AII) and arginine vasopressin (AVP). Rats were chronically instrumented for measurement of arterial blood pressure and vascular conductances in the renal, mesenteric and hindquarters beds. Key results:, Anandamide dose-dependently decreased the mean arterial blood pressure of rats made hypertensive by AII-AVP infusion, but not normotensive rats. Interestingly, acute hypertension also revealed a hypotensive response to WIN55212-2, which caused hypertension in normotensive animals. The enhanced depressor effects of the cannabinoids in acute hypertension were associated with increased vasodilatation in hindquarters, renal and mesenteric vascular beds. Treatment with URB597, which inhibits anandamide degradation by fatty acid amide hydrolase, potentiated the depressor and mesenteric vasodilator responses to anandamide. Furthermore, haemodynamic responses to WIN55212-2, but not to anandamide, were attenuated by the CB1 receptor antagonist, AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide]. Conclusions and implications:, These results broadly support the literature showing that the cardiovascular effects of cannabinoids can be exaggerated in hypertension, but highlight the involvement of non-CB1 receptor-mediated mechanisms in the actions of anandamide. [source] Donitriptan, but not sumatriptan, inhibits capsaicin-induced canine external carotid vasodilatation via 5-HT1B rather than 5-HT1D receptorsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2006E Muñoz-Islas Background and purpose: It has been suggested that during a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception; hence, trigeminal inhibition may prevent this vasodilatation and abort migraine headache. This study investigated the effects of the agonists sumatriptan (5-HT1B/1D water-soluble), donitriptan (5-HT1B/1D lipid-soluble), PNU-142633 (5-HT1D water-soluble) and PNU-109291 (5-HT1D lipid-soluble) on vasodilator responses to capsaicin, , -CGRP and acetylcholine in dog external carotid artery. Experimental approach: 59 vagosympathectomized dogs were anaesthetized with sodium pentobarbitone. Blood pressure and heart rate were recorded with a pressure transducer, connected to a cannula inserted into a femoral artery. A precalibrated flow probe was placed around the common carotid artery, with ligation of the internal carotid and occipital branches, and connected to an ultrasonic flowmeter. The thyroid artery was cannulated for infusion of agonists. Key results: Intracarotid infusions of capsaicin, , -CGRP and acetylcholine dose-dependently increased blood flow through the carotid artery. These responses remained unaffected after intravenous (i.v.) infusions of sumatriptan, PNU-142633, PNU-109291 or physiological saline; in contrast, donitriptan significantly attenuated the vasodilator responses to capsaicin, but not those to , -CGRP or acetylcholine. Only sumatriptan and donitriptan dose-dependently decreased the carotid blood flow. Interestingly, i.v. administration of the antagonist, SB224289 (5-HT1B), but not of BRL15572 (5-HT1D), abolished the inhibition by donitriptan. Conclusions and implications: Our results suggest that the inhibition produced by donitriptan of capsaicin-induced external carotid vasodilatation is mainly mediated by 5-HT1B, rather than 5-HT1D, receptors, probably by a central mechanism. British Journal of Pharmacology (2006) 149, 82,91. doi:10.1038/sj.bjp.0706839 [source] | ||||||||||