DOCSLIB.ORG

Enhanced Vasorelaxant Effects of the Endocannabinoid-Like Mediator, Oleamide, in Hypertension

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Enhanced Vasorelaxant Effects of the Endocannabinoid-Like Mediator, Oleamide, in Hypertension European Journal of Pharmacology 684 (2012) 102–107 Contents lists available at SciVerse ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar Cardiovascular Pharmacology Enhanced vasorelaxant effects of the endocannabinoid-like mediator, oleamide, in hypertension Jamie J. Hopps, William R. Dunn, Michael D. Randall ⁎ Cardiovascular Research Group, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, United Kingdom article info abstract Article history: Oleamide is an endocannabinoid-like, fatty acid amide with structural similarities to anandamide. The cardio- Received 30 September 2011 vascular effects of anandamide are enhanced in hypertension and we have now examined how hypertension Received in revised form 8 March 2012 affects responses to oleamide. Vasorelaxant responses to oleamide were significantly (Pb0.001) enhanced in Accepted 9 March 2012 aortic rings from spontaneously hypertensive rats (SHRs), such that the maximal relaxation to oleamide was Available online 23 March 2012 40.3±3.5%, compared to 15.7±3.9% in normotensive Wistar Kyoto (WKY) controls. The augmented re- sponses to oleamide in SHR arteries were unaffected by either inhibition of nitric oxide synthase (300 μM Keywords: μ Endocannabinoid-like substance L-NAME) or fatty acid amide hydrolase (1 M URB597) and independent of cannabinoid CB1 receptors or Endothelium the endothelium. The enhanced responses to oleamide were opposed by pre-treatment with capsaicin Oleamide (such that Rmax was reduced to 9.8±1.5%) and this occurred independently of TRPV1 receptor and sensory Hypertension nerve activity, as the TRPV1 antagonist capsazepine (1–5 μM) and the cation channel inhibitor ruthenium Capsaicin red (10 μM) had no effect on the responses to oleamide. However, inhibition of cyclooxygenase (10 μM indo- Cyclooxygenase methacin) enhanced the responses in the WKY aortae, such that the responses were comparable to those in the SHR. The results suggest that the cyclooxygenase pathway has a role in modulating vasorelaxation caused by oleamide in normotensive aortae and that this is lost in hypertension, possibly as an adaptation to the in- crease in blood pressure. © 2012 Elsevier B.V. All rights reserved. 1. Introduction mediated activity and the enhanced responses to anandamide in hy- pertension was proposed. The cardiovascular effects of cannabinoids are the subject of grow- Wheal and Randall (2009) examined the vascular effects of ananda- ing interest (Randall et al., 2004). The endocannabinoid, anandamide, mide in SHRs and in rats rendered hypertensive by chronic nitric oxide can have depressor effects (Ho and Gardiner, 2009; Varga et al., 1996; (NO) synthase inhibition with L-NAME. Anandamide caused enhanced Zakrzeska et al., 2010) and its production is upregulated in certain vasorelaxation in aortic rings from SHRs compared to normotensive pathophysiological states (Batkai et al., 2001; Caraceni et al., 2009; WKY control preparations. The increased effects of anandamide were 2010). The CB1 receptor and TRPV1 receptor have both been implicat- attributed to endothelium-dependent mechanisms. Conversely, anan- ed in the hypotensive effects of anandamide (Batkai et al., 2004; Lake damide caused decreased vasorelaxant effects in perfused mesenteric et al., 1997; Li et al., 2003; Wang et al., 2005). Li et al. (2003) showed beds taken from SHRs attributed to decreased NO-dependent vasore- that depressor responses to the stable analogue of anandamide, laxation (Wheal and Randall, 2009). In perfused mesenteric beds, methanandamide, were enhanced in spontaneously hypertensive from rats following chronic NO synthase inhibition, anandamide caused rats (SHRs) compared to normotensive Wistar Kyoto (WKY) controls. enhanced vasorelaxation (Mendizabal et al., 2001; Wheal et al., 2007). Antagonism of transient receptor potential vanilloid receptor type 1 The enhanced responses to anandamide in L-NAME treated rats were (TRPV1) receptors reduced this hypotensive response which was capsaicin-sensitive, suggesting an increase in sensory nerve activity. also associated with an upregulation of calcitonin gene-related pep- This was further supported by the finding that capsaicin was shown to tide activity in SHRs. Similarly, Wang et al. (2005) described enhanced cause enhanced relaxation in mesenteric beds from rats made hyper- vasorelaxation to anandamide in mesenteric beds in a salt-sensitive tensive by chronic NO inhibition. rat model of hypertension. Increased depressor effects were inhibited Oleamide (cis-9 10 octadecenoamide) is a fatty acid primary amide, by antagonism of TRPV1 and CB1 receptors, and TRPV1 expression was which was originally derived from sleep-deprived cats (Cravatt et al., upregulated in hypertension. Thus, a link between sensory nerve- 1995) and shares structural similarities with anandamide. In addition, oleamide is sensitive to FAAH degradation, exerts cannabimimetic effects in animal models and has been shown to be a selective agonist for canna- ⁎ Corresponding author. Tel.: +44 115 82 30185; fax: +44 115 82 30141. binoid CB1 receptors in vitro (Boger et al., 2000; Leggett et al., 2004). To E-mail address: [email protected] (M.D. Randall). date, oleamide has been shown to cause vasorelaxation in rat small 0014-2999/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2012.03.027 J.J. Hopps et al. / European Journal of Pharmacology 684 (2012) 102–107 103 mesenteric arteries (Hoi and Hiley, 2006; Sudhahar et al., 2009). Hoi CB1 antagonist (O'Sullivan et al., 2005). Some experiments were carried and Hiley (2006) demonstrated that the vasorelaxation was partly out in the presence of URB597 (1 μM), a fatty acid amide hydrolase endothelium-dependent, capsaicin-sensitive and involved calcium- (FAAH) inhibitor (Ho and Randall, 2007). activated potassium channels. It was postulated that oleamide may act via a novel cannabinoid receptor. Cannabinoid CB1 receptor and TRPV1 re- 2.3. Drugs and reagents ceptor activation have also been implicated in oleamide-induced vasore- laxation in the rat mesenteric resistance arteries (Sudhahar et al., 2009). Oleamide (cis-9 10 octadecenoamide) and AM251 (N-(piperidin- In light of the enhanced cardiovascular effects of anandamide in 1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole- hypertension, the major aim of the current study was to investigate 3-carboxamide) were obtained from Tocris Co. (UK). All other drugs the vasorelaxant effects of oleamide in the SHR model of hypertension. used in this investigation were purchased from Sigma Chemicals Co. (UK). Capsaicin and capsazepine were dissolved in ethanol at stock 2. Materials and methods concentrations of 10 mM. DMSO (Dimethyl sulfoxide) was used to dis- solve stock solutions of oleamide and AM251 at 10 mM and URB597 2.1. Animals (cyclohexylcarbamic acid 3′-carbamoyl-biphenyl-3-yl ester) at 1 mM. G All other drugs were dissolved in distilled water. L-NAME (N -Nitro- – – Male SHR and WKY rats (Charles River UK) (250 350 g; aged 12 L-arginine methyl ester hydrochloride), indomethacin, AM251 and 18 weeks) were used during this investigation. All rats used were capsazepine were incubated for approximately 20 min before pre- housed at the Biomedical Services Unit, University of Nottingham contraction of vessels with methoxamine. Ruthenium red (ammoniated with a 12 h light/dark cycle and in temperature-controlled conditions. ruthenium oxychloride) and niflumic acid were incubated for 30 min, while URB597 was incubated for 10 min before pre-contraction. 2.2. Methods 2.4. Statistical analysis 2.2.1. Aortic rings Rats were stunned by a blow to the back of the head and killed by All responses were expressed as mean data with the associated exsanguination. These procedures are in accordance with UK legisla- standard error of the mean (S.E.M). The GraphPad Prism 5.0 software tion and have been approved by institutional ethical review. This (San Diego, CA) was used to plot mean data as sigmoidal concentra- was followed by the removal of the abdominal aorta. Subsequently tion–response curves. The curves were used to determine potency the aorta was cleared of all connective tissue by blunt dissection and (pEC which is the negative log of the concentration causing 50% of cut into segmental rings (3 mm–5 mm). The aortic rings were placed 50 the maximal relaxation) and maximal response (R ) values. Statis- between two metal wires, with one being fixed and the other attached max tical significance was determined using Student's t-test between two via thread to an isometric transducer and placed in 50 ml organ baths. data sets or one-way ANOVA when comparing multiple data-sets. The organ baths were filled with modified Krebs'–Henseleit buffer solution (NaCl 118, KCl 4.7, MgSO4 1.2, KH2PO4 4.2, NaHCO3 25, 3. Results D-glucose 10, CaCl2 2 (mM)) at 37 °C and gassed (5% CO²/95% O²). The aortic rings were allowed to equilibrate to an optimal baseline tension of 9.8 mN for 1 h. Tension was measured by a Leitica force 3.1. Vascular responses to oleamide in isolated aortae from SHR and WKY transducer coupled to an ADInstruments MacLab recording system. rats Vessels were pre-contracted with the α1-adrenoceptor agonist, methoxamine (10 μM), to achieve submaximal contraction (ca. 10 mN) Oleamide caused concentration-dependent vasorelaxation of aor- prior to the addition of oleamide (10 nM–10 μM), which was added cu- tic segments from both SHR and WKY rats. Maximal relaxation was fi b mulatively at 5 minute intervals to construct concentration–response signi cantly (P 0.001) greater in SHRs (Rmax =40.3±3.5%, n=6) curves.Toinvestigatetheroleofsensorynerves,somevesselsweresub- when compared to that in aortae from WKY rats (Rmax =15.7±3.9%, jected to pre-treatment with 10 μM capsaicin for 1 h, which desensitises n=6) (Fig. 1). The potency of oleamide was comparable between SHR (pEC50 =6.49±0.55, n=6) and WKY aortae (pEC50 =6.08± the TRPV1 receptors and depletes the neurotransmitters (Zygmunt et al., 1999). Capsaicin pre-treatment was followed by a 20 min wash-out 0.55, n=6).
Load more

Recommended publications
  • N-Acyl-Dopamines: Novel Synthetic CB1 Cannabinoid-Receptor Ligands
    Biochem. J. (2000) 351, 817–824 (Printed in Great Britain) 817 N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo Tiziana BISOGNO*, Dominique MELCK*, Mikhail Yu. BOBROV†, Natalia M. GRETSKAYA†, Vladimir V. BEZUGLOV†, Luciano DE PETROCELLIS‡ and Vincenzo DI MARZO*1 *Istituto per la Chimica di Molecole di Interesse Biologico, C.N.R., Via Toiano 6, 80072 Arco Felice, Napoli, Italy, †Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, R. A. S., 16/10 Miklukho-Maklaya Str., 117871 Moscow GSP7, Russia, and ‡Istituto di Cibernetica, C.N.R., Via Toiano 6, 80072 Arco Felice, Napoli, Italy We reported previously that synthetic amides of polyunsaturated selectivity for the anandamide transporter over FAAH. AA-DA fatty acids with bioactive amines can result in substances that (0.1–10 µM) did not displace D1 and D2 dopamine-receptor interact with proteins of the endogenous cannabinoid system high-affinity ligands from rat brain membranes, thus suggesting (ECS). Here we synthesized a series of N-acyl-dopamines that this compound has little affinity for these receptors. AA-DA (NADAs) and studied their effects on the anandamide membrane was more potent and efficacious than anandamide as a CB" transporter, the anandamide amidohydrolase (fatty acid amide agonist, as assessed by measuring the stimulatory effect on intra- hydrolase, FAAH) and the two cannabinoid receptor subtypes, cellular Ca#+ mobilization in undifferentiated N18TG2 neuro- CB" and CB#. NADAs competitively inhibited FAAH from blastoma cells. This effect of AA-DA was counteracted by the l µ N18TG2 cells (IC&! 19–100 M), as well as the binding of the CB" antagonist SR141716A.
    [Show full text]
  • The Endogenous Cannabinoid 2-Arachidonoylglycerol Is Intravenously Self-Administered by Squirrel Monkeys
    The Journal of Neuroscience, May 11, 2011 • 31(19):7043–7048 • 7043 Brief Communications The Endogenous Cannabinoid 2-Arachidonoylglycerol Is Intravenously Self-Administered by Squirrel Monkeys Zuzana Justinova´,1,2 Sevil Yasar,3 Godfrey H. Redhi,1 and Steven R. Goldberg1 1Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, 2Maryland Psychiatric Research Centre, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21228, and 3Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224 Two endogenous ligands for cannabinoid CB1 receptors, anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol (2-AG), have been identified and characterized. 2-AG is the most prevalent endogenous cannabinoid ligand in the brain, and electrophysiological studies suggest 2-AG, rather than anandamide, is the true natural ligand for cannabinoid receptors and the key endocannabinoid involved in retrograde signaling in the brain. Here, we evaluated intravenously administered 2-AG for reinforcing effects in nonhuman primates. Squirrel monkeys that previously self-administered anandamide or nicotine under a fixed-ratio schedule with a 60 s timeout after each injection had their self-administration behavior extinguished by vehicle substitution and were then given the opportunity to self-administer 2-AG. Intravenous 2-AG was a very effective reinforcer of drug-taking behavior, maintaining higher numbers of self-administered injections per session and higher rates of responding than vehicle across a wide range of doses. To assess involvement of CB1 receptors in the reinforcing effects of 2-AG, we pretreated monkeys with the cannabinoid CB1 receptor inverse agonist/antagonist rimonabant [N-piperidino-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide].
    [Show full text]
  • The Cannabinoid WIN 55,212-2 Prevents Neuroendocrine Differentiation of Lncap Prostate Cancer Cells
    OPEN Prostate Cancer and Prostatic Diseases (2016) 19, 248–257 www.nature.com/pcan ORIGINAL ARTICLE The cannabinoid WIN 55,212-2 prevents neuroendocrine differentiation of LNCaP prostate cancer cells C Morell1, A Bort1, D Vara2, A Ramos-Torres1, N Rodríguez-Henche1 and I Díaz-Laviada1 BACKGROUND: Neuroendocrine (NE) differentiation represents a common feature of prostate cancer and is associated with accelerated disease progression and poor clinical outcome. Nowadays, there is no treatment for this aggressive form of prostate cancer. The aim of this study was to determine the influence of the cannabinoid WIN 55,212-2 (WIN, a non-selective cannabinoid CB1 and CB2 receptor agonist) on the NE differentiation of prostate cancer cells. METHODS: NE differentiation of prostate cancer LNCaP cells was induced by serum deprivation or by incubation with interleukin-6, for 6 days. Levels of NE markers and signaling proteins were determined by western blotting. Levels of cannabinoid receptors were determined by quantitative PCR. The involvement of signaling cascades was investigated by pharmacological inhibition and small interfering RNA. RESULTS: The differentiated LNCaP cells exhibited neurite outgrowth, and increased the expression of the typical NE markers neuron-specific enolase and βIII tubulin (βIII Tub). Treatment with 3 μM WIN inhibited NK differentiation of LNCaP cells. The cannabinoid WIN downregulated the PI3K/Akt/mTOR signaling pathway, resulting in NE differentiation inhibition. In addition, an activation of AMP-activated protein kinase (AMPK) was observed in WIN-treated cells, which correlated with a decrease in the NE markers expression. Our results also show that during NE differentiation the expression of cannabinoid receptors CB1 and CB2 dramatically decreases.
    [Show full text]
  • 208614788.Pdf
    0022-3565/02/3013-1020–1024$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 301, No. 3 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 0/986104 JPET 301:1020–1024, 2002 Printed in U.S.A. Characterization of a Novel Endocannabinoid, Virodhamine, with Antagonist Activity at the CB1 Receptor AMY C. PORTER, JOHN-MICHAEL SAUER, MICHAEL D. KNIERMAN, GERALD W. BECKER, MICHAEL J. BERNA, JINGQI BAO, GEORGE G. NOMIKOS, PETRA CARTER, FRANK P. BYMASTER, ANDREA BAKER LEESE, and CHRISTIAN C. FELDER Lilly Research Laboratories, Neuroscience Division (A.C.P., G.G.N., P.C., F.P.B., A.B.L., C.C.F.), Drug Disposition (J.-M.S., M.J.B., J.B.), and Research Technologies and Proteins (M.D.K., G.W.B.), Eli Lilly & Co., Lilly Corporate Center, Indianapolis, Indiana Received December 19, 2001; accepted February 18, 2002 This article is available online at http://jpet.aspetjournals.org Downloaded from ABSTRACT The first endocannabinoid, anandamide, was discovered in rodhamine concentrations were 2- to 9-fold higher than anan- 1992. Since then, two other endocannabinoid agonists have damide. In contrast to previously described endocannabinoids, been identified, 2-arachidonyl glycerol and, more recently, no- virodhamine was a partial agonist with in vivo antagonist activ- ladin ether. Here, we report the identification and pharmaco- ity at the CB1 receptor. However, at the CB2 receptor, vi- 14 logical characterization of a novel endocannabinoid, vi- rodhamine acted as a full agonist. Transport of [ C]anandam- jpet.aspetjournals.org rodhamine, with antagonist properties at the CB1 cannabinoid ide by RBL-2H3 cells was inhibited by virodhamine.
    [Show full text]
  • Beneficial Changes in Rat Vascular Endocannabinoid System In
    International Journal of Molecular Sciences Article Beneficial Changes in Rat Vascular Endocannabinoid System in Primary Hypertension and under Treatment with Chronic Inhibition of Fatty Acid Amide Hydrolase by URB597 Marta Baranowska-Kuczko 1,2,* , Hanna Kozłowska 1, Monika Kloza 1, Ewa Harasim-Symbor 3, Michał Biernacki 4 , Irena Kasacka 5 and Barbara Malinowska 1 1 Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland; [email protected] (H.K.); [email protected] (M.K.); [email protected] (B.M.) 2 Department of Clinical Pharmacy, Medical University of Białystok, ul. Mickiewicza 2A, 15-222 Białystok, Poland 3 Department of Physiology, Medical University of Białystok, ul. Mickiewicza 2C, 15-222 Białystok, Poland; [email protected] 4 Department of Analytical Chemistry, Medical University of Białystok, ul. Mickiewicza 2D, 15-222 Białystok, Poland; [email protected] 5 Department of Histology and Cytophysiology, Medical University of Białystok, ul. Mickiewicza 2C, 15-222 Białystok, Poland; [email protected] * Correspondence: [email protected]; Tel./Fax: +48-85-74-856-99 Citation: Baranowska-Kuczko, M.; Abstract: Our study aimed to examine the effects of hypertension and the chronic administration of Kozłowska, H.; Kloza, M.; the fatty acid amide hydrolase (FAAH) inhibitor URB597 on vascular function and the endocannabi- Harasim-Symbor, E.; Biernacki, M.; noid system in spontaneously hypertensive rats (SHR). Functional studies were performed on small Kasacka, I.; Malinowska, B. Beneficial mesenteric G3 arteries (sMA) and aortas isolated from SHR and normotensive Wistar Kyoto rats Changes in Rat Vascular (WKY) treated with URB597 (1 mg/kg; twice daily for 14 days).
    [Show full text]
  • Anandamide-Mediated CB1/CB2 Receptor-Independent NO Production in Rabbit Aortic Endothelial Cells
    JPET Fast Forward. Published on March 22, 2007 as DOI: 10.1124/jpet.106.117549 JPET FastThis article Forward. has not beenPublished copyedited on and Marchformatted. 22, The 2007 final version as DOI:10.1124/jpet.106.117549 may differ from this version. JPET # 117549 Anandamide-mediated CB1/CB2 receptor-independent NO production in rabbit aortic endothelial cells LaTronya McCollum, Allyn C. Howlett and Somnath Mukhopadhyay1 Neuroscience of Drug Abuse Research Program Julius. L. Chambers Biomedical/Biotechnology Research Institute North Carolina Central University, Durham, NC 27707 Downloaded from jpet.aspetjournals.org at ASPET Journals on September 30, 2021 1 Copyright 2007 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on March 22, 2007 as DOI: 10.1124/jpet.106.117549 This article has not been copyedited and formatted. The final version may differ from this version. JPET # 117549 Running title: Novel Anandamide receptor mediated eNOS activation 1Corresponding author Somnath Mukhopadhyay, Ph.D. Neuroscience of Drug Abuse Research Program J. L. Chambers Biomedical/Biotechnology Research Institute North Carolina Central University Downloaded from 700 George Street, Durham, NC 27707 Ph # (919) 530-7762 FAX (919) 530-7760 jpet.aspetjournals.org [email protected] Abbreviations used are: Abn-CBD, abnormal cannabidiol; DAF-DA, 4-amino-5- methylamino-2',7'-difluorofluorescein diacetate; ECL, enhanced chemiluminescence; eNOS, at ASPET Journals on September 30, 2021 endothelial NO synthase; MAPK, mitogen-activated protein kinase; PCR, polymerase chain reaction; PKA, cyclic AMP-dependent protein kinase; PI3-kinase, phosphatidylinositol 3-kinase; PVDF, polyvinylidene difluoride; PTX, pertussis toxin; RAEC, rabbit aortic endothelial cells; RT-PCR, reverse transcription-polymerase chain reaction; SDS-PAGE, sodium dodecyl sulfate- polyacrylamide gel electrophoresis.
    [Show full text]
  • Mice Display Differential Tolerance, Dependence, and Cannabinoid Receptor Adaptation After D9-Tetrahydrocannabinol and Anandamide Administration
    Neuropsychopharmacology (2010) 35, 1775–1787 & 2010 Nature Publishing Group All rights reserved 0893-133X/10 $32.00 www.neuropsychopharmacology.org FAAHÀ/À Mice Display Differential Tolerance, Dependence, and Cannabinoid Receptor Adaptation after D9-Tetrahydrocannabinol and Anandamide Administration 1 1 1 2 1 Katherine W Falenski , Andrew J Thorpe , Joel E Schlosburg , Benjamin F Cravatt , Rehab A Abdullah , 1 1 1 1 Tricia H Smith , Dana E Selley , Aron H Lichtman and Laura J Sim-Selley* 1Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA; 2 The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA 9 Repeated administration of D -tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa, induces profound tolerance that correlates with desensitization and downregulation of CB1 cannabinoid receptors in the CNS. However, the consequences of repeated administration of the endocannabinoid N-arachidonoyl ethanolamine (anandamide, AEA) on cannabinoid receptor regulation are unclear because of its rapid metabolism by fatty acid amide hydrolase (FAAH). FAAHÀ/À mice dosed subchronically with equi-active maximally effective doses of AEA or THC displayed greater rightward shifts in THC dose–effect curves for antinociception, catalepsy, and hypothermia than in AEA dose–effect curves. Subchronic THC significantly attenuated agonist- 35 3 stimulated [ S]GTPgS binding in brain
    [Show full text]
  • Cannabinoid CB1 and CB2 Receptors Antagonists AM251 and AM630
    Pharmacological Reports 71 (2019) 82–89 Contents lists available at ScienceDirect Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep Original article Cannabinoid CB1 and CB2 receptors antagonists AM251 and AM630 differentially modulate the chronotropic and inotropic effects of isoprenaline in isolated rat atria Jolanta Weresa, Anna Pe˛dzinska-Betiuk, Rafał Kossakowski, Barbara Malinowska* Department of Experimental Physiology and Pathophysiology, Medical University of Bialystok, Białystok, Poland A R T I C L E I N F O A B S T R A C T Article history: Background: Drugs targeting CB1 and CB2 receptors have been suggested to possess therapeutic benefit in Received 28 May 2018 cardiovascular disorders associated with elevated sympathetic tone. Limited data suggest cannabinoid Received in revised form 31 July 2018 ligands interact with postsynaptic β-adrenoceptors. The aim of this study was to examine the effects of Accepted 14 September 2018 CB1 and CB2 antagonists, AM251 and AM630, respectively, at functional cardiac β-adrenoceptors. Available online 17 September 2018 Methods: Experiments were carried out in isolated spontaneously beating right atria and paced left atria where inotropic and chronotropic increases were induced by isoprenaline and selective agonists of β1 and Keywords: β -adrenergic receptors. β-Adrenoceptor 2 Results: We found four different effects of AM251 and AM630 on the cardiostimulatory action of Cannabinoid receptor m AM251 isoprenaline: (1) both CB receptor antagonists 1 M enhanced the isoprenaline-induced increase in atrial AM630 rate, and AM630 1 mM enhanced the inotropic effect of isoprenaline; (2) AM251 1 mM decreased the Atria efficacy of the inotropic effect of isoprenaline; (3) AM251 0.1 and 3 mM and AM630 3 mM reduced the isoprenaline-induced increases in atrial rate; (4) AM630 0.1 and 3 mM enhanced the inotropic effect of isoprenaline, which was not changed by the same concentrations of AM251.
    [Show full text]
  • Discriminative Stimulus Properties of 3-Substituent Rimonabant Analogs
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2011 Discriminative stimulus properties of 3-substituent rimonabant analogs D. Matthew Walentiny Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Psychology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/223 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. DISCRIMINATIVE STIMULUS PROPERTIES OF 3-SUBSTITUENT RIMONABANT ANALOGS A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. by David Matthew Walentiny Master of Science, Virginia Commonwealth University, 2008 Director: Jenny L. Wiley, Ph.D. Professor Department of Pharmacology & Toxicology Virginia Commonwealth University Richmond, Virginia May, 2011 ii Acknowledgments There are a number of people who deserve recognition for supporting my efforts on this dissertation and my time in graduate school. First, I wish to extend my heartfelt gratitude to my advisor, Dr. Jenny Wiley, for offering me a position in her lab and all the training and support I have received from her since. I am also indebted to Dr. Robert Vann for taking a vested interest in my success and an active role in my development from the moment I began graduate school. I would also like to thank Dr. Joseph Porter for giving me my first research opportunity as an undergraduate student working in his lab, and for subsequently serving as my master’s thesis advisor.
    [Show full text]
  • Glycine Receptors in CNS Neurons As a Target for Nonretrograde Action of Cannabinoids
    The Journal of Neuroscience, August 17, 2005 • 25(33):7499–7506 • 7499 Cellular/Molecular Glycine Receptors in CNS Neurons as a Target for Nonretrograde Action of Cannabinoids Natalia Lozovaya,1* Natalia Yatsenko,1* Andrey Beketov,1 Timur Tsintsadze,1 and Nail Burnashev2 1Department of Cellular Membranology, Bogomoletz Institute of Physiology, 01204 Kiev, Ukraine, and 2Departments of Experimental Neurophysiology and Medical Pharmacology, Center for Neurogenomics and Cognitive Research, and Vrije Universiteit Medical Center, Vrije Universiteit Amsterdam, 1081HV Amsterdam, The Netherlands At many central synapses, endocannabinoids released by postsynaptic cells act retrogradely on presynaptic G-protein-coupled cannabi- noid receptors to inhibit neurotransmitter release. Here, we demonstrate that cannabinoids may directly affect the functioning of inhibitory glycine receptor (GlyR) channels. In isolated hippocampal pyramidal and Purkinje cerebellar neurons, endogenous cannabi- noidsanandamideand2-arachidonylglycerol,appliedatphysiologicalconcentrations,inhibitedtheamplitudeandalteredthekineticsof rise time, desensitization, and deactivation of the glycine-activated current (IGly ) in a concentration-dependent manner. These effects of cannabinoids were observed in the presence of cannabinoid CB1/CB3, vanilloid receptor 1 antagonists, and the G-protein inhibitor ␤ GDP S, suggesting a direct action of cannabinoids on GlyRs. The effect of cannabinoids on IGly desensitization was strongly voltage dependent. We also demonstrate that, in the presence of a GABAA receptor antagonist, GlyRs may contribute to the generation of seizure-like activity induced by short bursts (seven stimuli) of high-frequency stimulation of inputs to hippocampal CA1 region, because this activity was diminished by selective GlyR antagonists (strychnine and ginkgolides B and J). The GlyR-mediated rhythmic activity was also reduced by cannabinoids (anandamide) in the presence of a CB1 receptor antagonist.
    [Show full text]
  • Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products
    International Journal of Molecular Sciences Review Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products Dongchen An, Steve Peigneur , Louise Antonia Hendrickx and Jan Tytgat * Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg, O&N 2, Herestraat 49, P.O. Box 922, 3000 Leuven, Belgium; [email protected] (D.A.); [email protected] (S.P.); [email protected] (L.A.H.) * Correspondence: [email protected] Received: 12 June 2020; Accepted: 15 July 2020; Published: 17 July 2020 Abstract: Cannabinoid receptors (CB1 and CB2), as part of the endocannabinoid system, play a critical role in numerous human physiological and pathological conditions. Thus, considerable efforts have been made to develop ligands for CB1 and CB2, resulting in hundreds of phyto- and synthetic cannabinoids which have shown varying affinities relevant for the treatment of various diseases. However, only a few of these ligands are clinically used. Recently, more detailed structural information for cannabinoid receptors was revealed thanks to the powerfulness of cryo-electron microscopy, which now can accelerate structure-based drug discovery. At the same time, novel peptide-type cannabinoids from animal sources have arrived at the scene, with their potential in vivo therapeutic effects in relation to cannabinoid receptors. From a natural products perspective, it is expected that more novel cannabinoids will be discovered and forecasted as promising drug leads from diverse natural sources and species, such as animal venoms which constitute a true pharmacopeia of toxins modulating diverse targets, including voltage- and ligand-gated ion channels, G protein-coupled receptors such as CB1 and CB2, with astonishing affinity and selectivity.
    [Show full text]
  • (Cannabimimetics) in Serum, Hair, and Urine by Rapid and Sensitive HPLC Tandem Mass Spectrometry Screenings: Overview and Experience from Routine Testing
    DOI 10.1515/labmed-2012-0059 J Lab Med 2013; 37(4): 167–180 Drug Monitoring und Toxikologie/Drug Monitoring and Toxicology Redaktion: W. Steimer August Goebel , Marcus Boehm , Hartmut Kirchherr and W. Nikolaus K ü hn-Velten * Simultaneous identification and quantification of synthetic cannabinoids (cannabimimetics) in serum, hair, and urine by rapid and sensitive HPLC tandem mass spectrometry screenings: overview and experience from routine testing Simultane Identifizierung und Quantifizierung synthetischer Cannabinoide (Cannabimimetika) in Serum, Haar und Urin mittels schneller und sensitiver HPLC-Tandem- Massenspektrometrie-Screenings: Ü bersicht und Erfahrungen aus der Routineanalytik Abstract: Detection and quantification of synthetic can- Keywords: cannabimimetic; cannabinoid receptor nabinoids (synonym: cannabimimetics) used as a substi- agonist; designer drug; drug screening; LC-MS/MS; spice; tute for natural cannabis has been a real toxicological and synthetic cannabinoid; tandem-mass spectrometry. forensic issue since 2008. On the basis of a short overview of the pharmacological principle, chemical classification, Zusammenfassung: Der Nachweis und die Quantifizierung and legal situation in Germany, the development of sev- synthetischer Cannabinoide (Synonym: Cannabimime- eral analytical and screening approaches is presented. tika), die in Form von R ä uchermischungen als Cannabis- The paper further describes and validates a novel method ersatz in Gebrauch sind, ist seit 2008 ein aktuelles Thema for the simultaneous identification and quantification of der toxikologischen und forensischen Analytik. Auf der JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH- Grundlage einer kurzen Ü bersicht ü ber das pharma- 200, JWH-210, JWH-250, WIN48,098, WIN55,212-2, AM-694 kologische Prinzip, die chemische Klassifikation und die and CP47,497 by means of liquid chromatography-tandem gesetzliche Situation in Deutschland wird die Entwick- mass spectrometry (LC-MS/MS) in human serum and lung verschiedener Screeningmethoden dargestellt.
    [Show full text]