Effects of S9977 on adrenergic neurotransmission |
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| Institution: | 1. Faculty of Veterinary Science, The University of Sydney, NSW 2006, Australia;2. Centre for Veterinary Education, The University of Sydney, NSW 2006, Australia;1. University of Tiradentes (Unit), Biotechnological Postgraduate Program, Av Murilo Dantas, 300, 49010-390 Aracaju, Brazil;2. Institute of Technology and Research (ITP), Nanomedicine and Nanotechnology Laboratory (LNMed), Av Murilo Dantas, 300, 49010-390 Aracaju, Brazil;3. Department of Morphology, Federal University of Sergipe (UFS), Avenida Marechal Rondon, 49100-000 São Cristovão, Brazil;4. Department of Exact and Earth Sciences, Federal University of São Paulo, Rua Arthur Riedel, 275, Diadema 09972-270, Brazil;5. Laboratory of Biomaterials and Nanotechnology for the Development and Evaluation of Bioactive Substances, University of Sorocaba, Rodovia Raposo Tavares Km 925, 18023-000 Sorocaba, São Paulo, Brazil;6. Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain;7. Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain;8. Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal;9. CEB – Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal;10. Tiradentes Institute, 150 Mt Vernon St, Dorchester, MA 02125, USA;1. Center for Research Development and Evolution of Pharmaceutical Excipients and Generic Drugs, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China;2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China;1. Pharmacy Department, Federal University of Sergipe, São Cristóvão, SE, Brazil;2. Instituto de Tecnologia e Pesquisa (ITP), Tiradentes University, Aracaju, SE, Brazil;3. Laboratory of Biomaterial and Nanotechnology, University of Sorocaba, Sorocaba, SP, Brazil;4. Chemistry Department, Federal University of Sergipe, São Cristóvão, SE, Brazil;1. ChEM-H Institute, Stanford University, Stanford, CA 94305, USA |
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| Abstract: | 1. Experiments were designed to determine whether or not the putative promnesic drug S9977 (1,3,7-trimethyl 8-3-(4-diethylaminocarbonyl-1-piperazinyl) 1-propyl]-3,7-dihydro (1H)2,6-purinedione hydrochloride) affects peripheral adrenergic neurotransmission.2. Rings of canine saphenous veins (without endothelium) were suspended for isometric tension recording in conventional organ chambers filled with modified Krebs-Ringer bicarbonate solution. The adrenergic nerve endings were activated with electrical impulses (9 V, 2 msec, 0.25–8 Hz).3. At 10−5 M, S9977 significantly reduced the contraction to 0.25, 0.5 and 1 Hz. The compound did not affect the response to higher stimulation frequencies or to exogenous noradrenaline. The inhibitory effect of S9977 was prevented by methiothepin, and not affected by atropine or 8-phenyltheophylline.4. Helical strips of canine saphenous veins were incubated with 3H]noradrenaline and suspended for superfusion and isometric tension recording. Under basal conditions, S9977 (10−4 M) augmented, the total 3H-overflow which was due mainly to an augmented overflow of 3H]deoxyphenylglycol (DOPEG); the extraneuronal metabolites 3,4-dihydromandelic acid (DOMA) and 3-methoxy-4-hydroxymandelic acid (VMA) were reduced.5. During electrical stimulation of the adrenergic nerves, S9977 (10−4 M) augmented the total 3H-overflow but reduced the contractile response; the evoked overflow of 3H]noradrenaline was not significantly affected.6. These experiments suggest that S9977 the displacement of noradrenaline from the adrenergic varicosities; most of the displaced transmitter is metabolized by intraneuronal monoamine oxidase before reaching the junctional cleft. In addition, S9977 exerts an inhibitory effect on the extraneuronal metabolism of catecholamines. S9977 does not inhibit the exocytotic release of the adrenergic neurotransmitter. |
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