Effects of 6-hydroxydopamine on pre- and post-junctional 5-HT1-like receptor-mediated responses in dog saphenous vein |
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Authors: | Andrew D. Medhurst Gerd E. K. Novotny Stephen G. Parker Nicola M. Deighton Alberto J. Kaumann |
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Affiliation: | (1) SmithKline Beecham Pharmaceuticals, The Frythe, AL6 9AR Welwyn, Herts, UK;(2) Medizinische Einrichtungen, Anatomisches Institut, Abteilung für Neuroanatomie, Heinrich-Heine-Universität, Moorenstrasse 5, W-4000 Düsseldorf 1, FRG;(3) Clinical Pharmacology Unit, Cambridge University, Addenbrooke's Hospital, Hills Road, CB2 2QQ Cambridge, UK |
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Abstract: | Summary To investigate whether 5-HT1-like receptor-mediated inhibition of adenosine 3 : 5-cyclic monophosphate (cyclic AMP) accumulation occurs in nerves or smooth muscle of saphenous vein, infusions of 6-hydroxydopamine (6-OHDA) were administered to dogs with the aim of inducing sympathetic nerve damage. The effects of 6-OHDA on other 5-HT1-like receptor-mediated responses at the pre- and post-junctional level were investigated for comparison by studying 5-hydroxytryptamine (5-HT)-induced inhibition of 3H-noradrenaline release and contraction of smooth muscle respectively.Disruption of nerve function by 6-OHDA was revealed by the lack of catecholaminergic fluorescence and neurogenic contractile responses in saphenous veins from dogs treated with 6-OHDA. In addition, severe impairment of neuronal uptake mechanisms were apparent since basal efflux of 3H-noradrenaline, electrically-evoked release of 3H-noradrenaline and remaining 3H-noradrenaline content were considerably reduced. Some 3H-noradrenaline was taken up and released in 6-OHDA treated tissues which is consistent with the existence of nerve varicosities resistant to the present dosing regime of 6-OHDA, an observation substantiated by electron microscopy studies showing inconsistent lesions of nerve terminals.6-OHDA pre-treatment potentiated the smooth muscle contractile responses mediated by 5-HT1-like receptors as well as potentiating 5-HT-evoked inhibition of prostaglandin E2-stimulated cyclic AMP accumulation. It did not, however, affect 5-HT-induced inhibition of 3H-noradrenaline release. The present results suggest that inhibition of cyclic AMP accumulation by 5-HT occurs predominantly in smooth muscle.Correspondence to A. J. Kaumann at the above address |
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Keywords: | Dog saphenous vein Pre- and post-junctional 5-HT1-like receptors Noradrenaline release Smooth muscle contraction Cyclic AMP inhibition 6-Hydroxydopamine |
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