Effects of 6-hydroxydopamine on pre- and post-junctional 5-HT1-like receptor-mediated responses in dog saphenous vein.
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.
SmithKline Beecham Pharmaceuticals, Welwyn, Herts, UK.
A D
AD
Medhurst
G E
GE
Novotny
S G
SG
Parker
N M
NM
Deighton
A J
AJ
Kaumann
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008853:Microscopy; D008854:Microscopy, Electron; D009451:Neuroeffector Junction / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D016627:Oxidopamine / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012501:Saphenous Vein / Q000187:drug effects / Q000294:innervation*; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D011985:Receptors, Serotonin; D012701:Serotonin; D016627:Oxidopamine; D000242:Cyclic AMP; D011188:Potassium; D009638:Norepinephrine