Simultaneous measurement of [3H]noradrenaline release and neurogenic contraction under identical conditions, to determine the prejunctional inhibitory effects of SKF 99101H and BRL 56905 in dog saphenous vein.
Using a tissue bath system which allowed the simultaneous measurement of electrically-induced [3H]noradrenaline release and neurogenic contraction under identical conditions, we investigated the prejunctional inhibitory activity of the selective 5-HT(1D/1B) receptor agonists BRL 56905 ((+/-)-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole) and SKF 99101H (3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate), compared to sumatriptan and 5-HT. Transmural electrical stimulation (2 Hz) of dog saphenous vein induced consistent increases in [3H]noradrenaline release as well as reproducible contractile responses (<10% decrease over four stimulation periods). BRL 56905, SKF 99101H, sumatriptan and 5-HT (60 nM-6 microM) inhibited electrically-evoked [3H]noradrenaline release and neurogenic contractile responses in dog saphenous vein. However, despite being measured under identical conditions, the inhibition of [3H]noradrenaline release was consistently greater than the inhibition of neurogenic contraction induced by a particular concentration of agonist, suggesting that neurogenic contractile responses in dog saphenous vein result from the combined release of noradrenaline and other non-noradrenergic neurotransmitters. Under the present assay conditions, since the agonists produced only small (BRL 56905, sumatriptan and 5-HT) or marginal (SKF 99101H) contractile responses, it is unlikely that this is the cause of the discrepancy observed between inhibition of release and inhibition of contraction. The inhibitory effects of BRL 56905, sumatriptan and 5-HT were blocked by the 5-HT(1D/1B) receptor antagonist methiothepin, consistent with the involvement of canine ca-5-HT(1D/1B) receptors in inhibiting neurotransmitter release and subsequent smooth muscle contraction in dog saphenous vein. The present results show that the novel 5-HT(1D/1B) receptor agonists BRL 56905 and SKF 99101H are at least as potent as sumatriptan and 5-HT, at activating prejunctional inhibitory ca-5-HT(1D/1B) heteroreceptors on sympathetic axon terminals in dog saphenous vein. In addition, when measured simultaneously in the same tissue preparation, [3H]noradrenaline release was inhibited to a much greater extent than neurogenic contraction by any particular agonist.
Medhurst
A D
AD
Department of Neurology Research, SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Brown
A M
AM
Kaumann
A J
AJ
Parsons
A A
AA
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism*; D012501:Saphenous Vein / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology
D002227:Carbazoles; D017366:Serotonin Receptor Agonists; C081764:3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole; D018170:Sumatriptan; D009638:Norepinephrine