Modulation of noradrenaline release from the sympathetic nerves of the human saphenous vein and pulmonary artery by presynaptic EP3- and DP-receptors.
1. Spirally cut strips of the human saphenous vein and pulmonary artery were used to determine the pharmacological properties of the presynaptic prostanoid receptors involved in the modulation of sympathetic [3H]-noradrenaline release. Strips preincubated with [3H]-noradenaline were superfused with physiological salt solution containing inhibitors of uptake1 and uptake2 and rauwolscine to eliminate involvement of presynaptic alpha 2-adrenoceptors. Tritium overflow was evoked by transmural electrical stimulation (standard frequency: 2 Hz). 2. In the saphenous vein, prostaglandin E2 (PGE2) inhibited the electrically-evoked tritium overflow; at the highest concentration investigated, tritium overflow was inhibited by more than 75% and the pEC50 value was 7.00. These effects were mimicked by prostaglandin E1, the EP1/EP3 receptor agonist, sulprostone and the EP2/EP3 receptor agonist, misoprostol with the rank order (pEC50): sulprostone (8.60) > PGE1 (7.25) > misoprostol (6.96). This rank order of potency suggests that the inhibitory effect of the drugs is mediated by presynaptic EP3-receptors. In contrast, PGF2 alpha did not inhibit evoked tritium overflow; the IP/EP1 receptor agonist iloprost and the stable thromboxane A2 analogue U 46619 (9, 11-dideoxy-11 alpha,9 alpha-epoxy-methanoprostaglandin F2 alpha) produced inhibition only at concentrations above 1 microM. 3. The EP1-receptor antagonist, AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) had no effect on the evoked tritium overflow nor did it modify the inhibitory effect of PGE2, further excluding involvement of inhibitory presynaptic EP1-receptors. 4. PGD2 caused a facilitation of evoked tritium overflow in the saphenous vein; this facilitation is probably mediated by presynaptic DP-receptors, since it was abolished by the selective DP-receptor antagonist, BW A868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamino)hydantoin).5. In the pulmonary artery, sulprostone (pECm value 8.35), misoprostol (7.70) and PGE2 (6.80)inhibited electrically-evoked tritium overflow. This rank order of potency is consistent with the involvement of inhibitory presynaptic EP3-receptors.6. These results suggest that the sympathetic nerve fibres of both human saphenous vein and pulmonary artery are endowed with presynaptic inhibitory EP3 receptors. The EP3-receptors do not interact with the alpha 2-autoreceptors. In addition, the human saphenous vein seems to be endowed with presynaptic facilitatory DP-receptors.
Molderings
G J
GJ
Institut für Pharmakologie und Toxikologie, Rheinische Friedrich-Wilhelms-Universiät Bonn, Germany.
Colling
E
E
Likungu
J
J
Jakschik
J
J
Göthert
M
M
D000320:Adrenergic Fibers / Q000378:metabolism*; D000328:Adult; D000368:Aged; D015232:Dinoprostone / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009288:Naproxen / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D011651:Pulmonary Artery / Q000294:innervation*; D011667:Pulmonary Veins / Q000294:innervation*; D017661:Receptors, Presynaptic / Q000037:antagonists & inhibitors / Q000502:physiology*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000502:physiology*; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000502:physiology; D012501:Saphenous Vein / Q000294:innervation*; D014316:Tritium
D017661:Receptors, Presynaptic; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D014316:Tritium; D009288:Naproxen; D015232:Dinoprostone; D009638:Norepinephrine