Modulation of noradrenaline release in human saphenous vein via presynaptic α2-adrenoceptors

Naunyn-Schmiedeberg's Arch Pharmacol

Likungu

Göthert

1998

Self Cite

Strips of human right atrial appendages were preincubated with [3H]noradrenaline and then superfused with physiological salt solution containing inhibitors of uptake1 and uptake2. Tritium overflow was evoked by transmural electrical stimulation (standard frequency: 2 Hz). Prostaglandin E2 (PGE2) inhibited the electrically evoked tritium overflow; at the highest concentration investigated, tritium overflow was reduced by about 80% and the pIC50% value was 7.14. The effect of PGE2 was not affected by rauwolscine, which, by itself, increased the evoked overflow. Naproxen failed to affect the evoked tritium overflow and its inhibition by PGE2. The inhibitory effect of PGE2 on the electrically evoked tritium overflow was mimicked by prostaglandin E1, the EP1/EP3-receptor agonist sulprostone and the EP2/EP3-receptor agonist misoprostol with the rank order of potency (pEC50%): sulprostone (7.68) > misoprostol (7.10) > PGE1 (6.39). In contrast, PGF2alpha, the IP/EP1-receptor agonist iloprost and the stable thromboxane A2 analogue U46619 (9,11-dideoxy-11alpha,9alpha-epoxy-methanoprostaglandin++ + F2alpha) did not change evoked tritium overflow. PGD2 caused facilitation. These results suggest that the sympathetic nerve fibres innervating human atrial appendages are endowed with presynaptic inhibitory EP3 and facilitatory DP-receptors. The EP3-receptors appear not to be tonically activated and do not interact with the alpha2-autoreceptors.

Section: Discussionmentioning

confidence: 99%

Modulation of noradrenaline release from the sympathetic nerves of human right atrial appendages by presynaptic EP3- and DP-receptors

Naunyn-Schmiedeberg's Arch Pharmacol

Likungu

Göthert

1998

Self Cite

“…Under the conditions applied here (blockade of neuronal and extraneuronal uptake), electrically evoked tritium overflow from these blood vessels has been shown to be tetro-487 dotoxin-sensitive and Ca2+-dependent (rabbit pulmonary artery: Su and Bevan 1970;Endo et al 1977; human saphenous vein: G6thert et al 1984). The electrically-evoked tritium overflow mainly consists of [3H]noradrenaline and reflects action potential-induced release of unlabelled noradrenaline from the sympathetic neurones contained in the blood vessels (Endo et al 1977;G6thert et al 1984).…”

Section: Discussionmentioning

confidence: 99%

“…For this purpose, we determined the potencies of a few key drugs, a2-adrenoceptor agonists and antagonists, in inhibiting and facilitating noradrenaline release, respectively, to supplement our own previous data. The potencies determined in the present experiments together with those reported in our previous studies (G6thert et al 1984;G6thert and Molderings 1991;Molderings et al 1991) were compared with the affinities of the drugs for a2-adrenoceptor binding sites previously determined in radiologand binding studies. Some results have previously been reported at symposia (Molderings and G6thert 1992(Molderings and G6thert , 1993(Molderings and G6thert , 1994.…”

Section: Introductionmentioning

confidence: 99%

Subtype determination of presynaptic ?2-autoreceptors in the rabbit pulmonary artery and human saphenous vein

Naunyn-Schmiedeberg's Arch Pharmacol

Göthert

1995

The pharmacological properties of the presynaptic a2-autoreceptors mediating inhibition of noradrenaline release were investigated in human saphenous vein and rabbit pulmonary artery. Segments of these blood vessels were incubated with [3H]noradrenaline and subsequently superfused with physiological salt solution containing uptake1 and uptake2 blockers. The potencies of a2-adrenoceptor antagonists in facilitating (pEC40) the electrically (2 Hz) evoked tritium overflow were determined. The order of potency and potency ratios of a2-adrenoceptor antagonists obtained in our experiments were compared with the corresponding order of affinity and affinity ratios from radioligand binding studies in tissues and cells expressing only one of the alpha 2-adrenoceptor subtypes. In the rabbit pulmonary artery, oxymetazoline was a highly potent agonist at presynaptic a2-adrenoceptors, as reflected by its ability to inhibit at low concentrations the electrically evoked tritium overflow. However, in the human saphenous vein oxymetazoline behaved as a partial agonist, which, in interaction experiments with the a2-adrenoceptor agonist B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine), exhibited high potency in antagonizing the inhibitory effect of the latter drug on tritium overflow. Prazosin given alone at concentrations up to 1 mumol/l did not affect tritium overflow. The data obtained with oxymetazoline and prazosin make it very improbable that the a2-autoreceptors on the sympathetic nerves in both tissues are of the a2B- or a2C-subtype. In both blood vessels, rauwolscine given alone was highly potent in facilitating the electrically evoked overflow. In agreement with this, rauwolscine exhibited high potency in antagonizing the inhibitory effect of oxymetazoline on tritium overflow in the rabbit pulmonary artery and of B-HT 920 in the human saphenous vein. The ratio phentolamine/rauwolscine calculated from their potencies in increasing the electrically evoked tritium overflow was also used to discriminate between the various a2-adrenoceptor subtypes. Comparison of this potency ratio with the corresponding affinity ratios for a2-adrenergic binding sites on HT 29 cells, human platelets, bovine pineal gland, rat submaxillary gland, and cell lines transfected with the human a2 genes indicates that in the rabbit pulmonary artery and human saphenous vein the pharmacological characteristics of the autoreceptors conform best to those of a2A-adrenoceptors. Finally, in both blood vessels the potencies of the antagonists BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline), rauwolscine, corynanthine, phentolamine, idazoxan, SKF 104078 (6-chloro-9-[(3-methyl-2-butenyl) oxyl]-3-methyl-1H-2,3,4,5-tetrahydro-3-benzazepine), and/or tolazoline in facilitating evoked noradrenaline release was determined. The potencies of these drugs which can discriminate between a2A- and a2D-adrenoceptors (but not between these and a2B/2C-adrenoceptors) were correlated significantly with their affinities for a2A, but not a2D, sites ...

“…Under the conditions applied here (blockade of neuronal and extraneuronal uptake), electrically evoked tritium overflow from these blood vessels has been shown to be tetrodotoxinsensitive and Ca2+-dependent (Gothert et al, 1984;Gothert & Hentrich, 1985). The electrically-evoked tritium overflow consists mainly of [3H]-noradrenaline and reflects action potential-induced release of unlabelled noradrenaline from the sympathetic neurones contained in the blood vessels (for discussion of this point, see G6thert et al, 1984;Gothert & Hentrich 1985).…”

Section: Discussionmentioning

confidence: 99%

Modulation of noradrenaline release from the sympathetic nerves of the human saphenous vein and pulmonary artery by presynaptic EP₃‐ and DP‐receptors

Colling²,

Likungu³

et al. 1994

British J Pharmacology

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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 uptake, and uptake2 and rauwolscine to eliminate involvement of presynaptic M2-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 pECO value was 7.00. These effects were mimicked by prostaglandin El, the EPI/EP3 receptor agonist, sulprostone and the EP2/EP3 receptor agonist, misoprostol with the rank order (pECm): 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, did not inhibit evoked tritium overflow; the IP/EP1 receptor agonist iloprost and the stable thromboxane A2 analogue U 46619 (9, 11-dideoxy-lla,9a-epoxy-methanoprostaglandin F2.) produced inhibition only at concentrations above 1 JiM. 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 EPI-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). 5In 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 a2-autoreceptors. In addition, the human saphenous vein seems to be endowed with presynaptic facilitatory DP-receptors.