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

Abstract

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.

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…Similar effects were apparent for the DP 1 agonist BW 245C (Giles and Leff, 1988). Thus, despite evidence for presynaptic DP receptors that would enhance norepinephrine release (Molderings et al, 1994), this does not seem to translate into gross cardiovascular events. In contrast, the skin flushing associated with nicotinic acid used for treating dyslipidemia is DP 1 receptor-mediated (Cheng et al, 2006).…”

Further characterization of the ORL1 receptor‐mediated inhibition of noradrenaline release in the mouse brain in vitro

“…This possibility, however, can be discarded since 8-(p-sulphophenyl)theophylline, L-NAME and naproxen (drugs blocking the formation or the e ect of the three mediators at the concentrations used in the present study; von KuÈ gelgen et al, 1997;Chu & Etgen, 1996;Molderings et al, 1994) failed to in¯uence the e ect of nociceptin.…”

Penile Arteries and Erection

“…PGE 1 and PGE 2 cause relaxation of penile arterial and trabecular smooth muscle [147, 148], decrease noradrenaline release from sympathetic nerves [149], and in isolated smooth muscle cells, prostaglandin E 1 and E 2 decreases alpha-1d and alpha-2a-adrenoceptor mRNA [64], while PGE 1 injection in rats enhances neurogenic release of NO and upregulates eNOS and nNOS in the corpus cavernosum [86]. Inhibition of cyclo-oxygenase by indomethacin in penile resistance arteries is associated with contraction suggesting that vasorelaxant prostaglandins contribute to resting tone in the penile circulation [36].…”

“…PGE 1 promotes relaxation of penile arterial smooth muscle via IP receptors and of trabecular smooth muscle through interaction with EP 2 receptors [3, 154]. EP 2 and EP 4 receptors are probably also involved in downregulation of alpha-adrenoceptor mRNA and inhibition of collagen synthesis [61, 151], while the EP receptors involved in the inhibitory effect of PGE 1 and PGE 2 on noradrenaline release and effect on sensory nerves have not been characterised in erectile tissue, but like in vascular tissue they are probably of the EP 3 subtype [149]. …”