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.

1 In segments of human right atrial appendages and pulmonary arteries preincubated with [3 H]-noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, the involvement of imidazoline receptors in the modulation of [ 3 H]-noradrenaline release was investigated. 2 In human atrial appendages, the guanidines aganodine and DTG (1,3-di(2-tolyl)guanidine) which activate presynaptic imidazoline receptors, inhibited electrically-evoked [ 3 H]-noradrenaline release. The inhibition was not aected by blockade of a 2 -adrenoceptors with 1 mM rauwolscine, but antagonized by extremely high concentrations of this drug (10 and/or 30 mM; apparent pA 2 against aganodine and DTG: 5.55 and 5.21, respectively). 3 In the presence of 1 mM rauwolscine, [3 H]-noradrenaline release in human atrial appendages was also inhibited by the imidazolines idazoxan and cirazoline, but not by agmatine and noradrenaline. The inhibitory eects of 100 mM idazoxan and 30 mM cirazoline were abolished by 30 mM rauwolscine. 4 In the atrial appendages, the rank order of potency of all guanidines and imidazolines for their inhibitory eect on electrically-evoked [3 H]-noradrenaline release in the presence of 1 mM rauwolscine was: aganodine5BDF 6143 [4-chloro-2-(2-imidazolin-2-yl-amino)-isoindoline]4DTG5clonidine4cira-zoline4idazoxan (BDF 6143 and clonidine were previously studied under identical conditions). This potency order corresponded to that previously determined at the presynaptic imidazoline receptors in the rabbit aorta. 5 When, in the experiments in the human pulmonary artery, rauwolscine was absent from the superfusion¯uid, the concentration-response curve for BDF 6143 (a mixed a 2 -adrenoceptor antagonist/ imidazoline receptor agonist) for its facilitatory eect on electrically-evoked ]-idazoxan (de®ned by cirazoline 0.1 mM) to membranes of human atrial appendages was concentration-dependently inhibited by several imidazolines and guanidines, but not by rauwolscine and agmatine. In most cases, the competition curves were best ®tted to a two-site model. 7 The rank order of anity for the high anity site (in a few cases for the only detectable site; cirazoline=idazoxan4BDF 61434DTG5clonidine) is compatible with the pharmacological properties of I 2 -imidazoline binding sites, but is clearly dierent from the rank order of potency for inhibiting evoked noradrenaline release from sympathetic nerves in the same tissue. 8 It is concluded that noradrenaline release in the human atrium and, less well established, in the pulmonary artery is inhibited via presynaptic imidazoline receptors. These presynaptic imidazoline receptors appear to be related to those previously characterized in rabbit aorta and pulmonary artery, but dier clearly from I 1 and I 2 imidazoline binding sites.

A 6-wk-old male infant became unresponsive after an uneventful general anesthetic for hernia repair. His symptoms were consistent with central anticholinergic syndrome. He appeared to awaken after treatment with IV physostigmine in a dose of 0.04 mg/kg. Because of the recurrence of sedation, a second physostigmine infusion was administered, which again led to transient arousal. Finally, the patient awoke spontaneously after 24 h and recovered uneventfully.

We studied two families with five affected members suffering from ptosis and slowly progressive limb-girdle muscle weakness. All patients had abnormal decremental response on low-frequency nerve stimulation, but there were no repetitive responses to single stimuli. The patients improved on anti-acetylcholinesterase drugs. Intercostal muscle was obtained for special studies from one patient of each family. In vitro microelectrode studies were done in Patient 1. Miniature end-plate potentials were of low amplitude, and the quantal content of the evoked end-plate potentials was normal. Light microscopy revealed a marked type 1 fiber predominance. Acetylcholinesterase reactivity was dispersed over increased length of individual fibers in Patient 2. On morphometry of the end-plate ultrastructure, the number of secondary synaptic clefts per neuromuscular junction and the expansion of the postsynaptic area were markedly reduced. In Patient 1, but not in Patient 2, the envelopment of the nerve terminal by Schwann cell was increased. Acetylcholine-receptor (AChR) density was reduced as judged by the reduced immunoreactivity to antibodies against different receptor subunits. Immunohistochemical analysis of proteins known to be involved in orchestrating the end-plate structure showed deficiency of the AChR-associated protein utrophin. These patients appear to have a defect in the development or maintenance of the postsynaptic clefts; whether this defect results from or causes a reduced expression of utrophin or AChR is unclear.

Intraarterial administration of Captopril can reduce the extent of damage in nonocclusive mesenterial ischaemia (nonocclusive disease) if therapy is initiated early enough.