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Effect of xylamine on sympathetic neuroeffector transmission in blood vessels
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We conclude that the effectiveness of alpha-2-adrenoceptor stimulation increases from the distal to the proximal regions of the canine saphenous vein, apparently due to a greater density of alpha-2-adrenoceptors.
Refevenees De Mey, &C- and P.M. Vanhoutte, lq81, Circ. Res. 48, 875. O ~ S., M.Q. Paiva and J.J. Polbnia, 1983, Progr. Neuropsychopharmacol. (Abstracts) (Suppl.) 155.
Effect of xy|amine on sympathetic neuroeffector transmission in blood vessels Nedergaard, O.A. a n d Cho *, A.K. Department of Pharmacology, School of Medicines, Odense Universi~, J.B. Winslows Vej 19, DK-5000 Odense C, Denmark and * Departnumt of Pharwa~71ogyand Brain Research Institute, School of Medicine, University of California, Los Angeles, California 90024, U.S.A.
Xylamine (N-2-chloroethyl-N-ethyl-2-n:ethyibenzylamine) is reputed to be an irreversible and selective inhibitor of catecholam'_me uptake into sympathetic neurones (Cho et al., 1980). In aqueous solution, xylamine undergoes intramo!ecular cyclization forming an aziridium ion, which can readily act with tissue aucleophiles (Fischer and Cho 1981). The blockade of noradtenaline uptake mechanism by xylamine is thought to be due to alkylation of the n o r a d r e n ~ e carrier or a clo~'~ely associated site (Ransom et al., 1984). Xylamine also causes a reduction in endogenous no~drenaline levels centrally and peripherally. However, it has been suggesteA that xylamine can ~'educe noradrenaline uptake activity without appreciably decreasing noradrenaline levels in tissues. The selective uptake-1 activity, of xylamine m~tkes this compound potentially useful in studies of sympathetic neuroeffector transmission. The aim of the present work was to examine the actions of xylamine on various aspects of noradrenergic neuroeffector transmission. Rabbit isolated aorta and pulmonary artery were used for this purpose. Xylamine (10-s-10 -6 M) caused a slowly progressing inhibition of the contractions of pulmonary artery evoked by electrical-field stimulation. At 10 - s and 10 -7 M, the inhibition reached an almost steady-state. The inhibition seen with 10 -7 M of xylamine was not reversed by repeated washing of the artery with drugfree salt solution. Cocaine (3 × 10 -s M) prevented the inhibitory action of xyiamine (10 -7 M). Xylamine (10-7-3 × 10 -s M) reduced the accmnulation of tritium by aorta preincubated with 3H-noradrenaline (10 -s M). Desipramine (10 -6 M) decreased markedly the 3H-accumulation by aorta incubated with 3H-noradrenaline. This decrease was augmented by xylamine (10-7-3 × 10 -5 M) and by corticosterone (10-7-3 × 10 -s M). Xylamine (10-7-10 -6 M) antagonized in a non-competitive manner the contractions evoked by noradrenaline (10-93 × 10 -5 lVO. The antagonism was more marked in the presence of co¢ame (3 × I0 -s M) plus corticosterone (4 × 10 -5 M). In the presence ,~f xylamine (10-7-10 -6 M), cumulative addition of near maximally effective concentrations of noradrenaline caused a sudden and complete relaxation of aorta. Removal of endothelial cells did not alter the concentration-response curve for noradrenaline or the antagonism caused by xylamine. Xylamine (10-7-10 -6 M) antagonized non-competitively the contractions of aorta evoked by serotonin (10-s-3 × 10 -4 M) in the presence of benextramine (10 -s M). Xylamine (10-7-10 -5 M) did not alter the contractions evoked by potassium
(17-55 raM). We conclude that xylamine is an inhibitor of neuronal and extraneuronal uptake, an adrenergic neurone blocking agent and a non-competitive antagonist for a~-adrenoceptors and serotonin (5-H1"2) receptors. Xylamine is not a direct acting v ~ l i l a t o r on smooth muscle. This study was supported by P. Carl Petersen's Fund. References Cho, A.K., Ransom, R.W., Fischer, J.B. and F~mmerer, R.C., 1980, J. Pharmacol. Exp. Ther. 214, 324. Fischer, LB. and Cho, A.K. 1982, J. Pharmacol. Exp. Ther. 220, 115. Ransom, R.W., Waggaman, L.A. and Cho, A.K., 1984, J. Neurochem. 42, 475.
We conclude that the effectiveness of alpha-2-adrenoceptor stimulation increases from the distal to the proximal regions of the canine saphenous vein, apparently due to a greater density of alpha-2-adrenoceptors.
Refevenees De Mey, &C- and P.M. Vanhoutte, lq81, Circ. Res. 48, 875. O ~ S., M.Q. Paiva and J.J. Polbnia, 1983, Progr. Neuropsychopharmacol. (Abstracts) (Suppl.) 155.
Effect of xy|amine on sympathetic neuroeffector transmission in blood vessels Nedergaard, O.A. a n d Cho *, A.K. Department of Pharmacology, School of Medicines, Odense Universi~, J.B. Winslows Vej 19, DK-5000 Odense C, Denmark and * Departnumt of Pharwa~71ogyand Brain Research Institute, School of Medicine, University of California, Los Angeles, California 90024, U.S.A.
Xylamine (N-2-chloroethyl-N-ethyl-2-n:ethyibenzylamine) is reputed to be an irreversible and selective inhibitor of catecholam'_me uptake into sympathetic neurones (Cho et al., 1980). In aqueous solution, xylamine undergoes intramo!ecular cyclization forming an aziridium ion, which can readily act with tissue aucleophiles (Fischer and Cho 1981). The blockade of noradtenaline uptake mechanism by xylamine is thought to be due to alkylation of the n o r a d r e n ~ e carrier or a clo~'~ely associated site (Ransom et al., 1984). Xylamine also causes a reduction in endogenous no~drenaline levels centrally and peripherally. However, it has been suggesteA that xylamine can ~'educe noradrenaline uptake activity without appreciably decreasing noradrenaline levels in tissues. The selective uptake-1 activity, of xylamine m~tkes this compound potentially useful in studies of sympathetic neuroeffector transmission. The aim of the present work was to examine the actions of xylamine on various aspects of noradrenergic neuroeffector transmission. Rabbit isolated aorta and pulmonary artery were used for this purpose. Xylamine (10-s-10 -6 M) caused a slowly progressing inhibition of the contractions of pulmonary artery evoked by electrical-field stimulation. At 10 - s and 10 -7 M, the inhibition reached an almost steady-state. The inhibition seen with 10 -7 M of xylamine was not reversed by repeated washing of the artery with drugfree salt solution. Cocaine (3 × 10 -s M) prevented the inhibitory action of xyiamine (10 -7 M). Xylamine (10-7-3 × 10 -s M) reduced the accmnulation of tritium by aorta preincubated with 3H-noradrenaline (10 -s M). Desipramine (10 -6 M) decreased markedly the 3H-accumulation by aorta incubated with 3H-noradrenaline. This decrease was augmented by xylamine (10-7-3 × 10 -5 M) and by corticosterone (10-7-3 × 10 -s M). Xylamine (10-7-10 -6 M) antagonized in a non-competitive manner the contractions evoked by noradrenaline (10-93 × 10 -5 lVO. The antagonism was more marked in the presence of co¢ame (3 × I0 -s M) plus corticosterone (4 × 10 -5 M). In the presence ,~f xylamine (10-7-10 -6 M), cumulative addition of near maximally effective concentrations of noradrenaline caused a sudden and complete relaxation of aorta. Removal of endothelial cells did not alter the concentration-response curve for noradrenaline or the antagonism caused by xylamine. Xylamine (10-7-10 -6 M) antagonized non-competitively the contractions of aorta evoked by serotonin (10-s-3 × 10 -4 M) in the presence of benextramine (10 -s M). Xylamine (10-7-10 -5 M) did not alter the contractions evoked by potassium
(17-55 raM). We conclude that xylamine is an inhibitor of neuronal and extraneuronal uptake, an adrenergic neurone blocking agent and a non-competitive antagonist for a~-adrenoceptors and serotonin (5-H1"2) receptors. Xylamine is not a direct acting v ~ l i l a t o r on smooth muscle. This study was supported by P. Carl Petersen's Fund. References Cho, A.K., Ransom, R.W., Fischer, J.B. and F~mmerer, R.C., 1980, J. Pharmacol. Exp. Ther. 214, 324. Fischer, LB. and Cho, A.K. 1982, J. Pharmacol. Exp. Ther. 220, 115. Ransom, R.W., Waggaman, L.A. and Cho, A.K., 1984, J. Neurochem. 42, 475.