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Prostaglandin and α-receptor mediated control of transmitter release from adrenergic nerves
lxx 9.
Frontiers in Catecholamine Research
Greengard, H., Roback, R. A. aad Ivy, A. C ., J. Pharmacol . exp . Ther., 74, 309, (1942) .
10 . Holz, P., Credner, K. and Stnibiag, C., Anche exp . Path. Pharmak ., 199, 145, (1942) . 11 . Shümana, H. J. and Heller, L, Arche exp . Path. Pharmak ., 236, 474, (1959) . 12 . Alm, P., Ehinger, B. and Falck, B., Lije Sci ., 6, 913, (1987) . 13 . Alm, P., Ehinger, B. and Falck, B., Acta Phyaiol . Scand., 76, 108, (1989) . 14 . Takeuchi, O., Satoh, S. aad Haehimoto, K., Tohoku J. exp . Med ., 104, 203, (1971) . 15 . Hashimoto, K., Satoh, S. and Takeuchi, O., Brit . J . Pharmacol ., 43, 739, (197)). 16 . Fureta, Y., Iwatsuki, K., Takeuchi, 0. and Hashimoto, K., Tohoku J . exp . Med ., 108, 353, (1972).
Takeuchi, O., Satoh, S. and Hashimoto, K., Jap . J. Pharmacol ., (in press), (1973) . 18 . Fureta, Y., Hashimoto, K., Iwatsuki, K. and Takeuchi, O., Brit . J . Pharmacol ., 17 .
47, 77, (1973) .
19 .
Hashimoto, K., Takeuchi, O., Iwatsuki, K. and Fureta, Y., Proceedings o( the
20. 21 . 22 .
Fureta, Y., Hashimoto, K. and Iwatsuki, K., will be published, (1973) . Iwatsuki, K., Fureta, Y. and Haehimoto, K., Experientia, (in press), (1873) . Haehimoto, K., Fureta, Y., Iwateuki, K. and Ishü, Y., will be published, (1973) .
Fifth-Int. Congress Pharneacology, (1972) .
PROSTAGLANDIN AND arRECEPTOR MEDIATED CONTROL OF TRANSMITTER RELEASE FROM ADRENERGIC NERVES Per Hedgvist
Department of Physiology I, Karolinska Institute, Stockholm, Sweden During recent years much interest has focused on possible mechanisms restricting the release of transmitter from adrenergic nerves . One candidate for such as action is represented by prostsglandins (PGs) of the E type . The PGEs are present is most mammalian tissues, and in a variety of sympathetically innervated organs is increased nerve activity associated with increased formation and release of PGs (cf. Bergstrôm et a1 . 1968, Hedqvist 1973 a) . In the cat spleen, the rabbit heart and the guinea pig vas deferens is the outflow of noradrenaline (NA) is response to nerve stimulation depressed by small PGE doses. Indirect evidence for the same type of prejunctional inhibition of sympathetic neurceffector transmission has been presented in still other tissues (cf. Hedqvist 1973 a, b) . Concerning the mechanism by which PGEs act prej unctionally on sympathetic neurceffector transmission there is good reason to believe that they do not alter physical or chemical inactivation of the transmitter . Nor do they seem to affect NA biosynthesis or to act directly on the NA storage particles . On the other hand an interaction between PGEs aad Ca++ has been demonstrated in many tissues including adrenergic nerves (cf. Bergstr8m et al. 1968 ; Hedgvist 1973 a, b) . This is particularly interesting in view of the NA release process
Frwitiers in Catecholamine Research
lxxi
being critically dependent upon Ca++ (cf. Hubhard 1968), and implies that PGEs restrict stimulated release of NA by inhibiting influx of Ca++ into the neuron . In this contest it is worth noticing that the PGEs have a depolarizing effect on cell membranes and that therefore presumed decreased influx of Ca++ in the presence of PGEs may be secondary to a reduced amplitude of the nerve action potential . Support for this latter view is given by the inability of PGEs to affect the Ca ++ -dependent hormon secretion from the adrenal medulla. In this tissue the resting membrane potential is rather low and stimulation does not lead to reversal and overshoot but only to a minimal local depolarization (Douglas et al . 1967). In a variety of sympathetically innervated tissues are the doses of PGEs needed to significantly affect neurceffector transmission of the same order of magnitude as those known to be released from respective organ in response to nerve activity. Moreover, according to both in vitro and in viuo experiments, administration of different unrelated blockers of PG formation and release seems to be generally associated with increased NA release in response to nerve activity (cf. Hedgvist 1973 a, b). Therefore, although not conclusively demonstrated, ample experimental evidence suggests that locally formed PGEs represent a significant mechanism for feed back control of transmitter release from adrenergic nerves . On the other hand, j udged from the effect of exogenous PGEs, the action at the effector cell level is variably inhibitory and stimulant. Since PGEs can be manufactured both by the nerves and by the effector cells, and assuming that the action of this newly formed PG is strictly local, it would mean that the net effect on sympathetic neuroeffector transmission depends on which site is primarily activated. Possibly as a complement to the action of the PGs, the reactivity of the effector cell has been suggested to feed back control transmitter release from sympathetic nerves (Häggendal 1970). Considerable support for this view is given by observations on the nerve stimulated mouse vas deferens and rabbit heart (Farnebo and Malmfors 1971, Starke 1972). Here NA overflow is increased after administration of a-receptor stimulating agents . a-receptor blockers increase transmitter overflow also in tissues in which the proportion of a-receptors in the effector organ is very small or absent, and is doses which do not affect the neuronal uptake mechanism (Adler et al . 1970, Enero et al. 1972). Therefore a-receptors of the effector cells and the neuronal uptake mechanism do not seem to be primarily involved in the promoting action on transmitter release by a-receptor blockens . As a consequence a negative feed back mechanism for control of transmitter release has bees envisaged by postulating the presence of
lxxü
Frontiers in Catecholamine Research
arreceptors prej unctionally located on the nerve endings (Farnebo and Malmfors 1971, Enero et al . 1972). Part of the reduced NA release after activation of these receptors could be explained as the result of increased local formation of PGs since PG formation and efflux is increased by arreceptor activation and abolished after arreceptor blockade (Davies et al . 1967, Gilmore et al. 1968). On the other hand arreceptor inhibition and activation causes increased respective decreased outflow of NA from the stimulated vas deferens, even after proper inhibition of local PG formation and of the neuronal uptake mechanism (Hedgvist 1973 c) . One therefore has to consider PGs and prej unctional ar receptor to represent at least in part two separate means for feed back control of transmitter release from sympathetic nerves . As to the specific target of action this may also be separated. On the other hand the two systems may mutually act to restrict, in one way or the other, the influx of Ca++ into the interior of the axon, and thereby reduce the ultimate extrusion of transmitter into the j unctional cleft. ACKNOWLEDGEMENTS Supported in part by the Swedish Medical Research Council, proj ect 04X3186, and by the Medical Faculty, Karolinska Institute. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 .
Adler, E., Rubio, M. C . and Langer, S. Z., Reaumenes de communicacionea de la III reunion de la aociedad Argentina de Farmacologia Experiments, 10-11, (1870) . Bergrtrôm, S., Carlron, L. A. sad Weekr, J. R., Pharmacol . Rev ., 20, 1-48, (1968) . Davier, B. N., Horton, E . W. and Withrington, P. G. J. Phyaiol . (Loud.) ., 188, 38P~8P, (1967) . Douglas, W . W., Kaano, T. and S. R. Sampron., J. Phyaiol . (Loud.) ., 188, 107-120, (1967) . Enero, M. A., Langer, S. Z ., Rothlin, R . P. and Stefaao, F . J. E., Brit . J. Pharmacol ., 44, 672-~88, (1972) . Farnebo, L.-0. and Malmfore, T., Acta phyaiol . stand., Suppl . 371 . 1-18, (1971) . Gilmore, N., Vane, J. R. and Wyllie, J. H., Brit. J . Pharmacol ., 32, 425P-426P, (1968) . Häggendal, J., BayertiSymposium II, Springer~Verlag, 100-109, (1970) . Hedgvirt, P., in 'Proetaglandinr' Vol. I, Ede, P. Ramwell and J. Shaw, Plenum Publ . Corp., N .. Y. 101-131, (1973) . Hedgvirt, P., Advances in the Bioaciencea, 9, (1973) . Hedgvirt, P., Acta phyaioi . stand., 87, 42~A-43A, (1973) . Hubhard, J. L, Progr . Biophya . and molecular Biol ., 21, 33-124, (1970) . Starke, K., Naunyn-Schmiedeberg'a Arch . Pharmacol, 274, 18-46, (1972) .
Frontiers in Catecholamine Research
Greengard, H., Roback, R. A. aad Ivy, A. C ., J. Pharmacol . exp . Ther., 74, 309, (1942) .
10 . Holz, P., Credner, K. and Stnibiag, C., Anche exp . Path. Pharmak ., 199, 145, (1942) . 11 . Shümana, H. J. and Heller, L, Arche exp . Path. Pharmak ., 236, 474, (1959) . 12 . Alm, P., Ehinger, B. and Falck, B., Lije Sci ., 6, 913, (1987) . 13 . Alm, P., Ehinger, B. and Falck, B., Acta Phyaiol . Scand., 76, 108, (1989) . 14 . Takeuchi, O., Satoh, S. aad Haehimoto, K., Tohoku J. exp . Med ., 104, 203, (1971) . 15 . Hashimoto, K., Satoh, S. and Takeuchi, O., Brit . J . Pharmacol ., 43, 739, (197)). 16 . Fureta, Y., Iwatsuki, K., Takeuchi, 0. and Hashimoto, K., Tohoku J . exp . Med ., 108, 353, (1972).
Takeuchi, O., Satoh, S. and Hashimoto, K., Jap . J. Pharmacol ., (in press), (1973) . 18 . Fureta, Y., Hashimoto, K., Iwatsuki, K. and Takeuchi, O., Brit . J . Pharmacol ., 17 .
47, 77, (1973) .
19 .
Hashimoto, K., Takeuchi, O., Iwatsuki, K. and Fureta, Y., Proceedings o( the
20. 21 . 22 .
Fureta, Y., Hashimoto, K. and Iwatsuki, K., will be published, (1973) . Iwatsuki, K., Fureta, Y. and Haehimoto, K., Experientia, (in press), (1873) . Haehimoto, K., Fureta, Y., Iwateuki, K. and Ishü, Y., will be published, (1973) .
Fifth-Int. Congress Pharneacology, (1972) .
PROSTAGLANDIN AND arRECEPTOR MEDIATED CONTROL OF TRANSMITTER RELEASE FROM ADRENERGIC NERVES Per Hedgvist
Department of Physiology I, Karolinska Institute, Stockholm, Sweden During recent years much interest has focused on possible mechanisms restricting the release of transmitter from adrenergic nerves . One candidate for such as action is represented by prostsglandins (PGs) of the E type . The PGEs are present is most mammalian tissues, and in a variety of sympathetically innervated organs is increased nerve activity associated with increased formation and release of PGs (cf. Bergstrôm et a1 . 1968, Hedqvist 1973 a) . In the cat spleen, the rabbit heart and the guinea pig vas deferens is the outflow of noradrenaline (NA) is response to nerve stimulation depressed by small PGE doses. Indirect evidence for the same type of prejunctional inhibition of sympathetic neurceffector transmission has been presented in still other tissues (cf. Hedqvist 1973 a, b) . Concerning the mechanism by which PGEs act prej unctionally on sympathetic neurceffector transmission there is good reason to believe that they do not alter physical or chemical inactivation of the transmitter . Nor do they seem to affect NA biosynthesis or to act directly on the NA storage particles . On the other hand an interaction between PGEs aad Ca++ has been demonstrated in many tissues including adrenergic nerves (cf. Bergstr8m et al. 1968 ; Hedgvist 1973 a, b) . This is particularly interesting in view of the NA release process
Frwitiers in Catecholamine Research
lxxi
being critically dependent upon Ca++ (cf. Hubhard 1968), and implies that PGEs restrict stimulated release of NA by inhibiting influx of Ca++ into the neuron . In this contest it is worth noticing that the PGEs have a depolarizing effect on cell membranes and that therefore presumed decreased influx of Ca++ in the presence of PGEs may be secondary to a reduced amplitude of the nerve action potential . Support for this latter view is given by the inability of PGEs to affect the Ca ++ -dependent hormon secretion from the adrenal medulla. In this tissue the resting membrane potential is rather low and stimulation does not lead to reversal and overshoot but only to a minimal local depolarization (Douglas et al . 1967). In a variety of sympathetically innervated tissues are the doses of PGEs needed to significantly affect neurceffector transmission of the same order of magnitude as those known to be released from respective organ in response to nerve activity. Moreover, according to both in vitro and in viuo experiments, administration of different unrelated blockers of PG formation and release seems to be generally associated with increased NA release in response to nerve activity (cf. Hedgvist 1973 a, b). Therefore, although not conclusively demonstrated, ample experimental evidence suggests that locally formed PGEs represent a significant mechanism for feed back control of transmitter release from adrenergic nerves . On the other hand, j udged from the effect of exogenous PGEs, the action at the effector cell level is variably inhibitory and stimulant. Since PGEs can be manufactured both by the nerves and by the effector cells, and assuming that the action of this newly formed PG is strictly local, it would mean that the net effect on sympathetic neuroeffector transmission depends on which site is primarily activated. Possibly as a complement to the action of the PGs, the reactivity of the effector cell has been suggested to feed back control transmitter release from sympathetic nerves (Häggendal 1970). Considerable support for this view is given by observations on the nerve stimulated mouse vas deferens and rabbit heart (Farnebo and Malmfors 1971, Starke 1972). Here NA overflow is increased after administration of a-receptor stimulating agents . a-receptor blockers increase transmitter overflow also in tissues in which the proportion of a-receptors in the effector organ is very small or absent, and is doses which do not affect the neuronal uptake mechanism (Adler et al . 1970, Enero et al. 1972). Therefore a-receptors of the effector cells and the neuronal uptake mechanism do not seem to be primarily involved in the promoting action on transmitter release by a-receptor blockens . As a consequence a negative feed back mechanism for control of transmitter release has bees envisaged by postulating the presence of
lxxü
Frontiers in Catecholamine Research
arreceptors prej unctionally located on the nerve endings (Farnebo and Malmfors 1971, Enero et al . 1972). Part of the reduced NA release after activation of these receptors could be explained as the result of increased local formation of PGs since PG formation and efflux is increased by arreceptor activation and abolished after arreceptor blockade (Davies et al . 1967, Gilmore et al. 1968). On the other hand arreceptor inhibition and activation causes increased respective decreased outflow of NA from the stimulated vas deferens, even after proper inhibition of local PG formation and of the neuronal uptake mechanism (Hedgvist 1973 c) . One therefore has to consider PGs and prej unctional ar receptor to represent at least in part two separate means for feed back control of transmitter release from sympathetic nerves . As to the specific target of action this may also be separated. On the other hand the two systems may mutually act to restrict, in one way or the other, the influx of Ca++ into the interior of the axon, and thereby reduce the ultimate extrusion of transmitter into the j unctional cleft. ACKNOWLEDGEMENTS Supported in part by the Swedish Medical Research Council, proj ect 04X3186, and by the Medical Faculty, Karolinska Institute. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 .
Adler, E., Rubio, M. C . and Langer, S. Z., Reaumenes de communicacionea de la III reunion de la aociedad Argentina de Farmacologia Experiments, 10-11, (1870) . Bergrtrôm, S., Carlron, L. A. sad Weekr, J. R., Pharmacol . Rev ., 20, 1-48, (1968) . Davier, B. N., Horton, E . W. and Withrington, P. G. J. Phyaiol . (Loud.) ., 188, 38P~8P, (1967) . Douglas, W . W., Kaano, T. and S. R. Sampron., J. Phyaiol . (Loud.) ., 188, 107-120, (1967) . Enero, M. A., Langer, S. Z ., Rothlin, R . P. and Stefaao, F . J. E., Brit . J. Pharmacol ., 44, 672-~88, (1972) . Farnebo, L.-0. and Malmfore, T., Acta phyaiol . stand., Suppl . 371 . 1-18, (1971) . Gilmore, N., Vane, J. R. and Wyllie, J. H., Brit. J . Pharmacol ., 32, 425P-426P, (1968) . Häggendal, J., BayertiSymposium II, Springer~Verlag, 100-109, (1970) . Hedgvirt, P., in 'Proetaglandinr' Vol. I, Ede, P. Ramwell and J. Shaw, Plenum Publ . Corp., N .. Y. 101-131, (1973) . Hedgvirt, P., Advances in the Bioaciencea, 9, (1973) . Hedgvirt, P., Acta phyaioi . stand., 87, 42~A-43A, (1973) . Hubhard, J. L, Progr . Biophya . and molecular Biol ., 21, 33-124, (1970) . Starke, K., Naunyn-Schmiedeberg'a Arch . Pharmacol, 274, 18-46, (1972) .