Abstract
The aim of this study was to determine whether the calmodulin inhibitors trifluoperazine (TFP) and calmidazolium (CMZ) could decrease the action-potential-evoked release of noradrenaline from mouse isolated atria incubated with [3H]-noradrenaline in support of the hypothesis that calmodulin is involved in neurotransmitter release.
TFP (10 μM and 30 μM) significantly enhanced stimulation-induced (S-1) outflow of radioactivity from mouse atria but had no effect at 1.0 μM or 70 μM. TFP (70 μM) also significantly increased the spontaneous outflow of radioactivity. The facilitatory effect of TFP (10 μM) on S-I outflow of radioactivity persisted in either the presence of 3-isobutyl-1-methylxanthine (100 μM) or atropine (0.3 μM) indicating that this effect of TFP was not mediated through either inhibition of phosphodiesterases or through interference with presynaptic muscarinic receptors, respectively. In the presence of phentolamine, the facilitatory effect of TFP (10 μM) on S-I outflow was reduced but there was no effect on S-I outflow at 70 μM. However, in the presence of a combination of both phentolamine (l.0 μM) and the neuronal uptake blocker desipramine (1.0 μM) a significant inhibitory effect of TFP (70 μM) on the S-I outflow of radioactivity was observed, indicating that effects of TFP on presynaptic a-adrenoceptors and neuronal uptake had disguised an inhibitory effect on S-1 noradrenaline release. Another inhibitor of the Ca2+-calmodulin complex, calmidazolium (CMZ, 10 μM) inhibited the S-1 outflow of radioactivity but had no effect at 1.0 μM. However, CMZ (10 μM) also induced a concomitant increase in the spontaneous outflow of radioactivity. In the presence of both phentolamine (1.0 μM) and desipramine (1.0 μM), CMZ (10 μM) also decreased S-1 outflow of radioactivity. The spontaneous outflow of radioactivity by calmidazolium (10 μM) was mainly attributable to a rise in unmetabolized noradrenaline.
Since concentrations of both TFP and CMZ, which inhibited S-1 noradrenaline release, also caused an increase in the spontaneous outflow of radioactivity, it is possible that the inhibitory effects on S-1 noradrenaline release may be secondary to changes in spontaneous outflow. This suggests that these drugs have complex effects on transmitter release dynamics which are perhaps due to multiple roles for calmodulin within the sympathetic nerve terminal.
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Correspondence to: M. Barrington at the above address
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Barrington, M., Majewski, H. Trifluoperazine and calmidazolium have multiple actions on the release of noradrenaline from sympathetic nerves of mouse atria. Naunyn-Schmiedeberg's Arch Pharmacol 349, 133–139 (1994). https://doi.org/10.1007/BF00169829
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DOI: https://doi.org/10.1007/BF00169829