Trifluoperazine and calmidazolium have multiple actions on the release of noradrenaline from sympathetic nerves of mouse atria.
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 microM and 30 microM) significantly enhanced stimulation-induced (S-I) outflow of radioactivity from mouse atria but had no effect at 1.0 microM or 70 microM. TFP (70 microM) also significantly increased the spontaneous outflow of radioactivity. The facilitatory effect of TFP (10 microM) on S-I outflow of radioactivity persisted in either the presence of 3-isobutyl-1-methylxanthine (100 microM) or atropine (0.3 microM) 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 microM) on S-I outflow was reduced but there was no effect on S-I outflow at 70 microM. However, in the presence of a combination of both phentolamine (1.0 microM) and the neuronal uptake blocker desipramine (1.0 microM) a significant inhibitory effect of TFP (70 microM) on the S-I outflow of radioactivity was observed, indicating that effects of TFP on presynaptic alpha-adrenoceptors and neuronal uptake had disguised an inhibitory effect on S-I noradrenaline release. Another inhibitor of the Ca(2+)-calmodulin complex, calmidazolium (CMZ, 10 microM) inhibited the S-I outflow of radioactivity but had no effect at 1.0 microM. However, CMZ (10 microM) also induced a concomitant increase in the spontaneous outflow of radioactivity.(ABSTRACT TRUNCATED AT 250 WORDS)
Barrington
M
M
Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia.
Majewski
H
H
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D003891:Desipramine / Q000494:pharmacology; D004558:Electric Stimulation; D004759:Enterochromaffin Cells / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000294:innervation*; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D010646:Phentolamine / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D014268:Trifluoperazine / Q000494:pharmacology*
D002147:Calmodulin; D007093:Imidazoles; D014268:Trifluoperazine; C031938:calmidazolium; D001285:Atropine; D015056:1-Methyl-3-isobutylxanthine; D003891:Desipramine; D009638:Norepinephrine; D010646:Phentolamine