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Noradrenaline release and the effect of endogenous activation of the phospholipase C/protein kinase C signalling pathway in rat atria
Author(s) -
Majewski H,
Kotsonis P,
Murphy T V,
Barrington M
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701236
Subject(s) - diacylglycerol kinase , protein kinase c , phospholipase c , stimulation , phospholipase , endocrinology , medicine , chemistry , biology , signal transduction , biochemistry , enzyme
It has been proposed that protein kinase C (PKC) in sympathetic nerves is activated during action‐potential evoked release of noradrenaline and helps maintain transmitter output. We studied this phenomenon further in rat atria radiolabelled with [ 3 H]‐noradrenaline. Noradrenaline release was elevated by continuous electrical stimulation of the atria for 10min at either 5 or 10Hz. Two inhibitors of PKC, polymyxin B (21μ m ) and Ro 318220 (3μ m ), markedly inhibited the release of noradrenaline but only at the higher stimulation frequency. Further experiments were conducted with 10Hz stimulation but for shorter train durations. In this case polymyxin B inhibited noradrenaline release during a 10 or 15s train of impulses but not during a 5s train. This suggests that PKC effects are induced during the stimulation train by some process. The diacylglycerol kinase inhibitor R59949 (10μ m ), which prevents the breakdown of diacylglycerol, enhanced noradrenaline release elicited by stimulation at 10Hz for 10 or 15s. This effect was not seen if polymyxin B was present and suggests that diacylglycerol is the endogenous activator of PKC. The source of the diacylglycerol may be through phospholipase C pathways, since the phospholipase C inhibitor U73122 (3μ m ) inhibited noradrenaline release at 10Hz for 10s and the effect was not seen if polymyxin B was also present. It is unlikely that phospholipase D is the source of diacylglycerol. Although the phospholipase D inhibitor wortmannin (1μ m ) inhibited noradrenaline release, this effect was still observed in the presence of polymyxin B. Furthermore ethanol, which inhibits diacylglycerol formation by phospholipase D, had no effect on noradrenaline release. We therefore suggest that during a train of high frequency pulses phospholipase C is activated and this results in the production of diacylglycerol which in turn activates PKC. This enables the neurones to maintain transmitter release at a high level.