Prejunctional effects of cromakalim, nicorandil and pinacidil on noradrenergic transmission in rat isolated mesenteric artery

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Abstract
The present study investigated the effects of cromakalim, nicorandil and pinacidil on resting and stimulation-induced (S-I) effluxes of radioactivity from rat isolated mesenteric artery preparations in which the noradrenergic transmitter stores had been radiolabelled with [3H]-noradrenaline. The efflux of radioactivity evoked by field stimulation of peri-arterial sympathetic nerves (pulses at 2 Hz frequency in trains of 60 s duration) was taken as an index of transmitter noradrenaline release. Cromakalim (1-100 microM) and nicorandil (1-1000 microM) produced minor effects on resting and S-I effluxes of radioactivity, but these did not exhibit concentration-dependency. Pinacidil (1-1000 microM) produced concentration-dependent increases, in both resting and S-I effluxes of radioactivity. With 1000 microM pinacidil, resting and S-I effluxes were increased to approximately 348% and 358% of their respective control values. The effects of pinacidil on resting and S-I effluxes were unaltered when the neuronal amine transport system was inhibited by desipramine (1 microM). Inhibition of monoamine oxidase with pargyline (100 microM) treatment markedly reduced the enhancement of resting efflux by 1000 microM pinacidil but did not alter its effect on S-I efflux. It is proposed that the enhanced resting efflux produced by pinacidil without pargyline treatment consists of deaminated [3H]-noradrenaline metabolites formed from [3H]-noradrenaline displaced from transmitter storage vesicles by pinacidil. The enhancement of S-I efflux by pinacidil does not appear to involve disruption of alpha 2-adrenoceptor auto-inhibition of transmitter release since equi-effective concentrations of phentolamine (1 microM) and pinacidil (1000 microM) produced additive effects on S-I efflux, whereas increasing the concentration of phentolamine from 1 to 2M produced no further increases in S-I efflux. In conclusion, this study has provided no evidence of a prejunctional inhibitory effect of the potassium channel openers cromakalim, nicorandil and pinacidil on transmitter noradrenaline release. However, the findings with pinacidil suggest that, in high concentrations, pinacidil displaces noradrenaline from transmitter stores, such that deaminated noradrenaline metabolites are released from the nerve terminals. Furthermore, pinacidil enhances S-I transmitter noradrenaline release, possibly by blocking neuronal potassium channels.