Inhibitory effects of propofol on catecholamine secretion and uptake in cultured bovine adrenal medullary cells

Abstract

In the central and peripheral noradrenergic neurons, the balance between noradrenaline release and reuptake determines the level of noradrenaline at the synaptic cleft or the nerve ending. In the present study, we examined the effects of propofol, an intravenous general anaesthetic, on catecholamine secretion and noradrenaline uptake in cultured bovine adrenal medullary cells and on the serum noradrenaline and blood pressure in rats. In cultured adrenal medullary cells, propofol (10-50 mumol/l) concentration-dependently inhibited catecholamine secretion stimulated by carbachol. Propofol suppressed carbachol-evoked 22Na+ influx as well as 45Ca2+ influx at concentrations similar to those which suppressed the catecholamine secretion. Propofol (10-50 mumol/l) also inhibited veratridine-evoked 22Na+ influx, 45Ca2+ influx and catecholamine secretion, whereas it had little effect on the 45Ca2+ influx and catecholamine secretion induced by 56 mmol/l K+. Cultured adrenal medullary cells show [3H] noradrenaline uptake which is sensitive to imipramine. Propofol (10-50 mumol/l) significantly inhibited the imipramine-sensitive uptake of [3H] noradrenaline. In rats, intravenous administration of propofol (2.5 mg/kg) lowered serum noradrenaline and arterial blood pressure. From these findings, in spite of inhibiting noradrenaline uptake, propofol at anaesthetic concentrations (10-30 mumol/l) seems to reduce catecholamine secretion by interfering with Na+ influx through voltage-dependent Na+ channels as well as nicotinic acetylcholine receptor-associated ion channels in the adrenal medulla and, probably, in the sympathetic nervous system. This may explain the propofol-induced hypotension during anaesthesia.

Inhibition by propofol of [3H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes

“…However, propofol does not affect KCl-evoked glutamate release from rat cortical slices (Bikler et al, 1995) or rat cortical synaptosomes (Ratnakumari & Hemmings, 1996), which indicates that propofol does not block the Ca2" channel type coupled to cortical glutamate release. The observations that propofol inhibits 4-aminopyridine-and veratridine-evoked (IC50 values of 39 gM and 30 gM, respectively), but not KCl-evoked, glutamate release from synaptosomes (Ratnakumari & Hemmings, 1996) and veratridine-evoked, but not KCl-evoked, [3H]-noradrenaline release from bovine adrenal chromaffin cells (Minami et al, 1996), suggest that Na+ channels are more sensitive to inhibition by propofol than are the Ca' channels coupled to neurotransmitter release. It should also be noted that propofol inhibits [3H]-PN 200-110 binding to L-type Ca2" channels in rat cerebrocortical membranes with an IC50 of 97gM (Hirota & Lambert, 1996), which is 4 times higher than its ICW (26 gM) for inhibition of [3H]-BTX-B binding to intact synaptosomes isolated from rat cerebral cortex (Figure 1).…”

“…Propofol was found to reduce Na+ channel opentime (ED50 = 20 giM) by electrophysiological recording of single Na' channels from human cerebral cortex (Frenkel & Urban, 1991). Inhibition of Na+ channels by propofol has been implicated in its effects on veratridine-evoked [3H]-noradrenaline release from bovine cultured adrenal medullary chromaffin cells (Minami et al, 1996) and veratridine-evoked glutamate release from cerebrocortical synaptosomes (Ratnakumari & Hemmings, 1996). Blockade of presynaptic Na+ channels may also underlie inhibition of neurotransmitter release by volatile anaesthetics in synaptosomes (Schlame & Hemmings, 1995 , the inhibitory action of propofol in both assays probably involves a selective allosteric interaction with this site.…”

“…This hypothesis is also consistent with the observed difference between the concentration of propofol that exerts a significant effect on equilibrium binding of [3H]-BTX-B to synaptosomes (10 gM -wherein propofol has to interact with channels that are in the resting or inactive state) and that which affects the dissociation rate of [3H]-BTX-B from the receptor complex (200 gM -wherein propofol has to interact with activated channels, i.e., channels already bound to [3H]-BTX-B). Inhibition of Na+ channels has been implicated in the inhibitory effects of propofol on neurotransmitter release from neuroendocrine cells (Minami et al, 1996) and synaptosomes (Ratnakumari & Hemmings, 1996). The voltage-dependent Na' channel is a sensitive and functionally relevant site of propofol action that may contribute to its anaesthetic, anticonvulsant, neuroprotective and haemodynamic effects.…”

Pentazocine Inhibits Norepinephrine Transporter Function by Reducing its Surface Expression in Bovine Adrenal Medullary Cells

“…Indeed, in the present study, PTZ inhibited not only NET function but also SERT function, suggesting a preferential inhibition by PTZ of monoamine transporter functions. Furthermore, several anesthetics such as ketamine and propofol also inhibited the NET function (36,37). Taken together with these results, it is intriguing to propose that PTZ induces antinociceptive effects via the down-regulation of NET and/or SERT in addition to the activation of opioid receptors.…”

Adrenomedullin Inhibits the Pressor Effects and Decrease in Renal Blood Flow Induced by Norepinephrine or Angiotensin II in Anesthetized Rats

“…A polyvinyl chloride catheter was placed in the femoral artery and arterial blood pressure was measured using a calibrated pressure transducer (Baxter Healthcare, Santa Ana, CA, USA) positioned one third the distance from the brisket to the top of the back and recorded using a polygraph (Datascope 870 monitor; Datascope Corporation, Paramus, NJ, USA) and a Maclab / 2 data acquisition system (AD Instruments Pty. Ltd., Castle Hill, NSW, Australia), as previously reported (15). Another catheter was inserted into the tail vein for administration of test compounds, and Ringer's lactate solution was infused at 4 ml /h with an infusion pump (SP-500; JMS, Hiroshima).…”