Receptor mediated presynaptic modulation of the release of noradrenaline in human papillary muscle.

OBJECTIVE: The aim was to determine the presynaptic modulation of noradrenaline (NA) release from the sympathetic nerve terminals in human isolated papillary muscle. METHODS: Papillary muscle and the right atrial appendage were obtained from operations on 22 patients (10 men and 12 women). The papillary muscle preparations were preincubated with [3H]NA and the release of [3H] at rest and in response to field stimulation was measured. RESULTS: Using an immunohistochemical method dopamine-beta-hydroxylase-positive neurones were found in the papillary muscle and right atrial appendage sample. The release of noradrenaline from the papillary muscle, associated with axonal activity, was enhanced by 7,8(methylenedioxy)-14-alpha-hydroxyalloberbane HCl (CH-38083), a selective alpha 2 adrenoceptor antagonist, and inhibited by xylazine, an alpha 2 adrenoceptor agonist, indicating that negative feedback modulation was functioning. In addition, the release of [3H]NA was enhanced by atropine, pancuronium, and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), a selective M3 muscarinic receptor antagonist, and reduced by oxotremorine, a selective muscarinic receptor agonist, indicating that acetylcholine released from the parasympathetic nerve ending was able to reach the varicose noradrenergic axon terminals that are equipped with inhibitory M3 muscarinic receptors. CONCLUSIONS: These findings, obtained for the first time in human papillary muscle, indicate that the release of noradrenaline is modulated by alpha 2 autoreceptors activated by noradrenaline and M3 muscarinic heteroreceptors. Thus during parasympathetic stimulation the release of noradrenaline from the sympathetic axon terminals is presynaptically controlled through muscarinic receptors.

Effect of atracurium and laudanosine on the release of 3H-noradrenaline.

We examined the effects of atracurium and its breakdown product, laudanosine, on resting and stimulation-evoked release of 3H-noradrenaline (3H-NA) from sympathetic axon terminals of isolated right atria of guinea pigs. Both atracurium 1-100 mumol litre-1 and laudanosine 1-50 mumol litre-1 enhanced the release of 3H-NA evoked by field stimulation (2 Hz, 24 stimuli), but did not affect resting release. When the production of laudanosine from atracurium was inhibited by maintaining the atracurium solution at 4 degrees C, atracurium did not enhance the release of 3H-NA as occurred when it was kept at 37 degrees C. However, atracurium antagonized the inhibitory effect of oxotremorine on release of 3H-NA, whereas laudanosine did not. These data suggest that atracurium possesses an antimuscarinic effect. Its metabolite, laudanosine, in concentrations which would be expected following prolonged administration of atracurium, produced a marked increase in release of 3H-NA. This effect of laudanosine may explain some of the unwanted effects seen following administration of atracurium.

Effects of non-depolarizing neuromuscular blocking agents on norepinephrine release from human atrial tissue obtained during cardiac surgery.

We have studied the effect of non-depolarizing neuromuscular blocking agents, at concentrations present in serum during anaesthesia, on release of [3H]-norepinephrine ([3H]NE) from superfused atrial appendage obtained during cardiac surgery from 48 patients. Three of the neuromuscular blocking agents (pancuronium, gallamine and rocuronium), which are known to cause an increase in heart rate during anaesthesia, increased stimulation-evoked release of [3H]NE. In contrast, (+)tubocurarine and pipecuronium, neuromuscular blocking agents that do not cause tachycardia, did not affect release of NE. Org 9487 significantly enhanced release while SZ1677 was ineffective, even at concentrations higher than those expected after administration of a 2 x ED95 dose. Atropine enhanced release. These data suggest that the axon terminals of sympathetic nerves in human heart have muscarinic heteroreceptors whose activation by acetylcholine (ACh) released from the vagal nerve reduces release of NE. This action contributes to lowering of heart rate. Therefore, any neuromuscular blocking agent with antimuscarinic actions and capable of increasing the release of NE may produce tachycardia.

In vitro comparison of the neuromuscular antinicotinic and intestinal antimuscarinic effects of different nondepolarizing muscle relaxants.

The postsynaptic antimuscarinic properties of different nondepolarizing muscle relaxants were compared with their postsynaptic antinicotinic effect. d-Tubocurarine, pipecuronium and vecuronium were the most selective antagonists on postsynaptic nicotinic receptors. Gallamine, diadonium and Duador (RGH-4201) had relatively greater effect on postsynaptic muscarinic receptors. Therefore, much less side effect is expected to occur when pipecuronium, d-tubocurarine or vecuronium are used.

Direct evidence that pancuronium and gallamine enhance the release of norepinephrine from the atrial sympathetic nerve by inhibiting prejunctional muscarinic receptors.

The effect of different non-depolarizing muscle relaxants (gallamine, pancuronium, vecuronium, D-tubocurarine) on [3H]norepinephrine release in response to electrical stimulation was studied in isolated guinea-pig atrium. High pressure liquid chromatography combined with electrochemical and radiochemical detection revealed that the released radioactivity was mainly in the form of [3H]norepinephrine release. Oxotremorine, a pure muscarinic agonist, reduced the release of tritium. Gallamine and pancuronium, like atropine, prevented the inhibitory effect of oxotremorine. D-Tubocurarine and vecuronium had no such effect. These findings indicate that gallamine and pancuronium exert a presynaptic antimuscarinic, atropine-like effect, by inhibiting muscarinic receptors located on the axon terminals of sympathetic neurons thereby enhancing norepinephrine release. It is suggested that this phenomenon might play some role in tachycardia observed during surgical anaesthesia when gallamine or pancuronium have been administered.

Tubocurarine and pancuronium inhibit evoked release of acetylcholine from the mouse hemidiaphragm preparation.

Using a sensitive radioactive method that measures selectively the evoked release of acetylcholine, it was demonstrated that, when stimulating at 50 Hz, tubocurarine or pancuronium 2 X 10(-5) mol litre-1 or hexamethonium 10(-3) mol litre-1 significantly decreased the evoked release of acetylcholine in the mouse in vitro phrenic nerve-hemidiaphragm preparation.