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

The aim was to determine the presynaptic modulation of noradrenaline (NA) release from the sympathetic nerve terminals in human isolated papillary muscle.

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.

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.

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.