RECEPTOR-MEDIATED PRESYNAPTIC MODULATION OF THE RELEASE OF NORADRENALINE IN HUMAN PAPILLARY-MUSCLE

Objective: The aim was to determine the presynaptic modulation of nora drenaline (NA) release from the sympathetic nerve terminals in human i solated papillary muscle. Methods: Papillary muscle and the right atri al appendage were obtained from operations on 22 patients (10 men and 12 women). The papillary muscle preparations were preincubated with [H -3]NA and the release of [3H] at rest and in response to field stimula tion was measured. Results: Using an immunohistochemical method dopami ne-beta-hydroxylase-positive neurones were found in the papillary musc le and right atrial appendage sample. The release of noradrenaline fro m the papillary muscle, associated with axonal activity, was enhanced by 7,8(methylenedioxy)-14-alpha-hydroxyalloberbane HCl (CH-38083), a s elective alpha(2) adrenoceptor antagonist, and inhibited by xylazine, an alpha(2) adrenoceptor agonist, indicating that negative feedback mo dulation was functioning. In addition, the release of [H-3]NA was enha nced by atropine, pancuronium, and 4-diphenylacetoxy-N-methylpiperidin e methiodide (4-DAMP), a selective M(3) muscarinic receptor antagonist , and reduced by oxotremorine, a selective muscarinic receptor agonist , indicating that acetylcholine released from the parasympathetic nerv e ending was able to reach the varicose noradrenergic axon terminals t hat are equipped with inhibitory M(3) muscarinic receptors. Conclusion s: These findings, obtained for the first time in human papillary musc le, indicate that the release of noradrenaline is modulated by alpha(2 ) autoreceptors activated by noradrenaline and M(3) muscarinic heteror eceptors. Thus during parasympathetic stimulation the release of norad renaline from the sympathetic axon terminals is presynaptically contro lled through muscarinic receptors.