Acetylcholine release in human heart atrium: influence of muscarinic autoreceptors, diabetes, and age.
BACKGROUND
An imbalance of sympathetic and parasympathetic drive to the heart is an important risk factor for cardiac death in patients with coronary heart disease, diabetes, and renal insufficiency. The amount of neurotransmitter released from peripheral autonomic nerves is modulated by presynaptic receptor systems. In analogy to alpha-autoreceptors on sympathetic nerves, muscarinic autoreceptors activated by endogenous acetylcholine may exist on parasympathetic nerves in the human heart.


RESULTS
We developed a technique to study acetylcholine release from human atria and investigated muscarinic autoreceptor function. A pharmacological and molecular approach was used to characterize the subtype involved. Of the 5 muscarinic receptor subtypes cloned, only mRNA encoding for M(2)- and M(3)-receptors were detected. Potencies of several muscarinic antagonists against the release-inhibiting effect of the nonselective muscarinic agonist carbachol at the cardiac autoreceptor were correlated with published data for human cloned M(1)- through M(5)-receptors.


CONCLUSIONS
This analysis clearly indicates that acetylcholine release in human atria is controlled by muscarinic M(2)-receptors. Blockade of these receptors by atropine doubles the amount of acetylcholine released at a stimulation frequency of 5 Hz. In atria of patients >70 years of age and patients with late diabetic complications, acetylcholine release is reduced. Locally impaired cardiac acetylcholine release may therefore represent a pathophysiological link to sudden cardiac death in elderly and diabetic patients.
Medizinische Universitätsklinik, Innere Medizin IV, Freiburg, Germany.
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V
Oberhauser
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Schwertfeger
T
T
Rutz
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F
Beyersdorf
L C
LC
Rump
D000109:Acetylcholine / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D001285:Atropine / Q000008:administration & dosage; D017660:Autoreceptors / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D006325:Heart Atria / Q000294:innervation / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000008:administration & dosage; D018727:Muscarinic Antagonists / Q000008:administration & dosage; D010275:Parasympathetic Nervous System / Q000378:metabolism; D010477:Perfusion; D012333:RNA, Messenger / Q000378:metabolism; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017660:Autoreceptors; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D012333:RNA, Messenger; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D001285:Atropine; D000109:Acetylcholine