| Constitutive
Inhibitory Action of Muscarinic Receptors on
Adenylyl Cyclase in Cardiac Membranes and Its
Stereospecific Suppression by Hyoscyamine
J.
ŘÍČNÝ, F. GUALTIERI1, S. TUČEK
Institute of Physiology, Academy of Sciences of
the Czech Republic, Prague, Czech Republic and 1Department
of Pharmaceutical Sciences, University of
Florence, Florence, Italy
Received September 20, 2000
Accepted October 19, 2001
Summary
Muscarinic acetylcholine receptors in
the heart have been shown to display
agonist-independent spontaneous (constitutive)
activity which causes changes in the opening of
cardiac ion channels and in the activity of G
proteins. We investigated whether an inhibition
of the constitutive activity of muscarinic
receptors induced by the binding of antagonist
brings about a change in the synthesis of cyclic
AMP in rat cardiac membranes, and whether the
action of the antagonist is stereospecific.
Atropine and S-(-)-hyoscyamine were indeed found
to enhance the forskolin-stimulated synthesis of
cyclic AMP in rat cardiac (both atrial and
ventricular) membranes by up to 24%. The effect
was stereospecific and the potency of
R-(+)-hyoscyamine was 30 fold lower than that of
the S-(-) enantiomer, confirming that the action
of hyoscyamine is receptor-mediated. The effect
did not depend on the presence of endogenous
acetylcholine in the system used. The results
strongly suggest that the adenylyl cyclase in the
heart is exposed to continuous mild inhibition by
constitutively active muscarinic receptors in the
membranes of cardiomyocytes.
.
Key
words
Muscarinic
receptors · Adenylyl cyclase · Constitutive
activity of receptors · Hyoscyamine · Atropine
· Heart · Inverse agonist action
Reprint
requests
Dr. Jan Říčný, Institute of Physiology AV
ČR, Vídeňská 1083, 14220 Prague, Czech
Republic; e-mail ricny@biomed.cas.cz
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