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Laboratoire de Cardiologie Cellulaire et
Moléculaire, Institut National de la Santé et de la
Recherche Médicale U-446,Université de Paris-Sud,
Faculté de Pharmacie, F-92296 Châtenay-Malabry, France
We studied the mechanism of action of methylene blue (Mblue), a
putative guanylyl cyclase inhibitor, on the L-type calcium current
(ICa) and the muscarinic activated K+ current
(IK,ACh) in rat ventricular and atrial myocytes,
respectively, and on the binding of [3H]quinuclidinyl
benzylate in rat ventricular membranes. Superfusion, but not internal
dialysis, with 30 µM Mblue antagonized the inhibitory effect of acetylcholine (ACh, 1 µM) on 
-adrenergic
stimulation of ICa with isoprenaline (Iso, 10 nM or 1 µM). However, Mblue had no effect on
the basal ICa or on the stimulation of ICa by Iso in the absence of ACh. The activation of IK,ACh by 3 µM ACh was also antagonized by Mblue in a dose-dependent
manner. In contrast, Mblue had no effect on the activation of
IK,ACh by either
guanosine-5
-O-(3-thio)triphosphate or
guanosine-5-(,
-imido)triphosphate. Chlorpromazine (CPZ), a
piperazine derivative like Mblue, also inhibited the muscarinic activation of IK,ACh in a dose-dependent manner. The
specific binding of [3H]QNB, a muscarinic ligand, to rat
ventricular membranes was displaced in a dose-dependent manner by Mblue
and CPZ. The piperazine derivatives behaved like competitive
antagonists of [3H]QNB binding, exhibiting equilibrium
dissociation constant (Ki) values of
187 nM for Mblue and 366 nM for CPZ.
In conclusion, Mblue exerts antimuscarinic effects on ICa
and IK,ACh in rat cardiac myocytes that are best explained
by the binding of Mblue to the M2 subtype of muscarinic receptors. This
property probably contributes to the antimuscarinic effect of the
putative guanylyl cyclase inhibitor reported in previous studies.
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