RT Journal Article
SR Electronic
T1 Methylene Blue Is a Muscarinic Antagonist in Cardiac Myocytes
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 482
OP 490
DO 10.1124/mol.52.3.482
VO 52
IS 3
A1 Najah Abi-Gerges
A1 Thomas Eschenhagen
A1 Leif Hove-Madsen
A1 Rodolphe Fischmeister
A1 Pierre-François Mery
YR 1997
UL http://molpharm.aspetjournals.org/content/52/3/482.abstract
AB 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 β-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′-(β,γ-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 ICaand 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.