© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Mechanism for muscarinic inhibition of ICa(L) is determined by the path for elevating cyclic AMP in cardiac myocytes
Department of Pharmacology, MC-6125, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA
* Corresponding author. Tel.: +1-860-679-2410; fax: +1-860-679-3693 pappano{at}nso1.uchc.edu
Objective: Does carbachol (CCh) require NO/cGMP for inhibition of L-type calcium current (ICa(L)) when either adenylyl cyclase activation or phosphodiesterase suppression is used to raise cAMP? Methods: The effects of the NO donor SIN-1 (3-morpholino-sydnonimine), CCh and atrial natriuretic peptide (ANP) were evaluated when ICa(L) had been stimulated by isoproterenol (ISO) or 3-isobutyl-1-methylxanthine (IBMX) in guinea pig isolated ventricular myocytes (35°C). Results: Carbachol, SIN-1 or ANP did not affect basal ICa(L); each inhibited IBMX-stimulated ICa(L). Dialyzed (30–100 µM) ODQ (1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one), a soluble guanylyl cyclase (sGC) inactivator, blocked inhibition of IBMX-stimulated ICa(L) by SIN-1 (10 µM) but not by CCh (1–100 µM) or ANP (100 nM). Dialysis with 3 µM LY83583 (6-anilino-5,8-quinolinedione), a particulate (pGC) and sGC inactivator, opposed muscarinic-, ANP- and SIN-1-induced inhibition of IBMX-stimulated ICa(L). Thus CCh can increase cGMP synthesis via pGC. Even with 100 µM [LY83583]pip, CCh inhibited ISO-stimulated ICa(L), an effect referable to suppression of adenylyl cyclase activity. However, 3 µM [LY83583]pip prevented inhibition of ISO-stimulated ICa(L) by ANP. [LY83583]pip did not affect inhibition by 8 bromo-cGMP (100 µM) of ISO- or IBMX-stimulated ICa(L). The observations indicate that: (1) myocytes have ODQ-sensitive sGC activated by NO and LY8353-sensitive pGC activated by ANP, (2) CCh does not inhibit ICa(L) via NO, (3) the mechanism for muscarinic inhibition depends upon the cAMP-elevating agent and (4) LY83583 distinguishes between two pathways for muscarinic inhibition. Conclusion: The nature of the stimulant pathway that increases cAMP determines intracellular transduction of muscarinic inhibition. This hypothesis accords with distinct cyclic nucleotide compartments for the differential expression of muscarinic inhibition of ICa(L).
KEYWORDS Ca-channel; Muscarinic (ant)agonist; Second messengers; Nitric oxide; Signal transduction
1 Present address: Department of Internal Medicine (Cardiology), Teikyo University Ichihara Hospital, Ichihara City, Chiba 299-0111, Japan.
2 Present address: Department of Cardiology, The First Affiliated Hospital, Suzhou Medical College, Suzhou, Jiangsu 215006, PR China.
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