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Nitric oxide, a key signaling molecule in the murine early embryonic heart
Author(s) -
Malan Daniela,
Ji Guanju,
Schmidt Annette,
Addicks Klaus,
Hescheler Jürgen,
Levi Renzo C.,
Bloch Wilhelm,
Fleischmann Bernd K.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-1158fje
Subject(s) - muscarinic acetylcholine receptor , medicine , endocrinology , microbiology and biotechnology , signal transduction , biology , nitric oxide synthase , chemistry , nitric oxide , receptor
Nitric oxide (NO) is thought to play an important role as a signaling molecule in embryonic and adult cardiomyocytes; however, its involvement in muscarinic signaling is still unclear. The aim of the present work was to analyze the muscarinic modulation of the L‐type Ca 2+ current (I Ca ) in early‐ and late‐stage embryonic ventricular cardiomyocytes. Muscarinic stimulation depressed basal I Ca by 30.1 ± 3.2% ( n= 27) in early‐stage cardiomyocytes. Pharmacological evidence suggested that the muscarinic modulation was mediated through generation of NO, activation of cGMP‐dependent phosphodiesterase (PDE) 2, and ensuing lowering of cyclic AMP/protein kinase A (cAMP/PKA) levels. Conversely, in late‐stage cardiomyocytes, muscarinic regulation of I Ca occurred in a NO‐independent manner via inhibition of prestimulated adenylyl cyclase (AC). To unequivocally prove the involvement of NO and to identify the nitric oxide synthase (NOS) isoform(s), we analyzed muscarinic signaling in embryonic ventricular cardiomyocytes of NOS2 (–/–) and NOS3 (–/–) mice. The early‐stage NOS3 (–/–) cardiomyocytes lacked muscarinic modulation, whereas it was preserved in NOS2 (–/–) cells. Moreover, at the late embryonic stage, muscarinic modulation of I Ca was intact in both strains. Thus, NO is the key regulator of muscarinic signaling in the early embryonic ventricle, whereas at later stages, signaling occurs through a NO‐independent pathway.